OrabyBiochemistry P.2 PDF
OrabyBiochemistry P.2 PDF
OrabyBiochemistry P.2 PDF
By
(I I)
Twelfth Edition
I
D£DICATION.
T() IllY wife
Note:
Dear student I colleague:
If you have any comment about this edition or further editions , please
mail your suggestions to: m s [email protected].
Oraby's illustrated reviews of Biochemistry
Copyright© 2013
CBioenergetics
1. DEFINITIONS:
A. Energy is the capacity to do work. It may be mechanical, chemical or
electrical energy.
B. Bioenergetics or thermodynamics is the study of the energy changes
accompanying biochemical reactions.
- 1-
Oraby's illustrated review of biochemistry 2
means that the free energy content of (B) is more than that of
product (A).
a) There is net gain of energy.
b) The reaction does not go spontaneously from B to A except
after addition of energy (ATP) from another source. This
source is the catabolism of carbohydrate, lipids (fatty acids)
and amino acids.
c) The reaction is said to be endergonlc
B A
Energy (ATP)
t
Carbohydrate
Lipids
Amino acids
d) Examples:
!Creatine+ ATP ~ Creatine-P + ADP + +AG 1.5 Kcallmoll
Bioenergetics and biologic oxidation 3
Catabolism
ADP
ATP
(Endergonic reactions)
Anabolism
Biologic body work
A1P Is the link between energy-producing and energy-consuming
biologic processes (ATP-ADP cycle). orahy
B. Structure:
I. It is a member of a class of compounds called nucleotide
triphosphates (ATP, GTP, UTP, CTP and TTP).
Oraby's illustrated review of biochemistry 4
N~
t~)
}
Adenine
o- o- o- N N
1 I I
-o-P-O-P-O-P-O-CH2
A A 8 1/o,
~~-- ~~
H 1""""r H
} RiOO~
Triphosphate moiety HO OH
Structure of ATP.
C. Importance of ATP:
1. The most important parts of the ATP molecule are its 2-
phosphoanhydrlde bonds (bonds between phosphate molecules
number 1 &2 and 2&3). Breakdown of either of these bonds is
accompanied by a large decrease in free energy i.e. release
energy.
~------------------------------------------~
t
7.3 Kcal/ mol
(]Jiofooic o~iaation
1. Introduction:
A. Energy is required to maintain the structure and function of the living
Cells. This energy is derived from oxidation of carbohydrates, lipids
and proteins of diet.
B. The energy liberated is partly converted into useful form ATP, which is
known as energy currency of the living cells.
C. Each gram of carbohydrate and protein gives about 4 Kcal on
oxidation, while each gram of fat gives about 9 Kcal.
2 H2 + 02 -+ 2 H 20 + energy
2. In this redox reaction, H2 is oxidized while 0 2 is reduced, and if
occurs it will be accompanied by a massive energy explosion.
3. This simple example is similar to the fundamental reactions
which provide energy in the living cells, and instead of massive
energy is liberated, hydrogen must be transferred to oxygen in
gradual steps. Thus, small fractions of energy are liberated and
stored for further use.
4. Note that hydrogen atom is formed of one electron (e) and one
proton (H.). The removal of hydrogen atom or electron from a
compound is always accompanied by a release of energy.
C. Redox potential ( =electron affinity):
I. Oxygen has the highest electron affinity i.e. highest redox
potential.
2. Hydrogen has the lowest electron affinity i.e. lowest· redox
potential.
3. Redox chain:
a) It Is a chain of different compounds of
Increasing redox potentials between
hydrogen and oxygen
(a)
b) The living cells depend on redox
reactions for their energy requirements.
The reactions start by removal of H2 from
the substrate, which Is then transferred
to different components of redox chain,
and finally to oxygen to form water. Model of energy loss by big
Components of redox chains have a rock rolling down hill using two
different pathways:
redox potential higher than hydrogen and a. Direct with massive energy
production.
lower than oxygen. b. Indirect In steps with release
of small amounts of energy.
c) During hydrogen (H+ and electron)
transfer through different components of the redox chain, energy
is liberated in steps and in small utilizable amounts instead of a
massive energy production, in the form of heat, which if happens
A:,:=>c : 2~ c :H2 ~
may destroy the living cells.
etc
Glucose
Fructose
Galactose Fatty acids
1 2
Glycolysis I~ l P..Oxldatlon I
ATP NADH
NADH FADH 3
Pyruvate
NADH ..1\
AcetyiCoA
GTP
5 NADH
FAOH,
Oxldltave
~0
phosphorylation
2
ATP
An overview of fuel catabolism
Substrat e
(reduced)
X
N~D+ .x FMNH2
'x_
Substrate
NADH+H FMN 1 1
(Oxidized) CoO Fe Fe '
c;.J,I!.JMt
Fumarate X FADH2
CoOH X Cytob
FeJ
•
Cytoc
Fe
2.
Succi~
El ectron transpon chain. [Note: Coplex V not shown).
3. Coenzyme Q:
a) It is quinine derivative with a long Isoprenoid tall. It is a
relatively mobile electron carrier.
b) Coenzyme Q can accept hydrogen atoms both from FMNH 2 ,
produced by NADH dehydrogenase (complex I) and from FADH 2 ,
which is produced by succinate dehydrogenase and other similar
enzymes (complex II).
4. Cytochromes:.
a) There are 5 types of cytochromes; cyto b, cyto c 1 , cyto c, cyto a
and cyto a3.
b) All cytochromes are conjugated proteins formed of protein
conjugated with heme ring. The heme ring contains iron (Fe).
This iron oscillates between ferric ions (Fe 3•) when it loses an
electron, and ferrous (Fe 2 •) when it accepts electrons.
c) Cytochrome b is associated with sulfur (S) In addition to iron
(Fe).
Bioenergetics and biologic oxidation 11
accept electrons.
c) Therefore, electrons flow from the pair with the more negative E.,
to that with the more positive Eo.
5. At three sites (see the figure), the free energy released per
electron pair transferred is sufficient to support the phosphorylation
of ADP to ATP, which required about 7 Kcal/mol.
Substrate Substrate
~ ~
NAD ~ Flavoprotein 7 a ~ Cyt b ~ c1 ~ c ~a --;--+ a3 ~ 112 02
:. ·. . .... ···.. . .... ···.
ADP Pi ADP Pi ADP Pi
......· ......· ......·
ATP ATP
6. Electrons that enter the respiratory chain through the NAD-a
reductase complex support the synthesis of 3 mol of ATP. By
contrast, electrons join the chain directly at the level of
coenzyme a (as in case of FADH 2 of succinate
Bioenergetics and biologic oxidation 13
d) Oxidative phosphorylation:
A. Introduction:
1. Electrons are transferred down the respiratory chain from NADH•
to oxygen. This Is because NADH+ is a strong electron donor, while
oxygen Is a strong electron acceptor.
2. The flow of electrons from NADH• to oxygen (oxidation) results in
ATP synthesis by phosphorylation of ADP by inorganic phosphate,
Pi (phosphorylation). Therefore, there is a coupling between
oxidation and phosphorylation. Two theories explain the ATP
synthesis, chemlosmotlc hypothesis and membrane transport
system.
B. Chemiosmotic hypothesis:
Also called Mitchell hypothesis. This hypothesis is one form of
oxidative phosphorylation. It can be summarized as follows:
1. Proton pump:
a. The transport of electrons down the respiratory chain -+ Gives
energy.
b. This energy is used to transport H+ from the mitochondrial
matrix -+ from Inside to outside the membrane.
c. This Is done by complexes I, Ill and IV.
d. This process creates across the inner mitochondrial membrane:
I. An electrical gradient: (with more positive charges on
the outside of the membrane than on the Inside).
Oraby 's illustra t ed revi ew of biochemistry 14
Mi!(:ll'tltMMJt&.ll
'"r\j, (t."'UJJM~u'
m("ml'\tilllft
+tw)
Pnnoples ol 1hc ChO<nlosmollc lhOOIY ol oxld&IIVO phosphoryiaiiOn Tho m.tln f>!Oion ctrcu~ IS crc.11od by
the couplong ol o~ltktllon trllhe rrsprrntory cllatn 10 pro1on transkx:.1t>~n I rom lho '""'do 10 lhe 001Slde of the membrane.
dnvPn by lhe rcsptrolory cho•n compk!xes I. Ill. and tV, each of whtelo Rei~ .1a n proton pump 0, ubtqumono; C. t;y·
tochromc c F. Fo- pr0111011 subunrls whteh u~llze energy from lhc proton lllildiCOI to promolo phosphorylalion Uncou·
piing agents such 1\8 d•Mrophcnol allow leakage ol H· across lho mr'ITibrann ll>us collapslfi<J 1he electrochemical protun
gradlcnl Olroornyon 'p4'(;ti1Clllly blucks conduclion ol H' lhrough Fu
----
lntermembrane
space
Electron transport chain shown coupled to transport of protons. 1Noto: Ccmplox nnot shown J
4. Uncouplers:
These are substances that allow oxidation· to proceed but prevent
phosphorylation. So energy released by electron transport will be
lost in the form of heat. This explains the cause of hotness after
intake of these substances. Examples:
a) Oligomycin: This drug binds to the stalk of the ATP synthase ,
closes the H• channel, and prevent re-entry of protons to the
mitochondrial matrix.
b) 2,4 Dinitrophenol: It increases the permeability of the inner
mitochondrial membrane to proton causing decrease proton
gradient.
c) Calcium and high doses of aspirin: this explains the fever that
accompanies toxic overdoses of these drugs.
d) lonophorea: e.g. antibiotics •valinomycin• and Nigerlcln. They
are lipophilic substances. They have the ability to make a
complex with cations as potassium ·K•• and facilitate their
transport Into mitochondria and other biological membranes.
They Inhibit phosphorylation because they decrease both
electrical and pH gradient.
c. Membrane transport systems:
The Inner mitochondrial membrane Is Impermeable to most charged or
hydrophilic substances. However It contains numerous transport
proteins (carrier) that permit passage of specific molecules from the
Oraby's illustrated review of biochemistry 16
Therefore, C~OP~
Glycerol
oxaloacetate 3·phoaphate
produced inside the
mitochondrial
Elecflolt.ftnapon ciYin ~2 ATP
cannot
DHAP Glycerol
called: 3-phosphate
transamination (see
protein metabolism). INNER MZTCJt:HONIJ(lrAL MEMBRANE
\·--
\( \
\ \
ln!ermcmbrane
Inner OUter
Membrane I 114ft
Mombrane
{})igestion
I. Introduction: More than 6o96 of our foods are carbohydrates.
A. Starch, glycogen, sucrose, lactose and
cellulose are the chief carbohydrates in
our food.
B. Before intestinal absorption, they are
hydrolyzed to monosaccharides (glucose,
galactose and fructose).
C. A family of glycosidases that hydrolyzes
carbohydrate into their monosaccharide Hydrolysis of a glycosidic bond.
components catalyzes hydrolysis of glycosidic bonds.
19-
Oraby's Illustra ted reviews of biochomistry 20
rv .Digestion of carlJohydrale
to
!:y panc1·eat·ic a- amylase UVER
VI.Digestion of cellulose:
A. Cellulose contains 1}(1-4) bonds between glucose molecules.
B. In humans, there is no p (1-4) glucosidase that can digest such
bonds. So cellulose passes as such in stool.
C. Cellulose helps water retention during the passage of food along the
intestine -+ producing larger and softer feces -+ preventing
constipation.
}1.6sorption
1. Introduction:
A. The end products of carbohydrate digestion are monosaccharides:
glucose, galactose and fructose. They are absorbed from the jejunum
to portal veins to the liver, where fructose and galactose arc
transformed into glucose.
B. Two mechanisms are responsible for absorption of
monosaccharides: active transport (against concentration
gradient i.e. from low to high concentration) and passive
transport (by facilitated diffusion).
C. For active transport to take place, the structure of sugar should
have:
I. Hexose ring.
2. OH group at position 2 at the right side. Both of which c
are present in glucose and galactose. Fructose, which {~
does not contain -OH group to the right at position 2 is
c 0
1 J
absorbed more slowly than glucose and galactose by
I
tt,l
passive diffusion (slow process). c
L...-----J
Inhibited by
ouabln 1+---~
(cardlao
glycoside)
To capillaries ~
Transport the glucose across the Intestinal oplthellum. Activo glucose transport
Is coupled to the Nl • K• pump.
1~
It occurs ea rly in c hildh ood .
C. Monosaccharides malabsorption:
This is a congenital co ndition in which
g lu cose and galac t ose are absorb ed only
s lowly due to defect tn the GLUT-1.
,. . .,...._COJvL f H20
..._ V'
q£VCOSt£ OXJ(])}lrz10!N
9dajorlPatliway
-
c -i
c
I1 s
0
li!
~
IJC
0
t
!
t 40BnL OoA
1J!
l
V-4--...-t-+Ooatraotlq
.1"'11. IIIUIOlel
t.
0
1(!)
P., OH
u~-c;·o- P ·-ou
C=O
I
liO·CI ·H
H .;C•Oil
I
H -1'!-0H 0 OH
T -o- \'-
CH ""' OH
2
Fructose 1,6 blsphosphate
(ALdolase)
H2·rt-OB
.~=0 ~ .... OH
u2 -t. ·D- :.p -.oa
Dlhydroxyacetone phosphate
Phosphtriosc
isomerase
.1
H·
.
0 aO
·I' H· 9 =0
H ·C-Olt
I
0 OH
ii ... ~ -c-ou
I
o
U.t'
ou
~2-0··P -O.H CH2•0·P ·OH
Glyceraldehyde -3- phosphate Glyceraldehyde -3- phosphat~
Carbohydrate metabolism 27
*u -c .. o COOH
I I
~ H -C -OH HO-C - H
I p, .... OH I
CH 2-o- P ·OH CH 3
Glyceraldehyde -3- phosphate Lactate
J
Lactate I
dchydrogcnosc]
r
~ p, .... 011
COO,., P -OH COOH
I I
(~: H -C ·OH
I ~ .... OH ~ c ..
I
0
CH 2 -o- P -OH CH 3
1, 3 Blsphosphoglycerate Pyruvate
Spontanous
COOH
I
COOH C - OH
I n
H -C -OH CH 2
I P,.,... OH
CH 2 -0- P -OH Enol pyruvate
3 Phosphoglycerate
I
COOH I
,'
I COOH
*H -c-o- 0......
