SUBJECT: BIOCHEMISTRY
TOPIC: CARBOHYDRATE METABOLISM 3
LECTURER: DR. ESPERANZA UY
DATE: DECEMBER, 2010
ALTERNATIVE PATHWAY FOR CARBOHYDRATE
METABOLISM (for clearer images, pls. refer to the ppt)
Question: How many ATPs do you need in the conversion of
FRUCTOSE-6-PHOSPHATE to PYRUVATE?
Answer: 1 ATP only since we have already bypassed the
major regulatory pathway of glycolysis which is
PHOSPHOFRUCTOKINASE 1
- It is not recommended to carbo load on fructose
since it cannot be controlled (Phosphofructokinase
regulates the amount that the body requires)
Question: How many ATPs do you need in the conversion of
SUCROSE to PYRUVATE? (It will come out in the exam.)
Answer: 3 ATPs. Sucrose is formed by glucose and fructose.
From glucose to pyruvate, 2 ATPs are needed. For fructose
to pyruvate, 1 ATP is required. In conclusion, 3 ATPs are
required since 2 ATPs are needed for the breakdown of
glucose and 1 ATP is needed for the breakdown of fructose
ALTERNATIVE PATHWAY OF METABOLISM
-Pentose Phosphate Pathway
-Uronic Acid Pathway
-Fructose Metabolism
-Metabolism of Galactose
-Sorbitol Pathway
-Ethanol Metabolism
-Hexosamine Formation
 HEXOSE MONOPHOSPHATE SHUNT
-aka PENTOSE PHOSPHATE PATHWAY
-an ALTERNATE ROUTE for glucose oxidation
-not the main main pathway
-major pathway is GLYCOLYSIS
-found in the CYTOSOL
-active in: liver, adipose tissue, lactating mammary gland,
adrenal cortex and RBC
-common among these organs: all are secretory organs,
except for RBC
-5 carbons are produced in this pathway
-the 1 carbon will be produced as CO2
-the only pathway that produces CO2 in cytoplasm
-carbon dioxide is normally produced in the
mitochondria but in this pathway, the carbon dioxide is in
the cytoplasm
-NADPH is important in this pathway (PPP is the major
source of NADPH in cells)
BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3
-This pathway is used as an alternative when there is a high
demand for NADPH which is required in FATTY ACID
SYNTHESIS
TISSUE DISTRIBUTION
-Demand for NADPH
• Biosynthetic pathways
-fatty acid synthesis (liver, adipose, mammary)
-cholesterol synthesis (liver)
-steroid hormone synthesis (adrenal, ovaries, testes)
• Detoxification (Cytochrome P450 system)  liver
• Reduced glutathione as an antioxidant in RBC to
maintain the shape of RBC
-preventing hemolysis
• Generation of superoxide (neutrophils)
**All these conditions will cause an INCREASE in NADPH
demand which can lead to the hexose monophosphate
shunt
FUNCTIONS
-Source of:
1. NADPH + H+  for REDUCTIVE BIOSYNTHETIC
PROCESSES (synthesis of cholesterol, fatty acids, steroid
hormones)
-more important function
2. Pentoses  for nucleotides, nucleic acids and
coenzymes
CHARACTERISTICS
-neither consumes nor produce ATP
-that is why it is not the major pathway
-branches off glycolysis at G6P (common to both glycolysis
and HMP shunt)
-most important molecule in this pathway is GLUCOSE-6-
PHOSPHATE
-glucose should first be converted to glucose-6-
phosphate before entering the hexose monophosphate
shunt
-GLUCOKINASE in the liver and HEXOKINASE in the
muscles  enzymes needed for the conversion of glucose
to glucose-6-phosphate
-common enzyme in glycolysis and HMP shunt
-re-entry is at FRUCTOSE-6-PHOSPHATE
-PHOSOHEXOSE ISOMERASE enzyme required for the
conversion of glucose-6-phosphate to fructose-6-phosphate
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CHARACTERISTIC DIFFERENCE WITH GLYCOLYSIS
-oxidation utilizes NADP rather than NAD
-carbon dioxide is a characteristic product of HMP shunt
-only source of carbon dioxide in the cytoplasm
-increase demand for NADP happens where there is an
increase in demand for fatty acid synthesis
-NO ATP is generated
PENTOSE PHOSPHATE PATHWAY HAS 2 PHASES
A. Glucose-6-Phosphate is oxidized and
decarboxylated to a pentose sugar (generates 2
moles of NADPH per G6P oxidized) -irreversible
**GLUCOSE-6-PHOSPHATE  substrate used in HMP
shunt
-fructose-6-phosphate and glycogen can also be
used as a substrate but they should first be converted
to glucose-6-phosphate
B. Interconversions of pentose phosphates lead to
intermediates of glycolysis – reversible
**FRUCTOSE-6-PHOSPHATE and GLYCERALDEHYDE 
important intermediates of glycolysis
OXIDATIVE PHASE
-irreversible
-generates NADPH  2 moles per glucose oxidized
-3 reactions  starts with glucose-6-phosphate and results
in ribulose-5-phosphate
