Nucleotide metabolism – Part 1

(purine biosynthesis)
 Biological significance of
nucleotide metabolism
• Nucleotides make up nucleic acids (DNA and
RNA)
• Nucleotide triphosphates are the “energy
carriers” in cells (primarily ATP)
• Many metabolic pathways are regulated by the
level of the individual nucleotides
– Example: cAMP regulation of glucose release
• Adenine nucleotides are components of many
of the coenzymes
– Examples: NAD+, NADP+, FAD, FMN, coenzyme A
 Dietary nucleotides
• do not contribute energy as do carbs,
proteins and fats
• are not incorporated into RNA or DNA
unless given I.V.
• normally metabolized to individual
components (bases, sugar and phosphate)
• purines are converted to uric acid which
is then excreted
 Medical significance of
nucleotide metabolism
• Anticancer agents:
• Rapidly dividing cells biosynthesize lots of
purines and pyrimidines, but other cells reuse
them. Cancer cells are rapidly dividing, so
inhibitor of nucleotide metabolism kill them
• Antiviral agents
– Zidovudine (Retrovir)
– Lamivudine (Epivir)
– Valacyclovir (Valtrex)
 Structures of nucleotide
building blocks and nucleotides

6 7 4
5
N 5
1 N 3N
8
2 2 6
N 4 N N
9
3 H 1

PURINE PYRIMIDINE
 Structures of nucleotide building
blocks and nucleotides
O O O
NH2 NH2
CH3
N N HN HN
N N N

N H2N N N O N O N O N
N
H H H H H
ADENINE GUANINE THYMINE URACIL CYTOSINE

guanine: comes from guano; thymine –thymus gland

 OH OH
Base Base
OH P O CH2 OH P O CH2
O O
O H H O H H
H H H H
OH OH OH H

RIBONUCLEOTIDE DEOXYRIBONUCLEOTIDE

Ribonucleotide – phosphate = ribonucleoside

Biosynthesis of the purine nucleotide system
 Synthesis of Inosine Monophosphate

• Basic pathway for biosynthesis of purine

ribonucleotides
• Starts from ribose-5-phosphate which is
derived from the pentose phosphate
pathway
• Requires 11 steps overall
• occurs primarily in the liver
The big picture
 Steps 1 thru 3
• Step 1:Activation of ribose-5-phosphate
– enzyme: ribose phosphate pyrophosphokinase
– product: 5-phosphoribosyl-a-pyrophosphate
(PRPP)
– PRPP is also a precursor in the biosynthesis of
pyrimidine nucleotides and the amino acids histidine
and tryptophan
Step 1: purine synthesis
 Steps 1 thru 3
• Step 2: acquisition of purine atom 9
– enzyme: amidophosphoribosyl transferase
– displacement of pyrophosphate group by
glutamine amide nitrogen (inversion of
configuration – a to b
– product: b-5-phosphoribosylamine

Steps 1 and 2 are tightly regulated by feedback inhibition

Step 2: purine synthesis:
commited step
 Steps 1 thru 3
• Step 3: acquisition of purine atoms C4,
C5, and N7
– enzyme: glycinamide synthetase
 b-phosphoribosylamine reacts with ATP and
glycine
– product: glycinamide ribotide (GAR)
Step 3 : purine synthesis
 Steps 4 thru 6
• Step 4: acquisition of purine atom C8
– formylation of free a-amino group of GAR
– enzyme: GAR transformylase
– co-factor of enzyme is N10-formyl THF
• Step 5: acquisition of purine atom N3
– The amide amino group of a second glutamine is
transferred to form formylglycinamidine ribotide
(FGAM)
• Step 6: closing of the imidazole ring or formation of 5-
aminoimidazole ribotide
Step 6: purine synthesis
 Step 7
• Step 7: acquisition of C6
– C6 is introduced as HCO3-
– enzyme: AIR carboxylase (aminoimidazole
ribotide carboxylase)
– product: CAIR (carboxyaminoimidazole
ribotide)
– enzyme composed of 2 proteins: PurE and
PurK (synergistic proteins)
Step 7: purine synthesis
 Steps 8 thru 11
• Step 8: acquisition of N1
– N1 is acquired from aspartate in an amide
condensation reaction
– enzyme: SAICAR synthetase
– product: 5-aminoimidazole-4-(N-
succinylocarboxamide)ribotide (SAICAR)
– reaction is driven by hydrolysis of ATP
Step 8: purine synthesis
 Steps 8 thru 11
• Step 9: elimination of fumarate
– Enzyme: adenylosuccinate lyase
– Product: 5-aminoimidazole-4-carboxamide
ribotide (AICAR)
• Step 10: acquisition of C2
– Another formylation reaction catalyzed by
AICAR transformylase
– Product: 5-formaminoimidazole-4-
carboxamide ribotide (FAICAR)
Step 9: purine synthesis
Step 10: purine
synthesis
 Step 11
• cyclization or ring closure to form IMP
• water is eliminated
• in contrast to step 6 (closure of the
imidazole ring), this reaction does not
require ATP hydrolysis
• once formed, IMP is rapidly converted to
AMP and GMP (it does not accumulate in
cells
Step 11: purine
synthesis
 O

