2012 Pentose Phosphate Pathway II

Pentose cycle, metabolism of
fructose and galactose
Vladimíra Kvasnicová
Syllabus of the lecture
1. use of glucose-6-phosphate in cells

2. glucuronic acid
3. pentose cycle
4. metabolism of fructose
5. metabolism of galactose
6. clinical correlations
MONOSACCHARIDES
glucose galactose fructose glucitol

(sugar alcohol)
H H
H H
H
ribose
glucuronic acid glyceraldehyde dihydroxyacetone
(sugar-derived acid) (simplest saccharides)
Monosaccharides
glucose
energy production (glycolysis)
energy storage (glycogen or conversion to fat)
conversion to other saccharides, e.g. ribose (pentose
phosphate cycle)
conversion to glucuronic acid (oxidation of glucose)
fructose ribose
conversion to glucose
nucleotide synthesis
energy production (glycolysis)
energy storage (conversion to fat) mannose
galactose synthesis of
conversion to glucose and lactose glycoproteins
synthesis of glycoproteins and proteoglycans

Synthesis of glucuronic acid
• synthesis of glycosaminoglycans
• conjugation reactions in the liver
adopted from http://www.kumc.edu/research/medicine/biochemistry/bioc800/car02fra.htm (Jan 2007)
PROTEOGLYCANS
core protein
+
glycosaminoglycans
(GAG)
(aminosugar-uronic acid)n
adopted from http://www.grandmeadows.com/archives/truth1.gif (October 2007)

Pentose phosphate pathway (cycle)
• also called „hexose monophosphate shunt“ due to glucose
oxidation in a form of a monophosphate (compared to glycolysis)
• it is an alternative oxidative breakdown of glucose using
NADP+, it looks like a „shunt of glycolysis“
• it does not produce ATP, NADH, FADH2 = no energy gain
from this pathway (no interconnection with respiratory chain)
• substrate: Glc-6-P / products: CO2, 2 NADPH, various
monosaccharides (their phosphates), mainly Rib-5-P
• regulatory enzyme: glc-6-P dehydrogenase, regulated by
NADP+/NADPH ratio; the enzyme deficiency results in
hemolytic anemia; insulin rises amount of the enzyme
• 2 parts: oxidative (irreversible) and interconversion of
sugar-phosphates (reversible)
• it proceeds either as a cycle (NADPH production), or as non-
cyclic (production of Rib-5-P for nucleotide synthesis)
Pentose cycle
(= Hexose MonoPhosphate Pathway, HMPP)
IRREVERSIBLE
REVERSIBLE
(interconversion of
saccharide
monophosphates)
adopted from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch15_pentose-alternatives.jpg

(Dec 2006)
The figure is found at http://web.indstate.edu/thcme/mwking/pentose-phosphate-pathway.html (Dec 2006)
synthesis of
nucleotides
intermediates of
glycolysis
The figure is found at http://web.indstate.edu/thcme/mwking/pentose-phosphate-pathway.html (Dec 2006)

The figure is found at http://www.richmond.edu/~jbell2/14F34.JPG (Dec 2006)
The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch15_pentose-
alternatives.jpg (Dec 2006)
Regulation of pentose cycle
• on the level of substrates availability and