**3 glucose-6-phosphate molecules are required
**NADPH producing reactions/ important enzymes needed
in the oxidative phase:
• Glucose-6-phosphate dehydrogenase
-coenzyme: NADP
-water is also needed to be reduced to NADPH + H
-product: 6-PHOSPHOGLUCONATE
• 6-phosphogluconate dehydrogenase
-NADP is required in this step
-decarboxylates 6-phosphogluconate which RELEASES
CARBON DIOXIDE from the cytoplasm
-product: ribulose-5-phosphate
Question: Why do we need 3 glucose-6-phophate
molecules?
Answer: To produce 2 fructose-6-phosphate molecules and
1 glyceraldehyde molecule through the interconversion of
the pentoses
BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3
NON-OXIDATIVE PHASE
-starts in the ribulose-5-phosphate molecule
-reversible (can go anywhere)
-rearrangement of sugars to enter glycolytic pathway
-provides a pathway for recycling excess pentoses
IMPORTANT ENZYMES: (refer to the diagram below as well)
1) 3-epimerase
-to convert ribulose-5-phosphate to xylulose-5-phosphate
**epimerase  translocation in only carbon
2) Ketoisomerase
-to convert ribulose-5-phosphate to ribose-5-phosphate
3) Transketolase
-will transfer 2 carbon atoms from xylulose-5-phosphate
to ribose-5-phosphate to form glyceraldehyde-3-phosphate
and sedoheptulose-7-phosphate
-important coenzyme: THIAMIN (Vit. B1)
-important cofactor: MAGNESIUM (Mg+)
-source: unpolished rice
** blocking transketolase activity may lead to pentosuria (a
pentose sugar, usually xylulose, is found in urine
** thiamine deficiency affects sedoheptulose 7 phosphate
since it affects transketolase activity too
4) Transaldolase
-will transfer 3 carbon atoms
-sedoheptulose-7-phosphate is a very unstable
compound that is why it will be acted upon by
TRANSALDOLASE to form erythrose-4-phosphate and
fructose-6-phosphate which will then be converted to
glucose-6-phosphate through the enzyme
PHOSPHOHEXOSE ISOMERASE
**Another TRANSKETOLASE (similar with the transketolase
mentioned above) will act on xylulose-5-phosphate to be
converted to FRUCTOSE-6-PHOSPHATE and
GLYCERALDEHYDE-3-PHOSPHATE
5) Phosphotriose isomerise
-converts glyceraldehydes-3-phosphate to fructose-1,6-
bisphosphate
6) Fructose-1,6-bisphosphatase
-also found in GLUCONEOGENESIS because it uses the
fructose-1,6-bisphosphate as a substrate
-converts fructose-1,6-bisphosphate to fructose-6-
phosphate
**all the other enzymes are also found in the glycolysis
pathway except the FRUCTOSE-1,6-BIPHOSPHATASE which
is found in the gluconeogenesis pathway
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**1/2 glucose-6-phosphate glyceraldehyde
**3 glucose-6-phosphate molecules are required, 6
molecules of NADPH + H+ are produced and 3 CO2 from
the cytoplasm are released to have the product, xylulose-5-
phosphate  irreversible
**the reversible process will ultimately produce 2
molecules of glucose-6-phosphate and 1 molecule of
glyceraldehydes. All of the three molecules will enter the
glycolytic pathway
-entry point GLYCERALDEHYDE-3-PHOSPHATE
DEHYDROGENASE
**defiency in thiamine (VIt.B1)  problem in transketolase
enzyme. This can cause hemolytic anemia and jaundice
OVERALL EQUATION:
Glucose -6- PO4 + 2 NADP+ + H2O ↔
ribose -5- PO4 + 2NADPH + 2 H+ + CO2
GLUCOSE-6-PHOSPHATE DEFICIENCY
-problem in glucose-6-phosphate dehydrogenase enzyme
-not evident in most cases
-common in the Philippines (usually affects males, while
women are carriers)
-induced by drugs:
 Antimalarials
 sulfa antibiotics
 antipyretics (aspirins,etc.)
-acute haemolytic anemia is due to decreased NADPH
production
-HMP is the major pathway of NADPH production in the red
blood cell (G6PD deficient RBCs = more prone to hemolysis)
-NADPH is responsible for maintaining glutathione in its
reduced state
-reduced glutathione is necessary for the integrity of the
erythrocyte membrane, thus rendering enzyme-deficient
red cells more susceptible to hemolysis by a wide range of
compounds
-exposure to anti-malarial drugs (Primaquine) results in
increased cellular production of superoxide and hydrogen
peroxide (Primaquine sensitivity)
-other chemicals known to increase oxidant stress
-sulfonamides (antibiotic)
-aspirin and NSAIDs
-quinidine and quinine
-naphthalene (mothballs)
-fava beans (vicine and isouramil)
ROLE OF NADPH IN THE RBC
1.Production of superoxide
2.Hb-Fe2+-O2  Hb-Fe3+ + O2-
3.O2- + 2H2O  2H2O2
4.Both O2- and H2O2 can produce reactive free radical
species, damage cell membranes and cause hemolysis