N
HN

N N
Aspartate + GTP
Synthesis of adenine IMP
Ribose-P
IMP dehydrogenase
GDP NAD+
and guanine nucleotides A.S.
synthetase NADH

COO-
O
-OOC

NH N
HN

N
N N
O N
Ribose-P
N H
N
Ribose-P
xanthine monophosphate
Adenylosuccinate
XMP
glutamine + ATP
A.S.
lyase
fumarate Glutamate + AMP
+ PPi
NH2 O

N N
N HN

N H2N N N
N
Ribose-P Ribose-P

AMP GMP
Purine nucleoside diphosphates and triphosphates:
- to be incorporated into DNA and RNA, nucleoside
monophosphates (NMP’s) must be converted into
nucleoside triphosphates (NTP’s)

- nucleoside monophosphate kinases (adenylate & guanylate kinases)

AMP + ATP 2 ADP
accomplished by separate enzymes

GMP + ATP GDP + ADP

- nucleoside diphosphate kinase

GDP + ATP GTP + ADP

same enzyme acts on all nucleotide di & triphosphates

nucleoside diphosphate kinase is an enzyme which plays
a key role in the activation of antiviral nucleosides such as Retrovir/AZT
 Regulation of purine nucleotide
biosynthesis
activation

amidophosphoribosyl
ribose-P-pyrophosphokinase transferase
Ribose-5-P PRPP 5-P-ribosylamine

AMP + GMP

ADP + GDP
 The purine salvage pathway
• Purine bases created by degradation of RNA or
DNA and intermediate of purine synthesis were
costly for the cell to make, so there are
pathways to recover these bases in the form of
nucleotides
• Two phosphoribosyl transferases are involved:
– APRT (adenine phosphoribosyl transferase) for
adenine
– HGPRT (hypoxanthine guanine phosphoribosyl
transferase) for guanine or hypoxanthine
 Salvage of purines

OH

OH P O CH 2 H
O
O O
O H H adenine
H O P O P O-
OH OH PPi
O- O-

NH2

N
N

Adenine OH N N
phosphoribosyltransferase OH P O CH 2
O
(APRT) O H H
H H
OH OH
 Salvage of purines
• Salvage is needed to maintain the purine pool (biosynthesis
is not completely adequate, especially in neural tissue)
• Hypoxanthine-guanine phosphoribosyltransferase
(HGPRT)
• Hypoxanthine + PRPP IMP + Ppi
• Guanine + PRPP GMP + Ppi
• Lack of HGPRT leads to Lesch-Nyhan syndrome. Lack of
enzyme leads to overproduction of purines which are
metabolized to uric acid, which damages cells
 Lesch-Nyhan syndrome
• there is a defect or lack in the HGPRT
enzyme
• the rate of purine synthesis is increased
about 200X
• uric acid level rises and there is gout
• in addition there are mental aberrations
• patients will self-mutilate by biting lips
and fingers off
Lesch-Nyhan syndrome
Salvage of purine bases
Nucleotide metabolism – Part 2
(pyrimidine biosynthesis)
 Synthesis of pyrimidine
ribonucleotides
• shorter pathway than for purines
• base is made first, then attached to ribose-P
(unlike purine biosynthesis)
• only 2 precursors (aspartate and glutamine,
plus HCO3-) contribute to the 6-membered ring
• requires 6 steps (instead of 11 for purine)
• the product is UMP (uridine monophosphate)
Origin of atoms in pyrimidine ring
The big picture
 Step 1: synthesis of carbamoyl
phosphate
• Condensation of glutamine, bicarbonate
in the presence of ATP
• Carbamoyl phosphate synthetase exists
in 2 types: CPS-I which is a
mitochondrial enzyme and is dedicated to
the urea cycle and arginine biosynthesis)
and CPS-II, a cytosolic enzyme used here
 Step 1: pyrimidine synthesis