P -on
OH { [Enolase)
(.;\ I P,.,... OH
~ \ ,..,g• (.;\ ~ • ~ C ·ON P ·OH
I
CH • *OH •
2 '" ~HOH CH 2
I
Cytosol 2 Phosphoglycerate f Phosphenolpyruvate
;
u \) v
MltochondriG
!
Respiratory ehGin J
4 ATP or 6 ATP
Oraby's illustrated reviews of biochemistry 28
Stages of glycolysis:
1. Stage one (the energy requiring stage):
a) One molecule of glucose is converted into two molecules of
glyceraldehyde-3-phosphate.
b) These steps requires 2 molecules of ATP (energy loss)
2. Stage two ( the energy producing stage):
a) The 2 molecules of glyceraldehyde-3-phosphate are
converted into 2 pyruvate molecules (aerobic glycolysis) or
2 lactate molecules (anaerobic glycolysis).
b) These steps produce ATP molecules (energy production).
1=[::1
F-6-p
F 1.6 biajlll.
@~P
!
~ 2HAD+-E'-,
~~2 NADHjtli+!:
® 1.3 lllsjlh. ~ l
[..-- 2AOP :
~!2ATP~~
@3~
~
®2·~
~
Q) Phosphoonol fii'IINUle
I,
aADP
~!2ATP!
®Pyruvate
v v
!
4 or 6 ATP
Energy production of
glycolysis
Carbohydrate metabolism 29
In 4ATP 2ATP
presence (Substrate level
of oxygen phosphorylation) • From glucose to 6ATP
(aerobic • 2ATP from 1,3 glucose-6-p.
glycolysis) BPG. or
• 2ATP from • From fructosc-6-
phosphocnol p to fructose t ,6
pyruvate bisphosphatc. 8ATP
+
4 ATP or 6 ATP
•(From oxidation
of 2 NADH + H
in mitochondria).
Glyceraldehyde- 3 p
J. Dlhydroxy acetone + epogennls
J phosphate
1,3 B!aphosphoglycerete
'
'
3 Phosphoglycerate
~~
'/'
2,3BPO
1
Pyruvate
I
Pyruvate
I
Actyl CoA
".. '
-1
I Krebs'\
IFunctions of glycolysis J
\cycle}
'·-"" ~
G. Regulation of glycolysis:
The rate of glycolysis is regulated by controlling of the three
irreversible enzymes (key enzymes). These enzymes catalyze what is
called committed reactions of the pathway. These enzymes nrc;
glucokinase (hexokinase), phosphofructokinase-! nnd pyruvate
kinase.
1. Hormonal rcKulntion;
a) Insulin: Stimulates synthesis of all key enzymes of
glycolysis. It is secreted after meal (in response to high blood
glucose level).
b) Glucagon: Inltibits the activity of all key enzymes of
glycolysis. It is secreted in response to low blood glucose
level.
1. Energy regulation:
a) High level of AT11 inhibits PFK-1 and pyruvate kinase.
b) High level of ADP nnd AMP stimulate PFK-1.
carbohydrate metabolism 31
3. Substrate regulation:
a) Glucose-6-phosphate inhibits hexokinase (and not
glucokinase).
b) Fructose 2,6 bisphosphate stimulates phosphofructokinnse-1.
c) Citrate inhibits phosphofr~ctokinase-1.
d) Fructose 1,6 bisphospbate stimulates pyruvate kinase.
4. Fructose z,6 bispbosphate:
a) This substrate is produced from fructose-6-pbosphate by
reaction catalyzed by: phosphofructokinase-2 (PFK-2)
enzyme.
b) Fructose 2,6 bisphosphate stimulates glycolysis by allosteric
stimulation of phosphofructokinase-1. It also inhibits
gluconeogenesis by inhibiting fructose 1,6 bisphosphatase
enzyme.
Glucose
n
Insulin - - - - - - . ® Glucokinase
Glucagon 9
===
Hexokinase 9 ~.-- Glucose-6-p
n
..-----. 9 ~
Insulin ___.....,_____..,_.., ® Phospho· 9
ATP
Citrate
Glucagon 9 fructoklnase-1 ®• AMP
®..,......._Fructose 2,6
· bisphosphale
n
Pyruvate
,
!' /
{JI ,'
I. /;"/
$2 I
F-6-P
XC: B:rATP
i.I~ADP()
\ ~
(+) ¢l1Fructose 2,6 blsphosphatal c::) (·)
PI ~
Fructose1,6 blsphosphata
Pyruvate Lactate ~
H-~-0 .----Glucose
H- -OH
H~-o-®
Glyceraldehyde 3-ptlosphlte
Pi~NAo•
GlYCIRALOEHVD£•3-Ptl~
I ·----~DI~H~Y~~D~~~N~~~--~
NAOH+H•
~
H-~=~~® ~BISPH~TE)
CH,-o-®
1,3·Bisphosphoglycerate ·
Al)p ~OOH
""o~~., 1 H-c;:-o-®
cti,-o-®
ATP 2,3-Sisphosphoglyceroto
~
OOH
H- -OH
H~-o-®
3·Phosphoglycerate
L--- -..Pyruvate
8 - Bu
- I ILi
H - C .. 0
I
:a~-
•
c-
I
O•n!
D - C - OU llaz-&H B-C-OB
a.-o-® C~r.-o-®
Glyceraldhydo-3-P
0 CIJ
• I "
s- Biz
~}O- p- I
c"""o-®
I c
CIJ cI 0D
H- C - OR Enz-8H J/ B • C • DB
C:u.-o-® a.-o-® ~
1,3 Blephouphoglycorata ozidlaed Bna-uube. co~ploz
o. Lactate dehydrogenase:
1. It is an enzyme which catalyzes the reaction:
Lactate ~ Pyruvate
2. This reaction helps the re-oxidation of NADH, H+ into NAD+.
3. It has 5 isoenzymes: LD" LD2, LD 3 , LD 4 and LD 5 •
4. Medical importance :
Estimation of the activity of lactate dehydrogenase enzyme in
plasma helps the diagnosis of heart and liver diseases:
a) LDa: Elevated in some heart diseases e.g. myocardial
infraction.
b) LD 5 : Elevated in some liver diseases as acute viral
hepatitis.
Oraby's illustrated reviews of biochemistry 36
Q. Fermentation:
1. Definition: This is conversion of glucose into ethanol by yeast
enzymes.
2. Pyruvate is formed by the same series of reactions of glycolysis.
Then pyruvate is converted into acetaldehyde, then ethanol as
follows:
3. Thus the end product of fermentation is CO:z and ethanol.
(Pyruvate decarboxylase!
al3- CBO I Alcoi!Gilc: J
.d•hy!lrog- CB 3 -CH 2 -0H
M&+ ii
C02 Acetaldehyde (\ • Ethanol
NADH+H+ NAD+
Liver
Glucose
t
-!-
Pyruvate
Lactate
\II 11f
Cori cycle.
2. Hexokinase deficiency:
It leads to hemolytic anemia due to decrease ATP production.
The mechanism is similar to that of PK deficiency.
3. Lactic acidosis:
a) Definition and mechanism of lactic acidosis :
I) It is the lowered blood pH and bicarbonate levels due
to increased blood lactate above normal level.
2) This depletes bicarbonate ,. ,J, pH of blood ,. Lactic
acidosis ,.may lead to coma.
OH OH
I I
CHa·CH·COOH + NaHCOa • CH 1 -CH-COONa + H 2 C0 1 • C0 2 + H 2 0
lactate Sodium bicarbonate Sodium lactate Carbonic acid
SH s
2) Lipoic acid • (reduced) ~ , (oxidized) ~I
'-sH '-s
3) Coenzyme A= CoASH.
4) Flavin adenine dinucleotide = FAD.
S) Nicotinamide adenine dinucleotide = NAD+.
c) Location: PDH is located within the mitochondrial matrix.
2. Reactions:
Thiamin CoASH
pyrophosphate
TPP Dlhydrol!poyl
transacetylaoe
~
acetaldehyde
FADH FAD
2
l 1
r l
NADH+H+
0 jPyruvate dehydrogenase! 0
II II
CH - C- COOH CH - C -SCoA
3 3
L,
... sI t
Pyruvate s Acetyl CoA
Co ASH NADH+H+
b) Pyruvate dehydrogenase
(PDH) kinase enzyme
converts active into
inactive PDH enzyme.
c) PDH Phosphatase
enzyme converts inactive
into active PDH enzyme.
I) Factors
stimulating [ +]
PDH:
>Pyruvate.
>CoASH.
> NAD+. ADP ATP'
Summary of regulation:
_, /
CoASH
3. Steps:
0
II
oa 3• 0,., SOoA
#/A Acetyl CoA
0 • 0 - 0008
I ~ IOITRATB SYRTHASBI
082·0008
oxaloacetate
IIALATB NADH+H~
DBBYDROGBRASB
NAD+
80 - OR - OOOR
I
08 2 - OOOB
Malate
-- OR,. - 0008
t -r H20 I r.
IFUMARASE I
., ,.
..... ...... ...... 0II - COOB
''\ OR - COOR
Cls-aconltate
08 - 0008 / Krebs' \
'
BOOO - OR I
\\ cycle
'
' ,.....-..t !ACONITASE l
OR2 - OOOB
l
NAD+
~
~ DBH!DROGBRASB
ISOOITRATB
OR2 - OOOR NADH+H
CoASH 9R - OOOR
0 • 0 - OOOR
SVOOIRATB Oxalosucclnate
TBIOKIRASB
.J
ISOOITRATB
C02 +-"""'~ DBRYDROOBHASE
3. Steps:
a) The enzymes of TCA cycle are present in the mitochondrial
matrix either free or attached to the inner surface of the
mitochondrial membrane.
b) The cycle is started by acetyl CoA (2 carbons) and oxaloacetate
(4 carbons) to form citrate (6 carbons). It ends by oxaloacetate
(4 carbons).
The difference between the starting compound (citrate, 6 carbons)
and the ending compound (oxaloacetate, 4 carbons) is 2 carbons
that are removed in the form of 2 C0 2 • These 2 carbons are
derived from acetyl Co A. For this reason acetyl Co A is completely
catabolized in TCA and never gin glucose.
produced by ....,._
\
catabolism of acetyl
CoA):
a) Oxidation of one
molecule of acetyl
CoA in TCA
produces 12 ATP
molecules, 11 by
respiratory chain
phosphorylation
and 1 by substrate
level
phosphorylation as
follows:
Enzyme Method of ATP production No. of ATP
Isocltrate dehydrogenase Oxidation of NADH+H+
by respiratory chain 3ATP
phosphorvlation
u-Ketoglutarate Oxidation of NADH+H+
dehydrogenase by respiratory chain 3ATP
phosphorylation
Succlnyl CoA thloklnase Substrate level
phosphorylation t ATP
Succinate dehydrogenase Oxidation of FADH by
respiratory chain 2ATP
phosphorvlation
Malate dehydrogenase Oxidation of NADH+H• 3ATP
by respiratory chain
phosphorvlation
Total= 12 ATP
Carbohydrate metabolism 43
Glucose
(Glycolysis] 6 or 8 ATP
Pyruvate Pyruvate
t
--vPyruvate v 1 v-
Pyruvate
12 ATP
12 ATP 12 ATP J
5. Oxidative decarboxylation of a-ketoglutarate to succinyl
Co A:
It is similar to the conversion of pyruvate to acetyl CoA.
a) Enzymes: a-ketoglutarate dehydrogenase complex.
b) Coenzymes: TPP, Lipoic acid, CoASH, FAD and NAD+.
lAcoNiTASE 1
DEIIY[)ROCI!HASE \ a ·Kotog~utorato
Succin~atc ) •• ,~!;
DEHYDROGENASE -
-·---~--
Succtnyl CoA e~
Long chain
.---- ................ --.---- ·--·------·. acyl CoA
i Acetyl CoA ••.• , i .:
Oxalo~cetate ~ t ~0
I
G jCitrate syn_tltasl!i e+
+
•'
•' ..-'*'. I
... . · 1
/ Citrate
~ Isocitrate
~ ............ E) 1 ,-~-s-oc_i_t_r__a_~_e_-D-Hj
\\ OxalTucoinato
\. a- ltetoglutrate
\ ........... 0 1\a-Ketogl~_!rat~ DR)
a) Citrate synthase :
1) Stimulated by acetyl CoA, oxaloacetate, ADP and NAD+.
2) Inhibited by long chain acyl CoA, citrate,. succinyl CoA,
ATP and NADH, H•.
Oraby's illustrated reviews of biochemistry 46
4) Cleavage of I
ca.-cooa 0g 1
al1 - C-SCoA
citrate: Citrate Al::etyl CoA Oxaloacetate
b) Fate of oxaloacetate:
I) Formation of citrate: By citrate synthase (first step in
TCA cycle).
0
2) Reduction to malate. I
CH3 - C- COOH
3) Transamination into Pyruvate
aspartic acid.
C02 _- ATP
Biotin
O•C-COOH
I
CH 2 - COOH
Oxaloacet.te
I .L I .~ ~~~..........
'T
1
;:1~
Malato Cltnlte
(iro~~~!i_OIIj
~rr
Aspartate
Sources and fate of oxaloacet.te.
Carbohydrate metabolism 47
t f
. DEHYDROGENASE . NADPH + W NAOPH + H• NADPH + H•
Oxidative)
(non-oxidative l
13·EPIMERASE I
I CO,
==-==n-;::-:;-,.,-,.,-- -·Ribulose 5-phosphate-- Ribulose
c, c
KETO·
ISOMERASE
I
J
C01
13-EPIMERASE s
• -
c
I
I C0 2
5·phosphate --Ribulose 5·phosphate---
Sedoheptulose 7-phosphate
c~
Fructose &-phosphate
c, ·
I ALDOLASE I
c3 I
Glyceraldehyde 3·phosphate
PHOSPHOTRiose
ISOMERASE
c. I
% Fructose 1,6-bisphosphate
FRUCT0Sfl.1,6·
BISPHOSPHATASE
% Fructose &·phosphate
C•J PHOSPHOHEXOSE
ISOMERASE
<='0
H-;- OH I COOH
I
H-~-
OH
HO-C- H 0
H-~-OH
H-~
I H:zO
Ho-y- H
H-C-OH
I
H-f- OH
CHz-o-® CH 2-o-®
6 Phoaphogluconolaclone
6 Pllotlphogluconlc acid
NACP•
rJ
COOH
I
H-~- OH_
6 Phospho-
gluconote
deh
NADPH•H•
enosc
II
y•o
H-C-OH
I
H-e- OH
I
CHz-o-®
3 Keto • 6 ohoaoho·
gluconic acid
nIIsomcrosel
H~•O
- Ribulose -5- phoaphalo
n
H~-OH
[Epimerosel
--
.
s
- - Ribulose -5· phosphate - -
[EpimeroseJ
HrJ- OH
H~-OH ~
:~t:~: ~~ ".:~:~
C•O
,.I
HO:~-H
H-J- OH
°CH 2 -o-® ~Ha-o-® cH 2 ~o-®
Rlboae -5- phos~phale
ITronske.:;:,osc I Xylulose -5- phosphate Xyluloae -5- phosphate
'\!:.."" H -"c a 0
ttf~-OH ~
=~.I •0
,.I
HO-oC-H
~· ~GlycoralH-"&a~:-®
dehyde-..-p
• hoap hal e
H-s- OH H!'C•O
H-e- OH ITronsoldolosc I H-"~-OH ..,__ _ _ __
H~-OH H~-OH
~ I
CHz-o-® °CHz-o-®
Sedohtptuose ·7· phosphate Erythrose -4· phosphate~
.