REGULATION
DETOXIFICATION OF SUPEROXIDE ANION AND HYDROGEN
1.Glucose-6-phosphate dehydrogenase PEROXIDE (H202)
-first step; where regulation acts most -Antioxidant enzymes
-rate limiting step -superoxide dismutase
-most important regulator -glutathione peroxidise
-abundant in the RBC -if the glutathione is in the reduced state, hydrogen
2.Allosteric regulation peroxide will be converted to water

-feedback inhibited by NADPH -glutathione reductase

-increase amounts of NADPH will cease the HMP shunt

-increased NADPH also entails and increased amount
of H ion which decreases intracellular pH (becomes more
acidic); can shrink and wrinkle the cell
3.Inducible enzyme
-induced by insulin
-also found in the glycolytic and glycogenesis pathway
-increased amounts of insulin can induce the HMP shunt
Question: In the formation of lactate from glucose-6-
(since much glucose needs to be distributed)
phosphate, how many ATPs are needed?
Answer: 2 ATPs

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 3

 THE URONIC ACID PATHWAY GLUCORONIDES FORMATION
-also encountered in HEME METABOLISM (for more details,
see Bilirubin Conjugation)
-catalyzes the conversion of glucose to glucuronic acid,
ascorbic acid and pentoses
**GLUCORONIC ACID  to conjugate bilirubin so that it
can be more soluble in water
-also an alternative oxidative pathway for glucose
-does not lead to ATP formation GLUCURONIC ACID: PHYSIOLOGICAL SIGNIFICANCE OF
GLUCURONIDE FORMATION
G6P  G1P  UDP-Glucose  UDP- Glucoronic -glucuronide formation is important during detoxification,
Acid Glucoronic Acid  L-Gulonic Acid (a direct steroid excretion, and bilirubin metabolism
Vit. C precursor as well)  3-Keto-L-Gulonic Acid
-the reaction is catalyzed by UDP-glucuronyl transferase,
(+CO2) L-Xylulose Xylitol (usual candy which may take several days to 2 weeks after birth to
component)  D-Xylulose  D-Xylulose-5-P become fully active in humans
-babies are always exposed to the sun to hasten the
**conversion of glucose-6-phosphate to glucose-1- process of bilirubin solubility
phosphate was also encountered in glycogenolysis
**PENTOSURIA  blocks the L-xylulose  xylitol pathway  FRUCTOSE METABOLISM
-causes the presence of xylulose in the urine ESSENTIAL FRUCTOSURIA
**xylulose-5-phosphate will then enter the HMP shunt -fructokinase is deficient in essential fructosuria, a benign
**The L-gulonate has 2 pathways: 1 for the formation of asymptomatic metabolic anomaly; autosomal recessive
xylulose-5-phosphate and the other for the formation of -following intake of fructose, blood and urinary fructose
ascorbic acid. levels of affected individuals are unusually high; however,
-However, the formation of ascorbic acid is not possible 90% of their fructose intake is eventually metabolized
in higher forms of life since the L-gulonolactone 2-
ketogulonolactone pathway is BLOCKED. So in humans, the
only possible route is for it to be converted to xylulose-5-
phosphate which will now enter the HMP shunt
-this means that Vitamin C cannot be produced by the
body and supplements should be taken in to supply the
body with Vit.C
-high amounts of Vit.C in the body can lead to stones