CPS-II is the major site of regulation in animals: UDP and

UTP inhibit the enzyme and ATP and PRPP activate it
It is the committed step in animals
 Step 2: synthesis of carbamoyl
aspartate
• enzyme is aspartate transcarbamoylase
(ATCase)
• catalyzes the condensation of carbamoyl
phosphate with aspartate with the release of Pi
• ATCase is the major site of regulation in
bacteria; it is activated by ATP and inhibited
by CTP
• carbamoyl phosphate is an “activated”
compound, so no energy input is needed at this
step
Step 2: pyrimidine synthesis
 Step 3: ring closure to form
dihydroorotate
• enzyme: dihydroorotase
• forms a pyrimidine from carbamoyl
aspartate
• water is released in this process
Step 3: pyrimidine
synthesis
• the first 3 enzymatic reactions are catalyzed by
3 separate proteins/enzymes in E. coli
• in animals, all 3 steps are found in a
multifunctional enzyme (210 kD). This allows
“channeling” of the substrates and products
between active sites without releasing them to
the medium where they could be degraded.
• The acronym CAD is used as a name for the
multienzyme: carbamoyl phosphate synthetase,
aspartate transcarbamoylase and
dihydroorotase
• channeling also increases the overall rate of
multistep processes
 Step 4: oxidation of
dihydroorotate to orotate
• an irreversible reaction
• enzyme: dihydroorotate dehydrogenase
• oxidizing power is derived from quinones
(thru coenzyme Q)
Step 4: pyrimidine synthesis
 Step 5: acquisition of ribose
phosphate moiety
• enzyme: orotate phosphoribosyl
transferase
• ribose phosphate originates from PRPP
• product is orotidine-5’-monophosphate
(OMP)
• orotate phosphoribosyl transferase is also
used in salvage of uracil and cytosine to
their corresponding nucleotide
Step 5: pyrimidine synthesis
 Step 6: decarboxylation of OMP

• enzyme: OMP decarboxylase

• product: uridine monophosphate (UMP)
• in animals, steps 5 and 6 are catalyzed by
a single polypeptide with 2 active sites
Step 6: pyrimidine
synthesis
 PRPP
O

HO P O CH2 H
O
OH
O O
H H
O
H O P O P O-

HN O- O-
OH OH

O N COO-
orotate phosphoribosyl transferase PPi
H

O
O

HN
HN
O O
O N COO-
HO P O CH2 O N
O HO P O CH2
O
OH OH
CO2
H H H H
H H H
H
OMP decarboxylase
(uses no cofactors)
OH OH OH OH

orotidine monophosphate (OMP)

The big picture again
 Orotic aciduria
• an inherited human disease caused by a
deficiency in the multifunctional enzyme
that catalyzes the last 2 steps in the
pyrimidine synthesis
• large amounts of orotic acid in urine
• retarded growth and severe anemia
• treat by administration (injection) of
uridine and/or cytidine
 Leflunomide (Arava)
• Leflunomide is an isoxazole
immunomodulatory agent which inhibits
dihydroorotate dehydrogenase) and has
antiproliferative activity. Several in vivo and in
vitro experimental models have demonstrated
an anti-inflammatory effect.
• It is currently used as a DMARD in patients
with serious rheumatoid arthritis
Leflunomide (Arava)
 Activation of leflunomide

O H
O H
C N CF3
NC C C N CF3

C
N HO CH3
CH3
O

Opening of the isoxazole yields a reactive compound which

can then inhibit the enzyme dihydroorotate dehydrogenase
 Synthesis of uridine and cytidine triphosphate

UMP + ATP UDP + ADP

nucleoside diphosphate kinase
UDP + ATP UTP + ADP

CTP synthase (cytidylate synthetase)

O glutamine + Glutamate + NH2

ATP ADP +Pi
H
N
N

O N
O N
Ribose 3 phosphate
Ribose 3 phosphate
UTP CTP

(in bacteria, ammonia donates the amino group)

 Regulation of pyrimidine nucleotide
biosynthesis

Glutamine + carbamoyl phosph.