products consumption
↑ NADPH / NADP+
reaction using NADP+ are inhibited by lack

of the coenzyme
Fructose
• sources in a diet:
sucrose = saccharose (Glc-Fru): cleaved by saccharase (intestine)
free in fruits („fruit sugar“ = fructose) and honey
• some fructose is converted to glucose in enterocytes, but
it is metabolized mainly in the liver
• fructokinase (Fru-1-P), hexokinase (Fru-6-P)
• aldolase B (deficiency: hereditary fructose intolerance)
• fructose does not increase insulin production, its entrance
to cells and metabolism is insulin-independent
• fructose-1-phosphate activates glycolysis (glucokinase) and
is metabolised faster than Glc (by passes PFK-1)
• fate: glycolysis, lipogenesis; synthesis of mannose (a component
of glycoproteins)
Metabolism of fructose in the liver
synthesis of TAG
glycolysis or gluconeogenesis
The figure is found at http://web.indstate.edu/thcme/mwking/glycolysis.html (Jan 2007)
Sorbitol
• sugar alcohol produced by reduction of a carbonyl-group
of fructose or glucose (hence its other name glucitol)
• sugar substitute: sweetener (E420) absorbs only a little in
GIT (polar compound)
• enzyme aldose reductase (glucose → sorbitol; NADPH): in
manny tissues, important in the liver, retina, eye lens,
peripheral nerves and kidneys (consequences in patiens with
hyperglycemia: osmotically active sorbitol binds water in cells, the
osmolarity change causes opacities of lenses, peripheral neuropathy
and vascular damages in kidneys and retina)
• sorbitol can be further oxidized to fructose by sorbitol

dehydrogenase (sorbitol → fructose; NAD+): important in
the liver and seminal vesicles (sperm. use Fru as energy source)
The figure was accepted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed.
Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2
Galactose
• blood concentration: 0 – 0,3 mM
• source in a diet: lactose (Gal-Glc) cleaved by lactase; also
formed by degradation of glycoproteins and glycolipids in lysosomes
• synthesis: from glucose (galactose is 4-epimer of glucose)
• entrance into cells is insulin-independent
• galactokinase (Gal-1-P), in many cells
• metabolised mainly in the liver to glucose
uridyl transferase: Gal-1-P + UDP-Glc → UDP-Gal + Glc-1-P
epimerase: UDP-Gal → UDP-Glc
• genetic deficiency of galaktokinase, epimerase or uridyl
transferase: results in galactosemia
• use: glycoproteins, glycolipids, glycosaminoglycans,
lactose in brest milk
Metabolism of galactose
epimerization
proceeds on
the level of
UDP-
derivatives
The figure is found at http://web.indstate.edu/thcme/mwking/glycolysis.html (Jan 2007)

GLYCOPROTEINS
adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005
ABO system (blood groups)
Fuc = L-deoxymonosaccharide fucose
adopted from http://www.life.umd.edu/classroom/bsci422/mosser/ABO.gif (March 2007)

Recapitulation
• glc-6-phosphate enters glycolysis, glycogen synthesis, pentose cycle,
and reactions converting glucose to galactose or glucuronic acid
• glucuronic acid is a product of glucose oxidation, it is used for the
synthesis of glycosaminoglycans and conjugation reactions in the liver
• pentose cycle proceeds either as a shunt of glycolysis or as an
alternative direct oxidation of glc-6-P by NADP+ to 6CO2 + 12 NADPH
- it is the main source of this coenzyme in cells
• common intermediates of pent.c. and glycolysis: glyceraldehyde-3-P
and fructose-6-P, they interconnect these two pathways
• products of pent.cycle: carbon dioxide, NADPH, ribose-5-P and other
phosphorylated monosaccharides
• fructose is metabolized faster than glucose, it is used for the
synthesis of amino-sugars and mannose - structural components of
glycosaminoglycans (= polysaccharides) and glycoproteins
• galactose is produced by epimerization of UDP-glucose, it is a
component of lactose and glycoproteins

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Pentose cycle, metabolism of

fructose and galactose

1. use of glucose-6-phosphate in cells

glucose galactose fructose glucitol

synthesis of glycoproteins and proteoglycans

adopted from http://www.grandmeadows.com/archives/truth1.gif (October 2007)

adopted from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch15_pentose-alternatives.jpg

The figure is found at http://web.indstate.edu/thcme/mwking/pentose-phosphate-pathway.html (Dec 2006)

• on the level of substrates availability and

reaction using NADP+ are inhibited by lack

• sorbitol can be further oxidized to fructose by sorbitol

The figure is found at http://web.indstate.edu/thcme/mwking/glycolysis.html (Jan 2007)

Fuc = L-deoxymonosaccharide fucose

adopted from http://www.life.umd.edu/classroom/bsci422/mosser/ABO.gif (March 2007)

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