Hf~- OH H-"c • o
Hr~- OH ,.I
n
Fructoae -6· phosphate
n
Glucoao -6· phosphate
Glucose -6· phosphate
i Glucose ·6· phosphate
1. Production of pentoses:
Which are essential for synthesis of nucleic acids (RNA and
DNA), nucleotides (as ATP, GTP) and coenzymes (as NAD•,
NADP, FAD).
2. Production of NADPH, H•: It is important for:
a) Synthesis of many substrates:
1) Synthesis of fatty acids (lipogenesis) cholesterol and
other steroid hormones.
2) Synthesis of sphingosine and galactolipids.
3) Essential for glucuronic acid metabolism.
4) Synthesis of non essential amino acids.
5) Synthesis of malate from pyruvate by malic enzyme.
b) In RBCs: Reduction of lutathlone:
G - S - S - G ____:G:..:l:::u.:..:ta:..:t:.=h;:io;;,:;n:::e...:r~e;,;:d~uc:.:t:.:a::.se=---•
........... '""':;; 2 G. SB
Oxidized KADPB+B+ NADP+ Reduced
glutathione glutathione
d) Phagocytosis by white
blood cells ~BACTERIUM
(respiratory burst):
1) Phagocytosis is the
~<>--- MACROPHAGE
engulfment of
02
.
microorganisms
NADPH ~~Jl!'
and foreign bodies Respiratory
1burst ..
by white blood ~
cells.
2) White blood cells
contain an enzyme
NADP+ 1
0 2 "(Superoxlde)'
1
Superoxide
dismutase
-
'
called:
NADPH+H+ HCr~H202f Fe
2•
oxidase enzyme 1 Myefo-
peroxidase
3
Fe •
present in cell H20 §
membrane. J ·-
"'L._
"""'HOCI• CHi~
~
3) After phagocytosis
has occurred,
•• •
NADPH+H• oxidase
converts oxygen, 02 '
{derived from
surrounding ~..................~~. . . ...
Neutrophil phagocytosis and the oxygen-
tissues) into super dependent myeloperoxidase system for
oxide ions {O:.d- killing bacteria in phagolysosomes.
NADP+ Insulin
~e~~
Glucose-6-P __ R~..::::G-6-~-
:...:...P..::Dehydrq=z=:asenase=::.:·
::L.)--+• 6 Phosphogluconolactone
NADPH,H+
JIG"Acetyl CoA
F. Differences between pentose phosphate pathway (ppp)
and glycolysis:
ppp Glvcolvsis
Location In certain cells In all cells
Oxidation of Oxidation occurs in the Phosphorylation occurs
glucose first reaction. first then oxidation
Coenzyme NADP• NAD•
EnerKY No enerJtY nroduction 2 or 8 ATP
CO a Produced Not produced
Pentoses Produced Not produced
•----xTronKidalase-:
··----. J
:x!Tronskctalase
r---~ I
Fruc:toso -6· pho$phate Glycor aldohydo -3· phosphat
(',.,r.q
2. Mechanism:
a) Deficiency of glucose-6-P dehydrogenase + Decreased
NADPH,H• production (which is essential to reduce
glutathione in RBCs) .
G - S - S - G ........:G:.::l:::u:.:.t::.at:::h:::i;;o;::ne:....::r:.:e;z::d~uc:.:t:.:a:.=B.:::.e_
;;;= c::::::;; .., 2 G • SH
Glutathione peroxidase
2 G-SB + 8 111 0 111 -----------> G-S-S-G + 2 HaO
_....:;[61;;;uc;;;osc~-~6;;-p;d~•;;hy;;d;;rog;;enos~~·l_ _. · 6 Phospho-
Glucose - 6 - phosphate
• 7 "\ • gluconate
+ +
\ I I /
-
NADP
~
,
NADPI-I+I-I
~: +--~',~.~~-~/~~~~---
1 ~\ \
2 GSI-I
I
. 2 GS
[61utathlonc reductase] J
Met-Hb ~
.
"~---....:0[;;;;;Pero;;;;;;;;i;;;x;;;;;ld;;i;;asc~)--------'-
l-lzOz~
Peroxldatln ,.
of fatty acids
H, .,o-®
H-~- OH I
c>
Glucose HO-C-H 0
H-~-OH
H-eI
I
CHz-OH
UDP • Glucuronate
Urldlnedlphosphate glucose
(UDP ·Glucose)
Glucuronatt -~....__.
NADPH+H+ ~
NADP+ ~
L·Xylulose .=:;z::=• D·· X)'lltol ~ D ·Xylulose
.(J.
pentose phosphate pathway
C'wS,
2. Conjugation reactions:
UDP-glucuronic acid is used for conjugation with many body
compounds to make them more soluble before excretion e.g.
steroid hormones and bilirubin.
3. Detoxification reactions:
UDP-glucuronic acid is used for conjugation with toxic
compounds to make them less toxic e.g. phenols (see chapter of
xenobiotics, part I).
q{ycogen 9deta6o{ism
1. Structure of glycogen:
A. Glycogen is homopolysaccharide formed of branched a D glp.cose
units (a 1,4 and a 1,6).
B. The main glycosidic bond is a1-4-linkage. Only at the branGhing
point, the chain is attached by a1-6 linkage.
C. Each branch is made of 12-14 glucose units.
a.1.4-
g!JcoSidlc
'lj.~O~~Ubond
bond 'lj.
I
0{)_!~
l-\ 0:~
... 011
Branched atructuro of
glycogen &howlng G•1,4
ond a-1,8 llnkogu.
Structure of glycogen
Oraby's illustrated reviews of biochemistry 56
111.Functions of glycogen:
A. Liver glycogen: It maintains normal
blood glucose concentration especially
during the early stage of fast (between
meals). After 12-18 hours fasting, liver
glycogen is depleted.
B. Muscle glycogen: It acts as a source LocaUon and funcUon of liver
and muscle glycogen.
of energy within the muscle itself
especially during muscle contractions.
Glycogen primer
Glucose Q UDP-Giucose _;....._...;;;;....___;,_ _~,_Glycogen
Glycogen synthase
Branching enzyme
Carbohydrate metabolism 57
~tgi/a~1~~~~1
M9••
lII[PHOSPiiO-=--l
~L..UCQ.I!QI~~
UDP-Gluc:ose
t 7""'\ Gluose-1-phosphate
PPI UTP
2. Formation of glycogen:
a) UDP-Glucose reacts with glycogen primer, which may be:
1) Few molecules of glucose linked together by o.1-4
linkage.
2) A protein called glycogenin. UDP-G molecules react
with -OH of tyrosine of that protein to initiate glycogen
synthesis.
b) Glycogen synthase enzyme:
By the action of glycogen synthase (key enzyme of
glycogenesis), UDP-G molecules are added to glycogen
primer causing elongation of the a1-4 branches up to 12-14
glucose units.
UDP-Giucose + _.I_G; ; ; Iy; ; c; ; ; og._e: ;:;n: ;:;sy: :n: ;:;th: ;:;as: ; ; e; ; ]~ Elongated glycogen primer
Glycogen primer + UDP
c) Branching enzyme:
It transfers parts of the elongated chains (5-8 glucose
residues) to the next chain forming a new o.I-6 glycosidic
bond. The new branches are elongated by the glycogen
synthase and the process is repeated.
y
Glycogen primer (glycogenin)
~F
UDP-Glucose(s)
:ycogen <uoP-.>
~ UDP(s)
(-\,'
\ \ c::::::::::::.. .
\ ·' 'i)
' ~ I
"'- 1-4 bonds
1=1 ~
'YN•waJ-6 bond
~
Further elongation by
glycogen synthase making
a-1-4 bonds
~
Further branching by
branching enzyme making
a-1-6 bonds
GLYCOGBR
]Do~~~lng
Vf" \ )
I
IP11os~l ~ ... I~Transferasej ~oj
-~--, 7\ )
/(1 ~
PI (s) Glucose-1-
.~._)
.
Hr> Glucose
(0)
phoaphato (s)
&6
1'"""~1
Glycogen
1
Glucose • 6 • phosphate / Musclu \.
-----~ IGIU:!!e-6-
phosphatase
~
Glucose
\ I
~~--
Lactate \1),\l\\\1!11//1
D,+-
Giucose
Phosphorylase
0
Glycogen synthase
e
--.tf
Glucose
t
burlng fasting _. ~Blood glucose.:!'
I. During fasting:
Protein kinase
Phosphorylase ----"~:..:..;::'S-=-..-...-=:::::::~=---+~ Phosphorylated
;r ")j phosphorylase
ATP ADP (active I
cAMP AMP
0 (Phosphorylase)
(Inactive)
P, Glycogen
~r
J
'
(active)
Glucose
Glucose
el Glycogen
ADP
t ATP
t
ADP t ATP
:g~ ~
.Q
.!!!
During fasting····- • Glucagon
' Epineplu-ine ~~
~
~
~
:li..
II Hormonal regulation of glycogenesis and glycogenolysis.
'§
s
Oraby's Illustrated reviews of biochemistry 62
Phosphorylated Phosphatase
--..:..::.~~ii===;..._--+• Phosphorylase
phosphorylase ~
\!Y !Inactive!
Notes:
I. cAMP is an intracellular compound , formed from ATP by an
enzyme called : adenylate cyclase and destroyed by an
enzyme called phosphodiesterase enzyme.
,.., ,..,
tX> tX>
HC~
!Adenylot cyclosel
I He-. !Phosphodiesterase)
I
HC
H-~-OH I iC , H-~OH I H-~-OH I
1
H-e-~
OHq PPI n-&'oli)q H-~·OHq
K-~·
51
OK OK
I I
OH
I
H-~~~ H• C .::.:J OH
CK 2 - O•P·O-P·O·P·OH ScH 2- o-r.- on ·scH 2- o-P·OH
II II II II
0 0 0 0 0
ATP AMP t_<~-~~
1
3 , 5' Cyclic AMP
['!]]] cAMP
[]]£]
lalal + lclc
Inactive Active
protein kinase protein kinase
Concentration 6% 196
0
0
qCuconeogenesis
1. Definition:
Gluconeogenesis is the formation of glucose from non-carbohydrate
sources. These sources include:
I. Lactate.
2. Pyruvate.
3. Glycerol.
4. Some amino acids.
5. Propionate (in ruminants only).
111.Location of gluconeogenesis::
A. Intracellular location: cytosol and mitochondria.
B. Organ location:
I. Liver (90%).
2. Kidney (10%).
IV.Steps:
The steps of gluconeogenesis are mainly the reversal of glycolysis,
except for the three irreversible kinases which are replaced by the
following enzymes:
Glycolysis Gluconeogenesis
1. Glucokinase 1. Glucose-6-uhosuhatase
2. Phosp_hofructokinase- 1 2. Fructose 1,6 bisphosphatase
3· Pyruvate kinase 3· Pyruvate carboxylase
4· Phosphoenolpyruvate
carboxykinase
Orsby's Illustrated reviews of biochemistry 66
enzymes:
a) Pyruvate carboxylase: present in mitochondria.
b) Phosphoenol pyruvate carboxykinase: present in cytosol.
~ I PyruvaEJ
-..:..~o::::;;li:B
~ -cooK 1~1 ~ -cooK
CH 3 -C-COOH
Pyruvate
8ii=lot:.r.ln;c~?=---+~ CH1 -cooH
~, Blotl ADP+Pi Ozaloacetate NIU>H+H~
/""'""""'\
+
~ CH1 -cooH
Malate
MltochaNfrto
..:..;·ioec=-=~y GLUCOSE~!
._,!auco=:.:•:...
-
·~
~
1'~
R-D~I
-
~~~~"'-"'"·:E_:_,
H10 ~~- ADP
~ t
a~~" ~-e.~
•nT~ 1:.-l
. T. GL'I'CSIOL
2•PHOSPHOGLYCERATE
~--------·PHOSPHOENOLPYRUVATE
t
~::11_,
~ATP
PYRUVATE LACTATE
PYRUVATE ...,_ _
OXALOACETATE ~ATP+COa
~P'IIIVVATIC-USl!
-::rt:~~~-~
MALATE,.4IH•''f-f---- \ •·~--
CITIII C ACID CYCLI
.......__......
- -. . FUMARATE SUCCIHYL- CoA .,......__ PROPIQHATE
Major pathways In gluconeogenesis In the liver. Entry points of glucogenlc amino acid• after trannmlnatlon aro
indicated by unlabolod arrows.
Oraby's illustrated reviews of biochemistry 68
Glucoae
~tthioKiK&} t
SCA.iu
~WJ~!t ' -..,,, Glycerald hyde-3·p~ Dlhydroxy+etone-p
T~gpg~phaK-···--l J
Oxaloacetate '
',
'a I
1
Phophoenol pyruvate
Olyco~ophoephate
l***~***l
GLYCEROL
t
Halate
~
Ala.Uu
... ·~.
..···------t> ,....:::·~····
Pyruvate ...,_ LACTATE
I *******
'
Pylvate
/ .
t 1 '
................