HCO 3- + Carbamoyl Orotate
ATP synthetase phosphate
orotate
phosphoribosyl
transferase

UTP + CTP UMP OMP

UTP and CTP are feeback inhibitors of CPS II

 Formation of deoxyribonucleotides
All pathways shown previously led to synthesis of ribonucleotides

ribonucleotide reductase

OH
Base OH
Base
OH P O CH2
O OH P O CH2
O
O H H
O H H
H H
H H
OH OH
OH H

dADP, dGDP, dUDP and dCDP are all synthesized by the same enzyme
Synthesized from nucleoside diphosphate (not mono or triphosphate) by
ribonucleotide reductase
 Synthesis of dTMP
• Methylation of d-UMP via N5,N10-
methylene THF
• Reaction inhibited by 5-fluorouracil
(Efudex)
 O H
H N N H
H2 N
HN
H
HN
O N H N
O-

-O P O CH 2 O O N R
H
O H
H H
H H

OH H

d-UMP

CH3 H
HN
H2 N N N H

O- O N H
HN
-O P O CH 2 O N

O H O H N R
H
H H

OH H
 H
H
H2N N N H
H2N N N H
H
H
HN
HN
N
N
O CH2 N R
O N R H
H
H

O O-

X X
HN HN
S cysteine attached to
protein
O N H O N H

R R
 H H
H2N N N H H2N N N H
H H
HN HN
N N
O N R O N R
O CH2
O H
X -B
on enzyme
HN CH2 XB
S HN
S
O N
H O N
R H
R
H O

H2N N N H CH3
HN
+
+ XB
HN
N O N H
-S
O N R R

H
 Activation of 5-fluorouracil

F
HN
O
O
O N H
HO P O CH2
F O
HN OH
H H
O N H H H

H
OH H
5-fluorouracil
 H
Glycine
H2 N N N H

H Serine
HN
N

O N R
H
H

thymidylate synthase
H
H
NADPH NADP+ H2 N N N H
H2N N N H
H
dihydrofolate reductase HN
HN N
N
O H N
O H N
H

ANTIFOLATES

OCH 3

H2 N N N H2 N N OCH 3

HN N
N OCH 3

NH2 H3 C N R NH2

Methotrexate Trimethoprim
Dihydrofolate reductase
Nucleotide metabolism – Part 3
(nucleotide degradation)
 Nucleotide degradation

Digestion: RNA + DNA Nucleotides Nucleosides

nucleosidase
Base + 1-P-ribose

base + ribose
 NH2 OH
Degradation H2 O NH3
N N
of AMP N N

AMP deaminase
N N N
N
Ribose-P Ribose-P
H2 O
H2 O
Nucleotidase
Nucleotidase Pi

Pi
O
NH2 NH3
H2O
N
N HN
N
Adenosine deaminase
N N
N N Pi
Ribose
Ribose Ribose-1-P
Purine nucleoside
phosphorylase
O

may be reused N
HN
through
salvage pathway
N N

H
hypoxanthine
 NH2
H2N OH
N N
N HN

N N N
N
Ribose Ribose

transition state
H
OH
N

HN
N
N
Ribose O

Pentostatin N
(a transition state analog) HN

shows promise in combination

with Ara-C (Vidarabine) N N

Ribose
MECHANISM OF ADENOSINE DEAMINASE
 PENTOSTATIN

previously called deoxycoformycin (DCF) H

OH
H
a purine analog with a 7-membered-ring N
N

potent inhibitor of adenosine deaminase N

N
ADA is a key enzyme which regulates
adenosine levels in cells HOCH2
O
H H
indicated for refractory hairy cell leukemia
H H

other uses: chronic lymphocytic leukemia OH H

and lymphomas 2'-DEOXYCOFORMYCIN
Adenosine deaminase
 ADA deficiency
• In the absence of ADA lymphocytes are
destroyed
• deoxyadenosine is not destroyed, is converted
to dAMP and then into dATP
• dATP is a potent feedback inhibitor of
deoxynucleotide biosynthesis
• this leads to SCID (severe combined
immunodeficiency disease)
• Infants with this deficiency have a high fatality
rate due to infections
 ADA deficiency
• treatment consists of administering
pegylated ADA which can remain in the
blood for 1 – 2 weeks
• more efficient is gene therapy: replacing
the gene that is missing or defective
• gene therapy has been performed on
selected patients
 O O