''ll&
Citrate
I4otue.e.ill&} \\ //
.. &tU01t.iu .. \ 1
Vat.tu •., \ /
'<-\ /
Succinyl CoA ~
(
•-
•-ICetoslutrate
•' • { H.U.Ud.iu
P~o.t4u
Hfi~Olt!/lf~OUK&
***********1
PROPIONIC
1*********** t
************
Transamination :
I
:
I ~9-iK.ill&
i**********'
GLUTAHATd,:3--·· __ ,,
0II
CH,-CH - C-SCoA
LcooH
Methylmalonyl CoA
D. Gluconeogenesis from
!
Coenzyme fonn
glycerol: Methytmlllotlyt eoAl
of vitamin a, 2
['-·_ _ _ _ _~
mutlJSfl (Deoxyadenosyl
I. Glycerol is mobilized from cobalamin)
adipose tissue during fasting.
Two molecules of glycerol are 9
CH2- C-SCoA
used to form glucose: I
CH2- COOH
Succlnyl CoA
cn.-on
I : Gly~-;~;j~ ~~~'-Oil
CH -OH
I
CH 1 -otr ("\- --. b:.~~~®
Glycerol ATP ADP Glycerol-3·
phosphate
NAD~~ phosphat•
Glycerol ·3·1
NADH + W uhydroguou
CR 1 -0H
I
.,. •• ~
cID 0
,,
,, ,, CH,-0-®
Dihydroxvacetone
~· phosphate
Glyceraldehvde-3- ~~
phosphate ~alas;-A)
1
Fructose 1,8 blsphosphate
®il;;.!i!..l
Fructose-&· phoaphate
llllmOIIIUGM I
Olucose-8- phosphate
®11~~1
Slucose
Note:
.
Two important c11cles are related to gluconeogenesis: Cori c11cle
(see glllcOillsis, part II) and alanine glucose Cl/cle (see protein
metabolism, part III).
Serine
Alanine
_ _ _ _ ___......
l
Glucose
Tr~tion lm,eol>'!_~l __ _
ILactate dehydro§cnasel
tb'loxtdatiw dellllination ..,Pyruvate~ ,.. Lactate
A. Sources:
l. Glucose oxidation: glycolysis.
2. Lactate: by lactate dehydrogenase.
3. Malate: by malic enzyme.
Oraby's illustrated reviews of biochemistry 72
4. Alanine: by transamination.
5. Serine: by non-oxidative deamination.
6. Other amino acids: methionine, cysteine, threonine and
glycine.
B. Fate:
I. Glucose formation: gluconeogenesis.
2. Lactate formation: by lactate dehydrogenase.
3. Malate formation: by malic enzyme.
4. Alanine formation: by transamination.
5. Oxaloacetate formation: by pyruvate carboxylase.
9r1.eta6o{ism of monosaccnarides
qa{actose meta6o{ism
I. Importance of galactose: In the form of UDP-galactose:
A. Synthesis of lactose (=milk sugar) .
. B. Synthesis of glycolipids (cerebrosides).
C. Synthesis of glycoproteins and proteoglycans.
D. Synthesis of glycosaminoglycans.
Galactose
11. Conversion of
galactose into ATP~I Goloctokinasel
ADP
Mg••
-
.
glucose:
Galactose -1- phosphate
A. Site: Liver. Urtdlnedlphospllate glucose
(UDP • Glucose)
B. Steps: Galactose -1- phosphate'
!uridyl transferase
u~P - Galactose·~
ep11nerose
1
UDP - Glucose
11-..
Glycogen
""'""!!
<G~ol~sls '
~---'
1
Glucose
Carbohydrate metabolism 73
C. Galactosemia:
I. Definition: It is increase blood galactose concentration due to
inability to metabolize galactose.
2. Causes: Inherited enzyme deficiency of:
a) Galactokinase.
b) Galactose-t-P uridyl transferase.
c) Epimerase.
3. Effect:
a) Cataract (=opacity of eye lens):
Galactose in the eye is reduced by an enzyme called aldose
reductase into galacticol, which accumulates causing cataract.
(Aldolse reductase)
Galactose Galacticol ~ Cataract
.,..•.>
b) Liver failure.
c) Mental retardation.
d) Galactosuria: excretion of galactose in urine.
ADP I PHOSPHOGLUCOMUTASE I
Glucose -6- phosphate - - - - - - Glucose ·1· phosphate
Glucose
Conversion of glucose into galactose and synthesis of lactose in mammary gland. ,........
L
~ ,
Pructose meta6o{ism
1. Dietary Sources offructose:
A. Sucrose: (table sugar): Hydrolysis of sucrose _. glucose and
fructose.
B. Fructose as a monosaccharide is present in honey and in
many fruits and vegetables.
III.Metabolism offructose:
A. In the liver:
1. Liver contains fructokinase enzyme, which phosphorylates
fructose into fructose-t-phosphate.
2. Fructose-t-phosphate by aldolase B enzyme _.
Dihydroxyacetone phosphate + glyceraldehyde.
3. Glyceraldehyde _. glyceraldehydes 3- phosphate.
Fructose
( F~inose)l ATP
. (Aldolase 8)
' - - - - - - - • Glyceraldehyde
61uconeogenosis i
Glucose
i OldciGtian
Pyruvate
B. In extra-hepatic tissues:
I. Because fructokinase is not available in muscles and adipose
tissue, fructose is metabolized by hexokinase and other enzymes
into pyruvate • oxidation.
Fructose
i!!,..ldnue).ATP
FRictose-6..phosphate
(Phosphfructoklnaae-1) ~ ATP
(/\
Fructose 1,8 blsphosphate
Dlhydroxyacetone:-P e Gtyceraldehyde-3.p
,ij.
Oxidation ,._ 2 Pyruvate fJ'~
(8{ootf g{ucose
1. Plasma glucose levels:
A. Fasting level = 6s-uo mg/dl (3.6-6.1 mmol/L)
B. One hour after carbohydrate meal = 120-150 mgfdl (6.7-
8.3 mmol/L).
C. Two hours after carbohydrate meal (PP): 65-140 mg/dl
(3.6-7.8 mmol/L).
Note: For glucose 1 millimole/L (mmoi/L) = 18 mg/dl.
t Growth hormone
stimulated by insulin.
Carbohydrate metabolism 79
IUISIIII
Role of liver
in J:epl.ation
of blood glucose
ADIPOII IISSUI
glucose.
2. Secretion of anterior pituitary
hormones:
a) Growth hormone: insulin
antagonist.
b) ACTH .,. Stimulation of
suprarenal cortex .,.
Glucocorticoids .,.
t Gluconeogenesis .,. t
Blood glucose.
Note:
I) Glucagon and epinephrine
Gluconeo enesis
are most important in the
acute, short-term regulation of blood glucose levels.
Carbohydrate metabolism 81
IV.Symptoms of hypoglycemia:
(I
.:. '
'\ ,,
' - - SWatina
Symptoms of hypoglycemia
·.·~
,,.
Carbohydrate metabolism 83
1fyperg[ycemia
1. Definition:
It is the rise of blood glucose above normal average level.
11. Causes:
I. Diabetes mellitus: Most common cause (discussed later).
2. In patients receiving intravenous fluid containing glucose.
3. Temporarily in severe stress.
4. After cerebro-vascular accidents.
5. Disturbance in hyperglycaemic hormones.
tDia6etes me{{itus
1. Definition:
A. It is an endocrine disease caused by a relative or absolute
deficiency of insulin hormone.
B. It is characterized by a chronic hyperglycemia.
C. Glycosuria (presence of glucose in urine) is usually present.
Treatment by oral
hypoglycemic
Young Old
I
Thin Obese '..J~
Strong
~
LessgenetJc
genetic
backgroun
background
10-20% 80-90%
Low Insulin
secretion
ketoslele ketosis Ia
common less common
Type1 Type2
(IDDM) (NIDDM)
----~--~--------~------------------~· ~
Types of diabetes mellitus. "'''
., .
Carbohydrate metabolism 85
A. Insulin-dependent (type I)
D. Microangiopathy:
1. It is a degeneration that affects small blood vessels as
capillaries especially those .of the kidneys and retina of the
eyes.
2. Thus two of common chronic complications of diabetes
mellitus are renal failure and blindness.
I) Insulin I
. .
Minerals Uplds
t lm~l
lml~ I· +
Loss ofwelght &
hypertlpldemla
...
;~71
~1--1
111~1 ~
iu I ·Polyurea
+
II
Biochemical disturbances of diabetes mellitus
Oraby's illustrated reviews of biochemistry 88
.
below normal, maximum rise is below normal and returns to
fasting level are very rapid.
Diabetic--.
-
i'
Q
.s
300 i...
l
300
.
•"•'""' "''''"•••••••
, . - Renal thrtshold ......
1 200 , . - Renalttlrwllold
0 ••••••••••••••••••••••••••••••••••••••••••
:Q
.5 .5
I
6
j
0+-----~----,-----~----r-
0 1 2 3 4 Hour• 0 1 2 3 4 Houra
Urine Urine
glucose 0 0 0 0 0 glucose 0 + ++ +++ ++
Blood glucose levels and glucose In urine Blood glucose levels and glucose In urine
after Ingestion of glucose In normal Individuals.
c..6y
after Ingestion of glucose In diabetic Individuals•
.,_,
i' ! aoo-
-
Cl
.s
300
.[
I 200 ••••••••••••••• c..~~-~~ ..... I 200· ••••••••••••••• c..~~·.~~---··
.5 .5 Hypoglycemia
§ 100
I
'
10G-
:s
6
O+-----T-----~----~----r-
0
0
-
0 1 2 3 4 Houra 0 1 2 a 4 Houra
Urine Urfne
glucose 0 + ++ 0 0 glucose 0 0 0 0 0
Blood glucose levels and glucose In urine Blood glucose levels and glucose In urine
after Ingestion of glucose In renal glycosuria after Ingestion of glucose In hypoglycemic
individuals. Individuals.
Carbohydrate metabolism 91
If there is no symptoms
1· OGTT
v. Types ofdiabetes:
A. Diabetes mellitus: caused by defective insulin action.
B. Diabetes insipidus: hereditary disease caused by defective
action of antidiuretic hormone.
c. Diabetes innocence (renal diabetes): caused by low renal
threshold for glucose reabsorption.
D. Bronze diabetes: It is a hereditary disease caused by excessive
absorption of iron and its precipitation in tissues as :
I. Skin: causing its bronze discoloration.
2. Pancreas: causing diabetes mellitus.
3. Liver: causing hepatic cirrhosis.
VII. Glycosuria:
A. Definition: It is the presence of glucose in urine in amount
detectable by ordinary methods.
B. Causes (types):
I. Diabetes mellitus: It is the most common cause of
glycosuria. It accounts about go% of all cases of glycosuria.
2. Excess excretion of diabetogenic hormones: as growth
hormone, glucocorticoids, epinephrine and glucagon.
3. Diabetes innocence (renal glycosuria): due to abnormal low
renal threshold for glucose absorption. It may be inherited as an
autosomal dominate trait.
4. Pregnancy glycosuria:
a) Occurs in 20% of all pregnancies.
b) It is due to increase of glomerular filtration rate by about so%
during pregnancy.
C. Detection of glycosuria:
1. Glucose oxidase method:
It is a specific test, because the enzyme does not react except with
glucose. This is d~ne by urine strips containing this enzyme.
l. Benedict' • test:
Benedict's reagent gives colored precipitate with urine contains
glucose. It is non-specific semi-quantitative test because it gives
positive results with other substance.s than glucose as vitamin c.
Summary of Carbohydrate pathways
Glycolysis Pyruvate to Krebs' cycle Pentose PP Uronic acid Glycogenesis Glycogenolysis Gluconeo-
Acetyl CoA pathway genesis
Glucose to Pyruvate to Acetyl CoA to is a process is a process ' Synthesis of Breakdown of Formation of
1 Definition
that generates that generates glucose from non
pyruvate or
lactate
Acetyl CoA H20, C02 and
Energy NADPH and
pentoses
Iglucuronic acid
glycogen glycogen
carbohydrate
sources
I. INTRODUCTION :
lipase enzymes. I
I
'+'
1. Lingual lipase : TO 8LOOO Llpases,
choles1eryl esterase
a) Secreted by Ebner 's glands on and phosphollpases
digest dietary lipi ds
the dorsal sur face of the I
I
I
tongue . '+'
Frl!e tally acid~
b) Because food remains for a I ••••• • • • • •• - • 2·Monoacylglyccrol
' Cholesterol
'
sho rt time in the mouth, '
'
Pl and GL
3. Pancreatic lipase:
a) It is the most important lipase in digestion of triacylglycerols.
b) It attacks the primary ester bonds of TG (position 1 & 3),
hydrolyzing them Into fatty acids and 2-monoacylglycerols.
c) The resulting 2-monoacylglycerols will undergo:
1) 72% are absorbed as such.
2) 28% are converted into 1-monoacylglycerols by isomerase
enzyme which are then :
i- Absorbed as 1-monoacylglycerols (6%)
ii- Hydrolyzed by pancreatic lipase into glycerol and fatty
acids (22%) which are then absorbed.
d) Pancreatic lipase Is secreted as Inactive enzyme:
1) Its secretion is stimulated by r - - - - - - -- - - - - - - - ,
0
pancreozymin hormone (secreted o 1c~-o-c-R,
II2'
Rz·C·O·CH 0
by the duodenum) and vagus 3CH2 -0-C-R3
nerve stimulation. Trt=ylglycerol
P•nc::l~
2) It is activated in the duodenum by
bile salts, calcium
colipase (protein produced by the
ions and
f ~:,~~~~d
'---=:.!llp~·=-·!J c 13)
pancreas). 0 CH20H
Vagal Stimulation
D Bile
salta
I ~
t Butyric acid
Butyric acid
Tributyrin .. J''
'CI
(triacylglycerols containing 3 butyric acids) hydrolyzing
them into glycerol and 3 bulyric acid molecules. Milk is rich in tributyrin.
C. Digestion of phospholipids:
1. Phospholipids may be absorbed as
such or digested by phospholipase
enzymes (A1, A2 (B), C and D) 0II
2. They act on phospholipids R-C-o
hydrolyzing them into fatty acids,
glycerol, phosphate and
Cholesteryl
nitrogenous bases.
esterase
Glycerol + - - - + - Glycerol
Portal circulation
Honoacylglyce~ ~
....
+
Honoacylglycerola
Triacylglycerols ~ ·~~ n
PI
+
(~ HYLO HI C R0 Ns·'~gcholeatero~
~ +
PI
/ ~ Cholesterol
• ~
I +
··· .....•..•.... --··-Phospholipids Phospholipids
a
Protein
Systlmic circulation
Digestion of lipids.