H N H N
N N

H2 N N N O N N

Ribose-P H Ribose-P
H2 O H2O
nucleotidase nucleotidase
Pi Pi

O
Degradation of O
H
GMP and XMP N
N H N
N

H2 N N N
O N N
Pi Ribose
Ribose
PNP H
Ribose-1P Pi
PNP
Ribose-1P
O
O
H N
N H N
N

H2 N N N
H2 O NH3 N
O N
H
H H
 NH2 OH

N N
N N N
N

N N H2N N N
N N
H H
H
ADENINE GUANINE
(6-AMINOPURINE) 2-AMINO-6-OXYPURINE) PURINE

OH OH OH

N N N
N N N
OH
N HO N N N
N HO N
H H H

HYPOXANTHINE XANTHINE URIC ACID

(6-OXYPURINE) (2,6-DIOXYPURINE) (LACTIM FORM)
 CATABOLISM OF PURINES
adenase
ADENINE + H 2O HYPOXANTHINE + AMMONIA

guanase XANTHINE + AMMONIA

GUANINE + H 2O

xanthine
HYPOXANTHINE + O 2 + H 2O oxidase XANTHINE + H 2O 2
xanthine
XANTHINE + O 2 + H 20 URIC ACID + H 2O 2
oxidase
 O O
H N H
N N
N

N N N
O N
O2 H202
H H
H
HYPOXANTHINE
XANTHINE

O2

H202

O O
H
H N H
N N
N
OH O
O N N N
O N
H H
H H
acidic proton
URIC ACID
 GOUT

• a disorder associated with abnormal

amounts of urates in the body
• early stage: recurring acute non-articular
arthritis
• late stage: chronic deforming polyarthritis
and eventual renal complication
• disease with rich history dating back to
ancient Greece
 GOUT

• once fashionable to associate gout with

intelligence
• people with gout:
– Isaac Newton
– Benjamin Frankin
– Martin Luther
– Charles Darwin
– Samuel Johnson
 Gout
• prevails mainly in adult males
• rarely encountered in premenopausal
women
• symptoms are cause by deposition of
crystals of monosodium urate
monohydrate (can be seen under
polarized light)
• usually affect joints in the lower
extremities (the big toe is the classic site)
Gout
 Four Stages of Gout

1. asymptomatic hyperuricemia
2. acute gouty arthritic attacks
3. asymptomatic intercritical period
4. tophaceous gout (characterized by the
formation of tophi in joints)
– podagra (big toe)
– cheiagra (wrist) according to Hippocrates
– gonadra (knee)
 Diagnostic features
• usually affect joints in the lower extremities
( 95%)
• onset is fast and sudden
• pain is usually severe; joint may be swollen,
red and hot
• attack may be accompanied by fever,
leukocytosis and an elevated ESR
 Drugs which may induce
hyperuricemia
• niacin
• thiazides and other diuretics
• low dose aspirin
• pyrazinamide
• ethambutol
• cyclosporine
• cytotoxic drugs
 Non-pharmacological
approaches
• Avoid purine rich foods:
– red meat and organ meat (liver, kidneys)
– shellfish, anchovies, mackerel, herring
– meat extracts and gravies
– peas and beans, aspargus, lentils
– beer, lager, other alcoholic beverages
• Weight loss
• Control alcohol (binge drinking)
 Pharmacological management of
gout
• based on the premise that the hyperuricemia is
due to both overproduction and
underexcretion of uric acid
• symptomatic relief of pain is also achieved
with analgesics (i.e. indomethacin)
• drugs used:
– analgesics (NSAIDs)
– uricosuric agents
– xanthine oxidase inhibitors
 Therapy of acute gout
• treat with colchicine or NSAIDs
• avoid aspirin
• do not treat with allopurinol or
uricosuric drugs
• uric acid lowering agents should never be
started or stopped during acute attack
• pain resolution occurs within 48-72 hrs
 Colchicine
CH 3O H
N

CH 3O C CH 3
O
OCH 3
O

OCH 3

COLCHICINE

a non-basic alkaloid from the seeds and corms of Colchicum autumnale

(Meadow Safron)
 COLCHICINE
• used in the symptomatic treatment of acute
attacks of gout
• decreases leukocyte motility, decreases
phagocytosis and lactic acid production
• not used in other forms of arthritis
• a very potent drug
• can cause severe GI distress and abdominal
pain
 Probenecid (Benemid)

O C3H7
HO2C S N

O C3H7

PROBENECID (BENEMID)
A uricosuric agent
 Probenecid (Benemid)