..
Triacylg~cerols' \
rUpoproteln Dpase) ~: :Glycerol ~Fatty acids
. ApoCII ·
B. Glycerol and fatty acids are taken up by different tissues for the following
fate:
Oraby's illustrated reviews of bio~hemistry 100
Lungs
0 Spleen
ApoUpoproteln C II
-------
Heart
Blood vessels of
t HEPARIN
Lipoprotein lipase J
Intestine
t Mast Cells
-f.-----•
,.. t,... 0
.
.·chylomlcrons: - - -... Glycerol & FFA--+
' ' ' ' ' '
-----------------------------------------------------------------~
1\ -.}!;t~•
Fate of absorbed chylomlcrons. "'
Upids metabolism 101
11. Lipogenesis:
CH 20H
A. Definition: Lipogenesis is the I
HO-C-H 0
synthesis of trlacylglycerols from fatty I II
CH2·0·PI -OH
acids (acyl CoA) and glycerol (glycerol-
OH
3-phosphate).
Glycerol phosphate
1. Activation of fatty acids Into fatty
0II
acyl CoA:
2 CoA-C-R,, ~-~---
ACJI Ce.\ (Acytrranstetase)
0II
R·COOH
I) ~ R-C-SCGA ~CoA
Fatty add AT~
CGA8H AMP+ PPI
AcyiCoA ,if
0II
+HP 0 C~-0-C-R,
II I
R2 -C-O-C-H 0
I II
2. Synthesis of glycerol phosphate : CH2-0-P-OH
I
a) In liver, kidney, intestine, and OH
lactating mammary glands: Ph01phatldlc acid
Glycerol phosphate is formed
H20 ""'\ (Phosphatase)
from glycerol by glyceroklnase
,~PI
or from glucose through
0II
m.-
1
[GJYC!!1 tfnue) 0 CH2 -0-C-R,
. v,,_., ~ • Glycerol phosphate II I
R11-c-o-c-
I
H
ATP ADP C~OH
glycolysis. Diacylglycerol
0II
b) In muscles and adipose tissue,
CoA-C·Ra~
glyceroklnase is deficient. In Aeyl Ce.\ (Ac:yft~ansfetue)
these tissues glycerol phosphate
Is formed from glucose (through ~CoA
'If
glycolysis) as follows: 0II
0II CH2·0-C-Rt
Glucose ~ Dihydroxyacetone-p I
R11-c-o-c-H oII
~ Glycerol phosphate
I
CH2 -0-C-Ra
Hormone sensitive
triccylglycerol rrpase
Trlacylglycerol . ) Diacylglycerol + Free fatty acid
MBchanlsm of lipolysis.
2. Fate of glycerol:
a} Glycerol may diffuse to blood and then taken up by the liver to give:
1) Glucose by gluconeogenesis.
2) Pyruvate by glycolysis.
3) Triacylglycerols by lipogenesis (outside adipose tissue).
Note: In adipose tissue, glycerokinase enzyme is deficient, which is
essential to convert glycerol into glycerol phosphate. Thus glycerol
in adipose tissue cannot be used in re-esterification of fatty acids
to form triacylglycerols.
Adipose
tissue
' \. .i..
, - - Glycerol f"f"A __.#
Glycerol-3-p
:~
: AT
~~
I~
:ADP
I
II l
D1hydroxyacetone-p
~GLYCOLYSIS
I
I
Glyc,Xol-3-p
Glucose
Plaslllll
2. After meal:
a) Insulin is secreted -. Stimulation of both phosphodiesterase
enzyme and lipase phosphatase enzyme -. dephosphoryl!iltion and
inactivation of hormone sensitive trlacylglycerol lipase enzyme -.
Inhibition of lipolysis
b) Caffeine is a substance present in coffee. It Inhibits
phosphodiesterase enzyme -. Stimulation of lipolysis.
Aller meal - - - - - ~
cAMP AMP 0
phosplaatase
TRIACYLGLYCEROL
I(
0 HotrrtottHensll ,...® Honnone ~ /t)aB9
(active) (inactive)
Fatty
acid
DIACYLGLYCEROL
During fasting - - - •• ~
1. p-Ox/dation:
A. Site:
1. Intracellular location: Mitochondria.
2. Organ location:
a) Liver, kidney, heart and skletal muscles.
b) p-Oxidation never occur in brain and RBCs.
B. Transport of fatty acids Into the mitochondria:
1. After the fatty acid is taken up by the cell, it is converted to the acyl
CoA in the cytosol:
0II
R-COOH R-C-SCoA
Fatty acid Fatly acyl CoA
iii- It transfers the acyl group from acyl CoA to carnitine to form
acyl carnitine.
2) Carnitine acylcarnitine translocase:
i- It is present in the inner mitochondrial membrane .
ii- It transports acyl carnitine across inner mitochondrial
membrane (in exchange with carnitine).
3) Carnitine acylcarnitine transferase II :
i- For palmitic acid, it is called carnitine palmitoyl transferase II.
ii - It is present in the inner mitochondrial membrane.
iii - It transfers the acyl group from acyl carni tin e to form acy l
CoA again.
ICYTOSOL) [ MfrOCHOND@ MfrOCHONORIAL MATRIX
i
!+-OUTER MfrOCHONDRIAL MEMBRANE +-INNER MfrOCHONDRIAL MEMBRANE
+AMP + PPI
H20 \
;
l!
\1
0
AC -CoA
Fatty acyl CoA
•••••••••••••• Camltlne
~
RC - CoA
Fatty acyl CoA
J,
U.loftYI c.•···
:I
> 0l
Acyl CoA
synthetase P-Oxidation
RC - OH
~ ) '\
~
i •-r- ........ ~
0
RC -camltlne CoASH
Fatly acid 1CoASH CoASH
Acylcamiline Acylcamitine
• : +ATP
-------------------------------------------------- ~~
Carnitine shuttle t,.;..\:
C. Steps of B-Oxidation:
1. Actlvati on of fatty ac i d and transport i n s id e the m itoc ho ndri a:
a) Catalyzed by fatty acyl CoA synthetase enzyme and carnitine
shuttle.
b) 2 high energy bonds (-P) are utilized: ATP +AMP+ PPi.
2. Un sat uration of fatty acids:
a) Catalyzed by fatty acyl CoA dehydrogenase enzyme .
b) This enzyme is one of flavoproteins and its reduced coenzyme
(FADH 2 ) gives 2 ATP when oxidized in the respiratory chain.
3. Hydration :
a) Catalyzed by enoyl CoA hydratase enzyme .
b) It helps the addition of water to saturate double bonds.
4. Oxidation:
a) Catalyzed by 13-hydroxyacyl CoA dehydrogenase enzyme.
b) Its reduced coenzyme (NADH+W) gives 3 ATP when oxidized in the
respiratory chain.
5. Splitting (cleavage) step:
a) Ca t alyzed by Acy CoA acyl transferase (thiolase) enzyme.
Oraby's illustrated reviews of biochemistry 108
b) It splits acyl CoA into acetyl CoA and acyl CoA (shorter than the
original one by 2 carbon atoms).
Jk:arbon
~
CH3 -(CH~x-CH2·CH2-C-SCoA
~
Fatty acyl CoA =
g
n
:::r 0II
FAD s: g CH3 - (Cti2lx-CH2 - C~-C- S- CoA
; §:
-<
0
g. e.
=
0 =
~
Fatty acyl CoA
0 §: =
I» C"
;
0II =
n
I»
¥+AMP+ PPI Acyl CoA
CHa- (CH2)x- CH=CH -C- SCoA 3 synthetase
&2..trans-Enoyl CoA =
=
~
CoA-SH + ATP G) (Activation)
(a. and ll Unsaturated acyl CoA) q
I»
=
en
"CC 0II
0
Q)
CHa-(CH2>x-CH-CH2-C-SCoA
E Cytosol
=
z:
p.tlydraxyacyl CoA
u
Q) NAD+
.,"
c
'i
-
0
0
II
0II
CHa-(Cti2lx- c-C~-C-SCoA
IS-Ketaacyl CoA
CoASH
(3- Oxidation
0
@ . 12ATP
~ 12ATP
~ 12ATP
----+12ATP
----·12ATP
~ 12ATP
----+12ATP
I ----·12ATP
~
CH:J-CH - C-CoA
11. a-Oxidation:
A. This type of oxidation occurs in a.
LcooH
llelhylmalonyt CoA
position and characterized by:
!
1. It is a mechanism mainly for oxidation Coenzyme fonn
., p 0.
(HYDROXYLASE!) 1 p 0.
R- CH2 - CH - CHa-COOH
I } ... R-CH2 - CH -CH -COOH
I I
CH3 CH3 OH
[0]
Branched ratty acid a. Hydroxy fatty acid
j (DeHYDROGENASE)
[2H]- ~
R-~Ha~ ~~ ·COOH
7 p 0.
R-CH2 - CH -C -COOH
CH3I
Lower chain ratty acid
I
CH, 0
II
a.·Koto acid
E. Refsum's disease:
1. This Is Inherited deficiency of enzymes responsible for a oxidation
of phytanic acid. This leads to accumulation of phytanic acid in nervous
tissue and produce nervous damage e.g. deafness and blindness.
!.,-
CH1 -(CH2 ) - COOH
n
A. It is oxidation of terminal CH3
~ (Acetyl CoA)
converted to adipic acid (6 carbons)
and suberic acid (8 carbons).
C. (I)-Oxidation is a minor pathway for
! ~epeated P· Oxidation)
fatty acid oxidation and catalyzed HOOC(CHJ....COOH Adipic acid
by hydroxylase enzymes of or HOOC(CHJ,-COOH Suberic acid
cytochrome P450.
ro ·Oxidation of fatty acids. fYwfty
1. Sources:
A. Lipids: Oxidation of fatty acids and ketone bodies.
B. Carbohydrate: Glucose oxidation _. Pyruvate • Acetyl CoA.
C. Proteins:
1. Ketogenic amino acids: Give directly acetyl CoA or indirectly give
acetoacetate ,. Acetyl CoA.
2. Glucogenlc amino acids _. Pyruvate ,. Acetyl CoA.
11. Fate:
A. Oxidation: Through Krebs' (citric acid cycle).
B. Lipogenesis: Formation of fatty acids and triacylglycerols.
C. Ketogenesis: Synthesis of ketone bodies.
D. Acetylcholine synthesis.
E. Cholesterol synthesis: which is the precursor for:
1. Bile acids.
2. Vitamin D3.
3. Steroid hormones: glucocorticoids, mineralocorticoids, male sex
hormones (testosterone) and female sex hormones (estrogens and
progesterone).
Lipids metaboltsm 113
(sources) Fsnyscids
I I I
~ Fauyacfds Cholescarol
synthesis
Ketone bodies Acetyl choline
~
synthesis synthesis
I
I
Bile
I
VitO
I
Stanlid
adds hormones
P}f.qt{~Jf.CJ(J)S S~m!JPESIS
1. INTRODUCTION:
A considerable number of fatty acids are derived from diet. Living organisms
have the capacity to synthesize fatty acids from acetyl CoA. Any substance
that gives acetyl CoA (e.g. glucose) is called lipogenic.
There are 2 mechanisms for fatty acids synthesis: cytoplasmic and
microsomal.
Note: Acetyl CoA used for fatty acid synthesis always derived from
glucose and never from fatty acids. This is because insulin hormone
secreted after meal stimulates both glucose oxidation (+acetyl CoA) and
lipogenesis (=Fatty acid synthesis) and Inhibits lipolysis (+Fatty acid
oxidation+Acetyl CoA).
GlycolySis ,
Olucoso
\
NAOH
Interrelationship between glucose metabolism and palmitate synthesis. [Note: OAA= Oxaloacetate).
,r- NADPH+~
d) Each monomer contains 2 -SH
COOH
groups, one provided by '
c::o
phosphopantotheine and attached to '
CH,
·= 1-c;::J-E;J
\
'
Fatty acid synthase complex. The active enzyme is a dimer of identical subunits.
and ATP.
(biotin)
b) It Is the committed step In the
pathway.
0II
HOOC -C~-C- S-CoA
2. Synthesis of palmitate:
SH. ~ • PALMITATE
HzO
Pllmltlte•S- /11:1
CII certlon•l
+------
(2)o(7)
E. Fate of palmitate:
1. Esterification:
Palmitate esterifieid with glycerol to from acylglycerols or with
cholesterol to form cholesteryl ester.
2. Chain elongation:
Palmitate may be elongated to form a longer fatty acid.
3. Desaturatlon: i.e. synthesis of unsaturated fatty acid: palmitate may
undergo desaturation at Cg-C1 o to form palmitoleic acid.
4. Sphingosine formation:
It is formed by condensation of palmityl CoA and the amino acid serine.
Oraby's tllustrated reviews of biochemistry 118
I
I
e
I
2 P'ynlwllo I ca. I
ln&ulln
0
Q ~
lrPoHI40/
____-/
T t;;;:,!l
•O
- , 1 CoA 0..1..-.to
F
B. The microsomal pathway needs malonyl CoA as 11. Ketoacyl· CO A
redcutase
HloO''
acetyl donor and NADPH+H+ as coenzyme .
C. Function : This system becomes active during OH 0
<>.... I • .I
.. . ...... -·tll -01, - c-s - c:.to
myelination of nerves in order to provide C 22 P· Hydroxyacyl· CO A
and C 2" fatty actds which are present tn
F
u.. ·Unsaturated
(18:1) . acyt. CoA reductase
NAOI' 0
2. Synthesi s of oleic acid (oleyl CoA) : It is
synthesized - in the microsomes - from stearyl 0
11 -'hf. -"c H1 -'011 .1~-1 - C..
CoA (active stearic acid). Acyl· CoA
B. Essential fatty acid: These are unsaturated fatty acids which contain more
than one double bond.
1. They are essential because they cannot be
STEI'RYL- Co A+ Eft1J1M
formed in the body and should be taken in
the diet
2. Examples: linoleic acid (18:2) linolenic (..... ~~] ~CoA·Sit
(18:3) and arachidonic acid (20:4).
STEARYL- EnlpM
3. Sources: Vegetable oils as corn oil and
cotton seed oil. ,------, v-ot+NADPH +H+
4. Functions: ( lft'OROIIIYI.ASE)
f£ICOS:ft.NOI(J)S
I. Definition: These are cyclic compounds that derived from arachidonic acid
(eicosatetraenoic) (20 C) after cyclization of its carbons chain to form a ring.