• inhibits the tubular reabsorption of uric acid

• it can also inhibit the tubular excretion of
certain organic acid via the transporter
• used in gout to promote the elimination of uric
acid (not effective in acute attack)
• also used to enhance plasma concentration of
certain antiinfectives (beta lactams)
 ALLOPURINOL (Zyloprim)
• prevention of attacks of gouty arthitis and
nephropathy
• also used during chemotherapy of cancer and
to prevent recurrent calcium oxalate calculi
• metabolized to oxypurinol (also an inhibitor
of xanthine oxidase)
• inhibits the metabolism of certain anticancer
drugs (6-MP, azathioprine)
 Allopurinol (Zyloprim)
OH

N
N

N N

ALLOPURINOL (ZYLOPRIM)

An inhibitor of xanthine oxidase; prevents the formation of uric acid from

precursorial purines
 Fate of uric acid
• in human and other primates uric acid is the final
product of purine degradation and is excreted in the
urine
• the same is true in bird, reptiles and many insects
• in other mammals uric acid is oxidized to allantoin
(urate oxidase)
• teleost (bony) fish convert allantoin to allantoic acid
• cartilaginous fish and amphibian further degrade
allantoic acid to urea
• and finally marine invertebrates decompose urea to
ammonia
 O
H
H
H N urate oxidase O
N N
O NH2
O
O N N
CO2 O N N
ALLANTOIN
H H
H H
H
URIC ACID
allantoinase

O
allantoicase H2N COOH NH2
H2N C NH2

UREA glyoxylic acid O N N O

H
H H

ALLANTOIC ACID
Rasburicase (Elitek)
A recombinant form of uric
acid oxidase. Used for initial
management of plasma uric
acid levels in pediatric
patients with leukemia,
lymphoma, and solid tumor
malignancies who are
receiving anticancer therapy
expected to result in tumor
lysis and subsequent elevation
of plasma uric acid.
Catabolism of a pyrimidine
 Formation of deoxyribonucleotides

• ribonucleotide reductase studied by JoAnne

Stubbe (Wisconsin, then MIT)
• very complex enzyme; contains:
• Tyrosine radical
• 2 non-heme irons
• Two catalytically active cysteine residues
• Cys are reduced by other proteins – thioredoxin
• Ribo. Reductase is the therapeutic target of the
anticancer drug hydroxyurea
 Mechanism of ribonucleotide
reductase
• Free radical mechanism involving tyrosyl
residues and cysteine residues on the
enzyme
• The enzyme is a dimer of dimers:
– R1 – a dimer of identical a subunits (85 kD
each)
– R2 – a dimer of identical b subunits (45 kD
each)
 Base Base
R O CH 2 R O CH 2
O O

H H H
H H OH H H
O
OH OH OH OH

Base
R O CH 2
O

SH SH SH S-
H
H H
H2 O
OH OH 2+

Base Base
R O CH 2 R O CH 2
O O
S -S
H
H H
H H H
H

OH OH H

Base
R O CH 2
O

H H
H H
OH O

OH H
 Reduction of the disulfide bond in
ribonucleotide reductase
• 2 proteins can perform this reductive
reaction:
– Thioredoxin (ubiquitous 12 kD monomer)
– Glutaredoxin which functions similarly to
thioredoxin. Oxidized glutredoxin is reduced
by glutathione (g-glutamylcysteinylglycine)
Regeneration of thioredoxin and ribonucleotide reductase
HYDROXYUREA (Hydrea)
• inhibits the enzyme ribonucleotide reductase
– this enzyme causes ribonucleotides to be converted to
deoxyribonucleotides
– DNA synthesis cannot occur
– cell are killed in the S phase
– drug holds other cells in the G1 phase
• primarily used to treat chronic myelogenous
leukemia H
• cancer cell develop resistance by: N OH

– increasing quantity of inhibited enzyme H2N

– decreasing sensitivity of enzyme for inhibitor O

• used orally HYDROXYUREA

• major side effect is leukopenia

 GEMCITABINE (Gemzar)
NH2

O N

HOCH 2
O
F

OH F

2',2'-DIFLUORODEOXYCYTIDINE

Another inhibitor of ribonucleotide reductase:indicated for

non-small cell lung cancer (usually with cisplatin) also first line
treatment for non-resectable pancreatic cancer
 H

H2 N N N

N
N

OH NR
O O H B

F F
HN HN

O N O N S
S
dRP dRP

H2 N N N
Inactivation of thymidylate synthase
by 5-fluoro-2'-deoxyuridylate
N
N

OH NHR
O

HN B
F

O S

dRP
The purine nucleotide cycle for
anaplerotic replenishment of citric acid
cycle intermediates in skeletal muscle