Lipids metabolism 121
2. Leukotrlens (LT):
a) They are present
platelets and mast cells.
In leucocytes, ~ -
~
...
m. SYNTHESIS OF PROSTANOIDSS:
A. The immediate precursor of prostanoids is
,. . . . . f::
P002
l~coo-
arachidonic acid, which is 20 carbon
polyunsaturated fatty acid that containing 4
double bonds (20:4 a 5 •8 •11 ' 14 ). Arachidonic acid 0 OH
Phospholipid
(from cell .............,
c,...,, ·--·~e~phollpase A2 J
Lyaophoaphollplda
15-LipoxygenaseJ (Cyclooxygenase)
lr -
Arachidonic acid
~ 9 -........J~:!:.,hGCin
· l I ,..,,..._,
PGOa
,----:------":":\
~ (Peroxidase, GSH)
POH1
Throboxanes ~
• ~pla..let~
• ProciUced ,.c-111 llr ~
e Vaodllallon
• lncrs1Nd VIIC"Iar pennoabUIIy
@ r
'
e~~ 8
• ~of wMe lllaocl ntll
•
• RlfHM of.,.._.. ..urmu
lncnued dletMtull ol ~
e VaiOCIIIIIIon e V-lltcUCift
e Rllula _ . , . muecle • CoftllacUcn of -~~~ IINICie
• PracfUHd llr _, tlll4lft • Procluccd llr _, Ita-
Leukotrlenes
Prostacyclln
•
G
lnldlllll plalelet ~liOn
e YIIOCIIIIIIon
• Produced ptlmarlly llr
,..MI,
cndolhlllum ot
~~------------~v~------------~/
Prostanoids
B. Leukotrlenes(LTA4):
1. Leukotrlenes 8 4 (L TB 4 ):
a) Movement and aggregation of white blood cells at the site of
lnflamatlon (chemotactic movement).
b) Release of lysosomal enzymes.
2. Leukotrlenes (L TC 4 , L TD 4 , L TE 4 ):
a) Bronchoconstrictlon.
b) Vasodilatation.
c) lncre~sed vascular permeability.
---- ~lttftslon
~h~--------~-+~~~~
NW~-------~~tl~~jt~~--~~
HaOIMI
·~
fllniiiOit
Aetl&llllood
now eacrealon at Nil·, IC •
(,l!rllle:)
""""'
IIJPttCGIIIIICUIIIJ
~rllu
PMYICpalft
( -(
[!}
Sat.FA J
(unsat. FA)
-®~
Glycerophotphollpldt
[1 I-
FA ]
0-< !!!:• )
Sphlngophospholiplds
Phospholipids.
CH 2 -cooR
I 011 CHa-cooR
I OM
CH-
I COOR
-®-oltO*M OM 54 CH - COOR ItO Oil A
tK2 - 0 -®-o~o-@
CH 2 - 0 011 KID. .•
7 '\I
OM 2ATP 2ADP 0
I
Phosphatldyllnosltol
®
Phosphatldyllnosltol 4,5 blsphosphate
CH.OH
l .. IGlliCWolclnasaJ
f
""
~~OH
HO-C•H --===;::::;~:!......-t•.- HO-y·H >4 ., Glycolysis
Ha~-OH f ~ t~zc-o-®
ATP ADP
Olycorol Glycerol Dlhydroxy
3-phosphate acetone
phosphate
2 ACYL.•CoA
2CIIA
0
I
H1y-o-c-R1
R1-c-o-c-H
& "•~-o-®
1,2 Diacylglycerol
Ohalln• phosphate
l•ti!Dnuomln.)
(Iarin•)
~:~
kina..
AOP
Dluylgllletrol phosphate COP-diacylglycerol
PHOSPHATASI! synthase
Phoaphochalln•
(PhollpllcNihanol·
amln•l
(Pholpho..rln•l
'• PPI
~
Ra-~-o-y-H '
"a~-o-c-R 1 "a~-o-c-R 1
Ra-~-o-y-H - - - - - - -...
0 ftaCOH
1,2 Diacylglycerol
0 HzC-~
emDOE
CDP-Diacylglycorol
1
Cardiolipin
Inositol
PhosphaUdyllnosltol
synthase
CMP
0
j I
ttay-o-c-R1 tcay-o-c-R,
R1•C•O•C•H Ra-~-o-~-H ~
Biosynthesis of phospholipids.
Oraby's illustrated reviews of biochemistry 126
v
CHa-CCHaJa- Cfta- CHa- C-S-c:oA
f!Ma
HOOC• ~-Cifa-OH
AfUI/nt ·Q,A SERINE
P'IRIOOXAL-p, MA1 +
'/;,------J
~
CH 1 - lCHata-CHa- etta- C·CjH·Cfta-OH
rota
.J ·KE'IfJDIN'IDROSI'HIN«JS/N£
I PHOSPHOLIPASE Ad
0II
'CH~-0 C-R,
R~-C-
9. 'C-H
I
PHOSPHOLIPASE oJ
I
'CH2 -0-I- P
9. 0-IN-BASEJ
1.-:P:-H:-:-O~SP:-H:-:-O..&.U-::-PAS~E~A:-a-,J
I PHOSPHOLIPASE c J
Sites of me hydroly1ic: activity of phospholi!IIMI on a phospholipid Biosynthesis of sphingosine. CFp, flaoprotein.l
substrate. p~s...:.t--.»y
H. Degradation of phospholipids:
1. Phosphoglycerldes are degraded by phosphllpases A1, A 2 , C and D.
They are present in most tissues and pancreatic juice.
2. Sphingomyelin is degraded by lysosomal enzymes, sphlngo-
myellnase. Its deficiency leads to a disease called Niemann Pick
disease. It is characterized by enlarged liver and spleen and death at
early life.
Uplds metabolism 127
(LCAT)
LECITHIN+ CHOLESTEROL --==-....,LYSOLECITHIN+ CHOLESTERYJ. QTER.
I. Functloos of ghoaghollglda:
1. Phospholipids enter in the structure of cell membrane.
2. Phospholipids containing choline (e.g. lecithin) act as
neurotransmitters. They also act as methyl donors in
transmethylation reaction.
3. Phospholipids act as lipotropic factors i.e. prevent accumulation of fat
In liver and hence prevent fatty liver.
4. Dipalmityl lecithin acts as surfactant in the lungs. It prevents
adherence of alveolar wall. Its deficiency leads to respiratory distress
syndrome In premature babies.
5. Cephalin has a role In coagulation mechanism.
8. Lipositol (Phosphatldyl inositol) acts as precursor for Inositol
triphosphate. The latter acts as 2"d messenger, mediating ·action of
some hormones Inside target cells.
7. Phospholipids In bile make cholesterol soluble. Their deficiency leads
to cholesterol gallstones.
UDP-GLUCOSE
11••........;
UOP-
ACYL- CoA CoA GALACTOSE UDP·
Acetoacetate
0II
CH3 -C- CH2- COOH
OH
P-Hydroxybutyrate CH3 -CH-CH2- COOH
0II
Acetone C~-C-CH 3
Lipids metabolism 129
E. Regulation of ketogenesis:
1. After meal, insulin is secreted, and this Inhibits lipolysis and in turn
Inhibits ketogenesis.
2. During fasting anti-insulin hormones are secreted e.g. glucagon. This
stimulates lipolysis and In turn ketogenesis.
3. Explanation:
a) Conditions causing excessive lipolysis in adipose tissue leads to
very high level of plasma free fatty acids (FFA).
b) The liver in both fed and fasting states has the ability to extract
30% of the free fatty acids passing through it. Thus at high
concentration of plasma FFA, the amount extracted by the liver is
increased.
c) In liver, FFA is activated to acyl CoA __. P-Oxidation to give acetyl
CoA.
d) Acetyl CoA is oxidized in citric acid cycle, but if the amount of
acetyl CoA molecules is more than the capacity of CAC, they are
used to form ketone bodies.
FfA-.~Acyl CoA
~ (lJ- oxidation)
Regulation of ketogenesis.
Lipids motabolism 131
JPtrtphtrol ttssuts
• ·t"•'
Ketone bodies synthesis in the liver [KETOGENESIS) and utilization In peripheral ti ssues (KETOLYSIS). ,\!~I
t""
l
4
CITRIC
ACfD
r'
\ CVCL.O
\
'.. .,.- ,,
,'
,
'~
:1co.~
:lCOa.
9vleta6o{ism of Clio{estero{
I. STRUCTURE:
HJclrocarlton '"tall""
A. Cholesterol is an animal sterol.
B. It is a solid alcohol having -OH group
at C3.
B. Precursor: Acetyi-CoA.
C. Steps:
1. Formation of acetoacetyl CoA: by condensation of two molecules of
acetyl CoA:
0 0 CH~ 0
cH3-~-s-eoA + cH3-~ ..... s-eoA Thiolase) oI • oil
C-CH:r- C...,S-COA
II
ACETYL-COA ACETYL-COA "'CoA•SH 0 ACETOACETYL-COA
Oraby's illustrated reviews of biochemistry 134
0
" ..
0
CHa(: • SCoA + CHa(: • SCoA
Acetyl COA ~ COA
0.
CH~-C~·
..
0
C· SCoA
~ICOA
HOtl~fCH~
.,..,.
HUG CM ACiiiVI
• CoA
COA
CoASH
0
" SCoA
CH,·C·
•
CH,·C·OH
' .
C~·COQH
F
HMGCOA
I HMG CoA
reductaee
2 NADPH•H+
2NADPH+H
CoASH
•
~-c..,
, Qtl
CH,·9·QH
CH,•COOH
Mevalonate
~
Sequallne
~
Lanosterol
~
Desmosterol
~
HO
Cholesterol
Lipids metabolism 135
D. Reaulatlon of cholesterol synthesis: HMG CoA reductase is the key
enzyme for cholesterol synthesis .
It is present in two forms: active
dephosphorylated and Inactive
oAIIP
..
hhoallll~
f cii~tt•rote ~
AMP
1:&:\
,_,..,...
~
phosphorylated. It Is Regulated
P1 Choleac..~l
through:
( .v.;
1. Feed back Inhibition: .
Cholesterol (the end product
HMG.CoA roductase ·® HMG.:CoA reductase # ••
(Inactive) (active) \
of the pathway) acts as feed HMG.COA
Cytosol
"" \
~
~mRNA ~
! TmiSiallon ...! ~=~I
• ~
41if·~'.... =
~ ~ e=~
~-
e~tiiiiiiiiiiiiiii[OivcqeftJi
41( ......, ~
HMOeo.\ "¥ \. §
$
+
Mevalonic acid ;
~ .
~$
J, '"""'''~,,,,,,,,,,,,~
~ ..,,,,,,,,,,
Regulation of cholesterol synthesis.
Oraby's illustrated reviews of biochemistry 136
I Cholesterol I
!
IPregnenolone I
tl'
l
rl1_7_h_y_d-ro-x-yp_r_e-gn_e_n_o-lo_n_e..
I Progesterone I
!
I Dehydroeplandrosterone I 117 a. hydroxyprogesterone II Corticosterone I
'\. tl' '\. !
Androstenedione
I I Cortisol
I I Aldosterone I
I Testosterone I
!
I Esterone 1-+ 117 P -Estradiol I
The biosynthesis of steroid hormones from cholesterol.
Lipids metabolism 137
tMCPH.... NADP"
0.\. ~r>
,(7a.-ttydrox~st} HO
c ..........
......
, ,.
......., ...rdiOIC-
dla : f :
....,
·J~-~
Dna J 8 *'
•"-..,.,._, .... HO
H
HO
c. Hypocholesterolemia:
1. Definition: It is decreased plasma cholesterol concentration below 140
mg/dl
2. Causes :
a) Prolonged fasting which causes decreased secretion of Insulin
(decreased activation of HMG-CoA reductase).
b) Diet rich In unsaturated fatty acids and poor In saturated fatty
acids, carbohydrate and cholesterol.
c) Liver diseases, as liver Is the site where most plasma cholesterol
Is synthesized.
d) Hyperthyroidism.
e) Chronic Infection as tuberculosis.
.............
Origin Chylomicron Chylomicron 1-
1- ..
~
(~Upoproteln)
LOL ~VLOL
Mobility
(Pre ~Upoprotmn) LDL
VLDL
l Anode
(+)
-
Electrophoresis
(a-Lipoprotein)
HOL
HOL
\
Ultracentrlfugatlon
Chylomlcrons VLDL
D TRIACYLGLYCEROL
•. PROTEIN
~ PHOSPHOUPIOS
CHOLSTEROL AND
liJ CHOLESTEROL ESTERS
5%
LDL HDL
D. Metabolism of chylomicrons:
1. Site of synthesis: Intestinal mucosa.
2. Functions: Chylomicrons transport dietary lipids from intestine +
Blood + Peripheral tissues.
3. Structure:
a) Lipids:
1) Triacylglycerols, TG (main component).
2) Cholesterol ester (CE) and phospholipids.
3) Fat soluble vitamins.
b) Proteins: 2% and include apo 84 8 , apo E and apo C (CII).
Oraby's illustrated reviews of biochemistry 142
4. Ca t a bol i s m :
a) The particles released by intestinal mucosal cells a r e called
"nascent" chy lomicrons and contains apolipoprotein 84 8
b) When it reaches the pl as ma, it receives - from circulating HDL- two
apolipoproteins E and C and converted into chylomicrons.
c) The triacylglycerols component of chylomicrons will be hydrolyzed
into glycerol and fatty acids. This reaction is catalyzed by
lipoprotein lipase enzyme, which is activated by apo Cll.
d) After hydrolysis of TG, the chylomicron particles begin to shrink. In
addition , the apo Cll returns to HDL. The remaining particles are
called chylomicron remnants.
Dietary fat
chylomicron•
S mall intestino
---.
{:q\
't~}
tl;.
Copllo,..or
r,/j ~rclu oncl
( ( odlpue tinuo
1\
~ ~ LlpOIIIO,Ieht llpolSt (lPll
Chylomicrons remnant
NascentVlDL
Metabolism of VLDL
Uplds metabolism 145
3. Structure:
a) Lipids: cholesterol, cholesteryl esters, and phospholipids.
b) Apoproteins (22%): include apo B1oo·
4. Catabolism:
a) The numbers between brackets refer to the corresponding numbers
on the following figure:
[1] The LDL receptors are negatively charged glycoprotein
molecules, made by the DNA of the cell. They are grouped in pits in
cell membranes. The intracellular side of the pits is coated with a
protein called clathrin.
[2] After binding with receptors, the LDL are internalized as intact
particles by endocytosis.
[3] The vesicle containing the LDL rapidly loses its clathrin coat and
fuses with other similar vesicles, forming large vesicle called
endosomes.
[4] The pH of the contents of endosomes falls, allowing separation
of the LDL from its receptors. The receptors then migrate to one
side of the endosome while the LDL stays free within the lumen of
the vesicle.
[5] The receptors can be returned to the cell membrane. The
lipoprotein remnants are hydrolyzed by lysosomal enzymes
releasing cholesterol, amino acids, fatty acids and phospholipids.
Murdc cell
--
\
0
(LCAT)
LECITHIN+CHOLESTEROL-.;;;;;;;;;;;;;;...~LYSOLECITNIN + CHOLESTER"I'l ESTER.
ApoA·1
~otelns
Cholester oiCCI ) Discoidal nasent HDL
Phospholipids (Pll
Cholesterol ester (CEI
TrlllcylgiYtetols ITGI
HDL receptors
Metabolism of HDL.
Dietary fat
.,._
~""'
IPI 41 •11 ""
"*-"-l<fl
}
Intestine
~~~--ttGt
Chylomlcrons
I
TG
~~
Chylomicron
~~I
remlnants
CE~
__..HDL. ~ ..
Muscles c
~·4----LDL44-----~~--
PL
\\\\lltllllll
other tissues
Oraby
1. Lipoprotein (a):
1. Lipoprotein A, commonly called Lp(a), is a major independent risk
factor for cardiovascular disease. The optimum laboratory level
should be under 20 mg/dl
Oraby's Illustrated reviews of biochemistry 150
Famllllll Type f
hyparllpoproltlneml• Type Ill
H
Uvcr
_ Chylom~ns ~f~ Chylomteron: ~po~
~ype V remnants ~
I Fomillalllpoproteln
llpue deftcleney
-
Familial
ertrlaey1glyeerolemla
VLDL
Type /
ll¥•P'•'fs liplu; LDL
Type uJ/
r
Femlllal Musde.s
1\
Familial lipoprotein
Qput dtfteleney
'"'"'"'i"t''"'
\,,..,,,,
OUwltllasu.,.
Hyperlipoproteinem ia .
Superoxl<le ~
* ._. .
010
LDL
VItamin E
Aseorblc acid High atflnlry rec:eptors
Nitric: oxide p-ca1otene apec:lllc for LDL be<:ome
Hydrogen peroxl<le Other antioxidants 1downrogulated whtn
o•t
0 the cell haa autflclent
Other oxl<lants c:holutorol.
MACROPHAGE
<
CD
(/1
(/1
CD
INTERIOR OF ARTERY
Acid lipase Moat tissues Lyaosomes Removes fatty acids Needs acid pH
from lipids taken Into
cella during
phaaocvtosls
Patty fiver
I. Definition of fatty liver: This Is an accumulation of abnormal amount of
fat In the liver for a long time with subsequent compression of liver cells.
This results In liver fibrosis and Impairment of liver function.
11. Causes:
D. Lipotropic factors:
1. Definition: Lipotropic factors are substances that help the mobilization
of fat from the liver.
2. They Include:
a) Substances enter In structure or help the formation of
phospholipids.
I) Essential fatty acids (polyunsaturated fatty acids).
2) Choline, enters In structure of lecithin, sphingomyelin.
3) Inositol, enters In structure of llposltol.
4) Amino acids: as
1- Methionine which Is a methyl donor essential for choline
formation.
II- Serine which enters In ~he structure of cephalin.
5) VItamins: VItamin B, 2 and folic acid have a role In synthesis
and transfer of methyl group (CH 3 ).
.i5. ~
Un~at. FA
_ ~Serine -+Chephaline
"'-- I.~ la~t;J \.~holln.e4 Lecithin
PhP,PMJJPI(It.. ~,
112
FoUo acl
-·.C1:13 ~ camwne ~·FA oxidation
+
Methionine
t·
Proteins of high biological value ~ Apoprotelns
Lipotropic factors.
Definition AcyiCoA + TG FA to Acetyl CoA to Acetyl CoA to Acetacetate, (3-hydroxybutyrlc Acetyl CoA to
Glycerol-3-p to to FA+ glycerol Krebs' cycle to give Palmitate acid and acetone cholesterol
TG energy
Location Cytosol Cytosol Mitochondria of liver Cytosol Mitochondria Mitochondria Cytosol
Liver &adipose t. Of adipose tissue ••etc of liver •• etc I
ofliver of extrahepatic
tissue
Liver •.
Thtoonlno
--- ~ Aceto·
ltoleuclno
-157-
Oraby's illustrated reviews of biochemistry 158
.... I
I ,.- ,.-
...~
+ ~,
Glucose ~CsandCNS
!
Dlhydroxvacetone Lactose by
phostate ~ammary glands
' '
Trlacyglycerol
Oraby's illustrated reviews of biochemistry 160
Pit e
...
DlqosllltHI
~.
Df g~, omlu ultb, ad ftlt 6y rlll'fou lfJJita In fA~ wll1td
!!2!!!!!.
11 Ko:24,000 kc•t
Gut
1
/~ (acelltl
Glucagon
I
0 Portal win
D.Liyer in starvation:
I. Carbohydrate metabolism: The liver maintains blood glucose levels first
by glycogen breakdown (glycogenolysis), then gluconeogenesis:
a) Increased glycogen breakdown (glycogenolysis): t glucagon and .J.
insulin + rapid mobilization of liver glycogen + Blood glucose. Note that
liver glycogen is formed 3-4 hours after meal and is nearly exhausted
after 18 to 24 hours of fasting,
b) Increased gluconeogenesis:
(i) The carbon skeletons for gluconeogenesis are derived primarily
from amino acids, glycerol and lactate.
(ii) Gluconeogenesis begins 4 to 6 hours after the last meal and
becomes fully active, after 18 to 24 hours (after exhaustion of
liver glycogen).
(iii) Gluconeogenesis plays an essential role in maintaining blood
glucose during both overnight and prolonged fasting.
Integration of Metabolism 165
2. Fat metabolism :
a) Increased fatty acid oxidation: The oxidation of fatty acids derived
from adipose tissue is the major source of energy in hepatic tissue in the
post absorptive state.
b) Increased synthesis of ketone bodies:
(I) Liver is the site of synthesis and release of ketone bodies for use as
fuels by peripheral tissues. Ketone bodies synthesis is increased
when the concentration of acetyl CoA, produced from fatty acid
metabolism exceeds the oxidation capacity of Krebs' cycle.
(U) The availability of circulating ketone bodies is important in
starvation because they can be used as fuel by most tissues including
brain.
3. Protein metabolism:
a) During the first few days of starvation, there is a rapid breakdown of muscle
protein providing amino acids that are used by the liver for
gluconeogenesis. After several weeks of starvation, the rate of muscle
breakdown decreases due to a decline in the need for glucose as a fuel for
the brain.
H. Summary of starvation:
I. The metabolic changes that occur during starvation ensure that all tissues
have an adequate supply of fuel molecules.
2. the following diagram summarizes the inter tissue relationship during
starvation.
f
I+---+-+-----
r~~,_~~,_,_,_ __ i
1 l
r I
Chapter 5 Cancer, Oncoaenes, 'Tumor
:M.ar~rs ana apoptosis
1. Introduction:
A. Cancer cells: are characterized by 3 properties:
1. Diminished control of growth.
2. Invasion of local tissues.
3. Spread (metastasis) to the other parts of the body.
B. Benign tumor cells: are also characterized by 3 properties:
1. Diminished control of growth.
2. Do not invade local tissues.
3. Do not spread to the other parts of the body.
C. Cancer is the second most common cause of death In the USA after
cardio vascular diseases. In Egypt, no statistical data about this issue
is available.
-168-
Cancer, Oncogenes, and Tumor Markers 169
B. Oncogenes:
Human genome contains two classes of genes:
1. Oncogenes: which are genes that promote development of cancer
(tumors).
2. Tumor suppressor gene: which are genes that suppress the
development of cancer (Tumors).
Oncogenes
1. Definitions:
A. Proto-oncogenes (C-oncogenes):
These are normal genes (about 100) present in human genome. They
have specific functions in cell growth and differentiation.
B. Oncogenes:
These are abnormal genes. They are mutant (altered) proto-
oncogenes. They can lead to malignant tumors.
Chromosome 9
lu
Break
>
Chromosome 22 ~~ ~
• Break
>
Chromosomal Rearrangement
D. Gene amplification:
1. This Is an Increase In number of copies of normal proto-oncogene
within the cell e.g. genes for certain enzymes e.g. dlhydrofolate
reductase.
2. Amplification results In:
a) An increase of enzyme activity + Resistance to certain anti-
• malignant drugs as methotrexate.
b) AmplificatiOJ:'I may play a role in the progression of tumor cells
to a more malignant state.
c) Such amplification may produce several hundred copies of the
protooncogenes in the tumor cell e.g. oncogene myc in
neuroblastoma and oncogene c-erb 82 In breast cancer. Each
of amplified copies ~ Proteins ~ Alter cell growth ~ Cancer
development.
Cancer, Oncogenes, and Tumor Markers 171
plified
gene
Inactive
......... Hydrolysis ~
........~
.. _ ------ .,. ,
ofGTP , ....
!'Ill"'
Stimulate cell
proiireratioD
v. Growth factors:
A. Growth factors are polypeptides exert a mitogenic response on their
target cells.
B. They affect many different types of cells e.g. blood cells, nervous
system, mesenchymal tissues and epithelial tissues.
C. Growth factors act in an endocrine. paracrlne or autocrlne
manner?
1. Endocrine manner: like hormones, they may be synthesized
elsewhere in the body and pass in circulation to their target cells.
2. Paracrlne manner: they may be synthesized in certain cells and
secreted from them to affect neighboring cells. However the cells
that synthesized the growth factors are not themselves affected,
because they lack suitable receptors.
Cancer, Oncogenes, and Tumor Markers 173
2) Sporadic Retinoblastoma:
In th is d isea se, bo t h inheri ted RB gene s are norma l but
later in life after birth , both genes undergo somatic
mu ta tion (often a deletion) ~ Retinobla sto m a.
c) In both forms of th e disease , the patient's life can be saved if
t he tumor(s) is detected soon e nough and the affec t ed eye(s)
removed .
53
2. P gene:
a) It is a tumor suppressor gene. Its pro t ein product is 53
kilodaltons (hence the name).
b) S it e : s ho rt arm of chromosome 17 in somatic and ga metogenic
cells.
c) It prevents the formation of some tumors . Its mutation may le ad
to:
1) Cancer lung.
2) Cancer b reas t.
3) Cancer colon.
53
3. Mechani sm of act ion of p prot e in:
a) Regulat ion of cel l division: P 53 acts as activator for
tra nscription , regul ating certain genes involved in ce ll division.
b) Control of DNA damage and repair: If excess damage to DNA
has occu r red ~ in creased p53 ~ Inhib iti on of ce ll divis ion and
al lowing time for repair.
c) Protection against vira l in fection: P 53 binds wi th specific
virus pro teins, forming co mpl ex that inhibits vira l activity.
d) P 5 3 has a role in apoptosis: Apoptosis is a programmed ce ll
death cont roll ed by specific gene. St imulation of this gene ~
Cancer, Oncogenes, and Tumor Markers 175
lfumor !M.arkJrs
I. INTRODUCTION:
A. Definition:
Tumor markers are biologic substances synthesized and released
by cancer cells; or produced by the host cells in response to the
presence of cancerous tissue.
B. Site:
Tumor markers may be present in circulation, in body fluids or
associated with cells: In the cytoplasm or on cell membrane.
c. Structure:
Tumor markers may be enzymes, hormones, and proteins (tumor
antigen).
IV. Types of tumor markers: They are divided Into 2 types cellular
and humoral.
A. Cellular (tissue) tumor markers:
They include antigens located on the cell membrane or
intra cellular components as oncogenes.
B. Humoral (serum) tumor markers:
1. These are substances, which can be detected in serum.
2. They are usually synthesized and excreted by tumor cells or
released on tumor disintegration or formed as a result of
reaction of the organism to a tumor.
c. Tumor antigens:
1. Oncofetal antigens:
a) These are proteins produced normally during fetal life. They
are present In high concentration In the sera of fetuses and
decrease to low levels or disappear after birth.
b) In cancer patients, these proteins re-appear.
c) The production of these proteins demonstrates that certain
genes are reactivated as the result of the malignant
transformation of cells.
d) They include carclnoemryonic antigen (CEA) and a-fetoprotein
(AFP).
2. Other tumor antigens:
a) Carbohydrate antigen 19.9 (CA 19.9).
b) Cancer antigen 125 (CA125).
c) Cancer antigen 15.3 (CA 15.3 ).
d) Cancer anfigen 50 (CA 50).
e) Cancer antigen 27.4 (CA 27.4 ).
f) Squamous carcinoma antigen (SCCA).
g) Prostatic specific antigen (PSA).
h) Tissue polypeptide antigen {TPA).
3. Proteins:
a) 82 macroglobulin.
b) Ferritin.
}lpoptosis
For every cell, there is a time to live and a time to die
1. Definitions:
A. Apoptosls Is a Greek word means: [apo = away from + ptosis =fall].
B. Apoptosls is a programmed cell death or "cell suicide". It is the
body's normal method of ending the life cycle of cells through the
cellular self-destruction.
C. Apoptosls leads to the elimination of cells without releasing harmful
substances Into the surrounding area.
D. The cell shrinks, dissolves its contents, and activates phagocytosis by
neighboring cells.
E. If apoptosls Is affected, then the cell will not die, causing a
malignant condition.
Cancer, Oncogenes, and Tumor Markers 180
I. Definition:
A. Hormones are organic compounds produced by the endocrine
system and secreted directly into the blood to act near to their
site of release or at a distant organ in the body.
B. The 4tndocrlne system Is all the hormones producing tissues.
-181-
Oraby's illustrated reviews of biochemistry 182
NUCLEUS
A+~
/
~==
atRNA
.,....protein
·~
........,......
Mechonlstn of action of~ I hMnOnu: (binding with lntrcacdlulor receptors).
GTP GTP
s,f ~ *i-~-~ 7 e
SGTP
>
~~
if~
~a
0l
~
\J J
~-
I
I
I?
__e_m_b_ra_n_e------------~~~----------------------
_M
Cytosol '\/
~
ATP cAMP
lmlctlve
protein
kinase
ILI=\::1
ATP
GTP
Hclrmone-t_ R..,.,
!KcAM,~
Adlnylau
pnJtlin cycle.
~ M2SfHNfi1MIII
~
CELL 5'-AMP
MEMBRANE
R
•
+
AotM
2~=-
~--
~VT
......
Pho~Dha-. Pllplolllllo
CH 2 -COOR
CH -COOR
CH 2 -0H
Diac:ylglyc:erol
Inositol
~:0 ~
triphosphate (!)
6. Calmodulin:
a) Calmodulin Is an intracellular protein of molecular weight
17000.
b) It Is similar to the muscle protein troponln c In structure
and function.
c) Calmodulin has 4 calcium binding sites. Full occupancy of
these sites leads to marked conformational changes and
activation of it.
Endaplamic relic:uiUrll
-~--------_..,
~ "~-~------~!----
c.'·- CalmoiUn :
I
I
I
I
I
''
I
I 1 I
\ ~--------,I '1
I ' -------~'
I
'
. PII'JSIOIDglc:al rnpoiiMS
Ca+u.t Ca++
0 +
Calmndnlin
4 Ca++ _ __._a.
Ca
.Active calmoclnl in
0
- - - - • + Calmodulin ~ Physiologic
Ca++ kinase effect
d) Functions of calmodulin:
1) Activation of certain intracellular enzymes important
for metabolism e.g. phosphorylase enzyme of
glycogenolysis.
2) Regulation of the activity of many structural elements
In the cells e.g. actlnomyosin complex of smooth
muscles, cell motility, mitosis, granular release and
endocytosis.
Hormones 189
Jfypotlia{amic liormones
I. Introduction:
A. Hypo th a l a mus is a protein of centra l nervous sys tem , lo cated at
th e base of th e brain just a bo ve the pituitary g l a nd .
B . Hypoth a l a mu s sec ret es r e l eas ing hormon es, vasop r ess in (ADH)
a nd oxytocin hormon es.
hypophyseal
-T-- - - efferent vein
Hypothalamic hormones.
Oraby's illustrated reviews of biochemistry 190
hormones:
1. Dopamine.
2. GAP (gonadotropin releasing
Hormones 191
0 A.QJ:i:
1. Th e Increased osmolality of th e pla s m a i s th e s timu lu s that
ac ti vates the s upraopti c nucl ei a nd ADH sec r e ti o n .
2. The increase d osmola l ity is m e di ated by osmoreceptors
located in th e hypoth ala mu s and by baroreceptors located in
the h ea rt and othe r r eg ions o f vasc ul a r syste m .
3. Other s timuli i n clude e motiona l , physical s tr ess a nd so me
phar m aco l ogic age n ts as acety l choline, ni co tin e a nd m o rphin e.
D. Mechanism of action of ADH:
1. AD H ac ts on di stal convo lut ed and collecti n g tub ul es of the
kidney causing wa t er reabsorption .
E. Di abetes inslpld..Y.§.:
1. Thi s Is a disease caused by a deficiency of ADH actio n .
2. It is c har ac t e ri ze d by th e excretio n of l a rge volum es of dilute
urin e .
3. Types of diabetes insipidus:
a) Primary diabete s Insipidus:
Oraby's illustrated reviews of biochemistry 192
a) Growth hormone.
b) Prolactin.
c) Placental lactogen (chorionic somatomammotropln; CS).
2. Glycoprotein hormone group : It Includes:
a) Thyroid stimulating hormones (TSH).
b) Luteinizing hormone (LH).
c) Follicle-stimulating hormone (FSH).
d) Chorionic gonadotropin (CG).
3. Pro-oplo-melano-cortln (POMC) peptide group: It includes:
a) ACTH.
b) Melanocyte stimulating hormone (MSH).
c) Jl-llpoproteln.
d) Endorphins.
e) Enkephalln.
Higtw ......
I " ~
1/
1-CNS
-- ~==- ~.
-
,..- I I I
MWior poluQty ~~ I
~
//1 \ ~
,..,.,.,. Adl'.no-
conicOtrDC>in
(ACllil
..,.......,no
~
Foil_,.
,.,..,.,.
L.....nmng
(LH)
~" ....,.,.
OtOWI!>
CGHI
O.yU>Cin ~"
(FSH)
I
l
Thylood
l
Jl Adr_, tertn JI
I
Tntas II
I
()Ny
I
I
lu- I
I
ThyrO>IIftO
I
Ad reno-
I
T.......,one
I
Ealrogon,
conlal progeot• one
I I
1...._,_, . .,.,.. _
alefolclo
I
·S..~-
I ll~gla..sll-1
ISoml-1
§ ., ~.,
The hypothalamus - pituitary - target organ relationship.
II. BIOSYNTHESIS:
A. There is a common metabolic pathway for the biosynthesis of all
steroid hormones. The fllrst step Is the conversion of cholesterol
Into pregnenolone.
1. This reaction Is the rate limiting step In steroidogenesis and
occurs In the mitochondria.
2. This reaction Is activated by AOTH.
3. It needs an enzyme called: cytochrome P-450 side chain
cleavage enzyme (P-450 sec).
4. It requirs NADPH and molecular oxygen.
H C
I I
ACTH • e-c-c-e
(cAMPI )r D \
0 c
(p-450 Sc:c:l
HO HO
,,
.,.,.,.
.....
I - · ·
Hr!JGU~alamu•
Tlltl~
Tlltlahydlocottlaone
Cottols, cortolones
(moaauroel as w:lnary
17-0H)
Hormones 201
r----•
I
I
I
I
I
Anglctensin II
Convetllng~t
cwyme :
I
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t
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COR'fllOL AHD IIBTABOLISII
OF IIINBRALOCORTICOIDS. ")I
I Anglolcn-
lllnogen
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t UIUI&Iy
alclosle1CM
moi&IIO!ttes
Jformones ofgonaas
I. The gonads have 2 functions which are production of germ cells and
sex hormones.
A. In males: testes produce spermatozoa and testosterone.
Hormones 203
OH
INADPHI
r-+ I Hypothalamus I
' Gn-RH
I Pituitary I
I Negative
FSH,~H
Negative
feedback
feedback
I
IFree testosterone 1- !+TISSUCS
n ~
p....;.... l-@ ~ ITestosteroae :SHBO I DHT
l
' '
Receptor
I ABPI ITestosterone I ~
Local production
Nucleus
I
'
Spermatoscnesis
cortex.
I. Functions of androgens:
1) The androgens, mainly testosterone and DHT are
involved in the following functions:
2. Sexual differentiation (male or female).
3. Spermatogenesis .
4. Development of secondary sex characters e.g. male voice,
male pattern of hair distribution.
5. Anabolic metabolism and gene regulation.
a) There Is an effect on brain, leading to characteristic male
sexual behaviour and aggressiveness.
Hormones 205
J. Hypogonadism:
1. This Is a c:ondltlon of deficiency of testosterone synthesis .
2. It may be due to:
a) Primary hypogonadism: due to absance or disease of the
testes.
b) Secondary hypogonadism: due to defective secretion of LH
&I or FSH •
3. It Is characterized by Impotence, obesity and molecular
wasting (due to loss of the protein anabollslng effect of
testosterone).
0 OH OH
OH
HO
Estradiol, Ba
C. Progestins (progesterone)
THECA CELL
are produced and secreted
Cholesterol
by corpus luteum.
D. Biosynthesis of · · · · · · · · · ·J
estrogens and Androstenedione & Testostemt
progesterone:
1. It is similar to those of FSH Receptor Androst~111dion~ Testo~erone
male hormones. ~
ATP cAMP .......................... Arcrnaltzolton
H. Functions:
1. Estrogens :
s) Estrogens stimulate the growth of ttte cells of uterus,
vagina, graaflan follicles of the ovary and the mammary
gland.
b) Estrogens are responsible for the development of
&econdary sexual characters e.g. female voice, female
pattern of hair and fat distribution.
c) Estrogens Induce, In the uterus and mammary gland , the
synthesis of progesterone receptors.
d) Estrogens are responsible for the maintenance of the
menstrual cycle.
e) Estrogens are required for the development of mammary
gland.
Hormones 207
ACETATE -
5~ 7
HO 6
20 hydroxlflaso
22 h11droxylase
1
20, 22 dasmolaao
~··
C•O
U-hydroxv-
dohydroaanase
••
17011-hydroxylaso/ PREGNENOLON 4-5 lsomorose
BIOstnfBBSIS OP
ISDOGBifS
PROGIS'l'DOBB
ARD
~~
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~·· ~
.~
rrs_
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17-HVDROXVPREGNENOLONE PROGESTERONE
1 1
17 20 desmolase
'
. aSP I
o•
17a&-hydroxylaso
c&d"
!"•
aSP
17,20 doamolaao
dehydrogenase o ••
64-llaomaraso·QSP 171 -hydroxy-
dohydroganasa
~ 0
ANDROSTENEDIONE TESTOSTERONE
l
aromatlzatlon
o•
0
17--hydroxv-
dahydroganue
...
aSP
•
laromatlzatlon
p
ESTRONE ESTRADIOL
2. Progesterone :
s) Progesterone Is necessary for the Implantation of fertilized
ovum In the uterus.
b) Progesterone Inhibits uterine contraction during pregnancy
(I.a. maintain pregnancy).
c) Progesterone stimulates the growth of the secretory glands
of uterus and mammary gland.
d) Progesterone Is responsible for the maintenance of
menstrual cycle (luteal phase).
e) Progesterone antagonizes the action of estrogens In
various tissues.
2. Its
Inside
second
target
messenger
cells are
1 25 D:3(0H) 2
/ f~Otnlivcr
calcium and cyclic AMP.
(Kidneys)
D. Functions of PTH:
1. Maintenance of plasma
calcium level within
normal level by:
s) Formation of calcltrlol
essential for Intestinal
calcium absorption .
Ill. CALCITONIN:
A. Calcltonlne Is a 32-amlno acid peptide secreted by the
parafolllcular C cells of the human thyroid.
B. Its function In regulation of plasma calcium In human Is uncertain.
However, it may have a role In decreasing plasma calcium by
Increasing deposition of calcium In bones.
II. There are 1-2 million Islets In human pancreas make up 1-2 % of Its
weight, and they are 4 types, each secretes a specific hormone:
A. A or alpha cells: secrete glucagon.
B. B or beta cells: secrete Insulin.
C. D or delta cells: secrete somatostatin.
D. F cells: secrete pancreatic polypeptide.
Ill. INSULIN:
A. Insulin: has an Impressive list of "firsts". It was:
1. The first protein proved to have hormonal action.
2. The first protein crystallzed .
3. The first protein sequenced for Its amino acids.
4. The first protein synthesized by chemical techniques.
5. The first protein shown to be synthesized as a large precursor
molecule"preprolnsulln".
6. The first protein prepared for commercial use by recombinate
DNA technology.
B. Structure:
1. Insulin Is composed of 51 amino acids arranged in two
polypeptide chains designated A (21 amino acids) and B (30
amino acids).
Ora by's illustra ted re v ie ws o f bioch emistry 212
C. Bolsynthesls:
1. Insulin is synthes iz ed as long polypeptide of 110 amino acids
ca ll ed : pre prolnsulin.
2 . 24 Amino ac id r es idu es " signal se quence " at the N- t er min a l
end of preproinsulin are cleaved In e ndoplasmi c reticu l um to
form anoth e r p r ecursor ca ll ed proinsulln (86 amino ac id s ).
3. Th e proinsulin is transferred to the Go l gl apparatus, where it
under goes protolysis to give In s ulin and c -p eptlde.
4 . In Golgi appara tu s a l so In su lin combines with z in c and packed
Into secretory granules. Zinc i s es s entia l for insulin act i vity .
5. Both in s ulin and c-peptide are secreted Into the ci r cu l ation an
eq uimo lar amou nts.
6. Approximately 50 units of i n s ul i n per day are required ; thi s as
about 1 / 5 of t h e amount sto r ed in the human pancreas .
.. ~
6olgo +
fndooiOSIIIOC
rc:t .cviUfn opporo tus
coo-
Insulin
C-oeptlde
Preprolnaulln P tOini UIIn
Hormones 213
6 p
A
A
s s
I I
s B
s +
I I 46SH
Active insulin Q; B
D
Inactive peptide a
Oraby's Illustrated reviews of biochemistry 214
Insulin
Nucleus
IV. GLUCAGON:
A. Glucagon Is a polypeptide hormone secreted primarily by the a.-
cells of the pancreatic Islets. Glucagon together with
epinephrine, cortisol and growth hormone oppose many of the
actions of Insulin.
B. Structure of glucagon: Glucagon Is composed of 29 amino acids
arranged In a single polypeptide chain.
C. Biosynthesis of glucagon: It Is synthesized as a large precursor
molecule Mpreproglucagon" that Is converted to glucagon through
a series of selective proteolytic cleavages, similar to those
described for Insulin biosynthesis.
D. Regulation of glucagon secretion:
1. Stimulation of secretion: glucagon secretion is stimulated by
low blood glucose, amino acids and epinephrine.
2. Inhibition of secretion: glucagon secretion is inhibited by
Increased blood sugar. This occurs after Ingestion of
carbohydrate-rich meal.
E. Functions (metabolic effects)of glucagon:
1. Effects on carbohydrate metabolism: It Increases blood
glucose level through:
Hormones 217
V. SOMATOSTATIN:
A. It Is 14-amino acid peptide which Is synthesized In D-cells of the
pancreatic Islets.
B. In addition to Its presence In pancreatic Islets, somatostatin Is
found In the hypothalamus and many gastrointestinal tissues.
C. Functions:
1. Pancreatic somatostatin :Inhibits the release of other Islets
cell hormones: Insulin, glucagon and pancreatic polypeptide.
2. Hypothalamic somatostatin: Inhibits the release of growth
hormone, TSH, FSH and ACTH.
3. Gastrointestinal somatostatin: Inhibits the absorption of
nutrients because:
a) It prolongs gastric emptying.
b) It decreases gastric secretion and gastric acid production.
c) It decreases the digestive enzymes secreted by pancreas.
d) It decreases visceral blood flow.
e) It slows sugar absorption.
Oraby's Illustrated reviews of biochemistry 218
1formones of tliyroitfaCantf
See protein metabolism, part Ill
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