**Fructose can also be a source of glucose through the

enzyme PHOSPHOFRUCTOISOMERASE
**hexokinase is still needed to form fructose-6-phosphate
**Aldolase A used in glycolysis
**Aldolase B  used in fructose metabolism
**Fructokinase  deficient in essential fructosuria
-no formation of fructose-1-phosphate and instead,
fructose from diet will be converted in the glycolysis
pathway (not that significant)
BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 4
HEREDITARY FRUCTOSE INTOLERANCE
-deficient aldolase B enzyme; autosomal recessive
-characterized by severe hypoglycaemia after ingestion of
fructose, and prolonged ingestion by affected young
children may lead to death
-fructose-1-phosphate aldolase is deficient and fructose 1-
phosphate accumulates intracellularly
-causes cataract formation
-will eventually go to the glycolytic pathway
 METABOLISM OF GALACTOSE
-from LACTOSE
-lactose  glucose + galactose
-abundant in human milk
-UDP-galactose is also formed from free galactose derived
from hydrolysis of lactose in the intestinal tract
-galactose is phosphorylated by galactokinase and ATP to
yield galactose-1-phosphate
-galactose-1-phosphate uridyltransferase froms UDP-
galactose from galactose 1-phosphate displacing glucose
1-phosphate from UDP-glucose
**1 ATP is required to form GALACTOSE-1-PHOSPHATE
**galactose-1-phosphate uridyl transferase came from
UDP-glucose from GLYCOGENOLYSIS PATHWAY
-blocked in galactosemia
BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3
GALACTOSEMIA
-inability to transform galactose into glucose
-individuals with this defect are unable to metabolize the
galactose derived from lactose (milk sugar) to glucose
metabolites
-can lead to cataract formation, growth failure, mental
retardation or death from liver failure
-may be due to deficiency of:
-GALACTOKINASE  leads to cataract formation
-GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE
leads to severe disease (liver disease)
**ALDOSE REDUCTASE which is abundant in the lens, liver,
mammary glands and kidneys
-through the NADPH from HMP shunt converts galactose
to GALATITOL which can cause cataracts
-not a significant enzyme, but only becomes important if
galactose levels are very high and a deficiency in
galactokinase
- Aldose Reductase Inhibitors = known side effects are
severe cardiovascular and GIT problems
> Classic Galactosemia – more severe than
galactosemia deficiency; patient may die at womb
 SORBITOL / POLYOL PATHWAY
-not found in the liver
-active in those tissues that are not insulin-sensitive
-lens
-peripheral nerves
-renal glomeruli
-maybe involved in the pathogenesis of diabetic cataracts
and diabetic peripheral neuropathy
-can have effects on the liver, lens and seminal vesicle (can
lead to infertility)
-found in the cytosol
**NADPH is needed
Page 5
  METABOLISM OF HEXOSAMINE OR AMINO SUGARS
-another mechanism in diabetic patients
-JUST REMEMBER: from glycogen, glycosaminoglycans,
sialic acid, gangliosides and glycoproteins in the brain can
be formed

COMPLEX POLYSACCHARIDES
-Glycoproteins
-Proteoglycans
**sorbitol dehydrogenase is not a very important enzyme
but only becomes essential if there is an increased amount
of glucose in the body GLYCOPROTEINS
**sorbitol pathway is NOT FOUND IN THE LIVER -conjugated proteins containing one or more saccharides
LACKING A SERIAL REPEAT UNIT and are bound covalently
**active in tissues that are not insulin sensitive
to a protein
**”UNIFYING PATHWAY OF DIABETICS”
-important in the biological functions of the membrane
**sorbitol attracts a lot of water
-constitutes of the mucus
-IMPORTANCE: lubrication and protection of the tissues
Night: Glycogenolysis: Glucose Fasting  inactive sorbitol lining the respiratory, GIT, and female reproductive system
pathway = clear eyesight
-examples: hormones, plasma proteins
Day: Gluconeolysis: Glucose Usage  active sorbitol
pathway = unclear eyesight (due to trapping in lens)
PROTEOGLYCANS
-contains 95% or more of carbohydrates
-carbohydrate chains are called GLYCOSAMINOGLYCANS or
MUCCOPOLYSACCHARIDES
-present in connective tissues
-6 classes:
-chondroitin sulfate
-dermatan sulfate
-keratin sulfate
-heparan sulfate
-heparin
-hyaluronate

GLYCOSAMINOGLYCANS (GAGs)
Common Features
1. GAGs are made up of dissacharide repeating units,
hexosamine and a uronic acid; highly (-) charged
2. they contain sulfate groups linked by ester bonds to
 ETHANOL METABOLISM certain monosaccharides orby amide bonds to the
amino group of glucosamine
Oxidation to acetate in the liver
3. only hyaluronate is not sulphated and is not
-ethanol is oxidized in the liver by CYTOSOLIC ALCOHOL attached to protein
DEHYDROGENASE to acetaldehyde
4. the carboxyls of uronic acids and the sulfate groups
-the acetaldehyde is further oxidized to acetate by contribute to the highly charged nature of GAGs
MITOCHONDRIAL ALDEHYDE DEHYDROGENASE
5. predominantly components of the extracellular
-much of the acetate produced from ethanol leaves the matrices and cell surfaces, and they participate in
liver and is converted by acetyl coA, which can be used to cell adhesion and signalling
provide energy via the TCA cycle
**GAGs are destroyed in diabetic nephropathy
-alcohol will be used for ATP production
-acetyl coA
may also be -------------------------------------END OF TRANX-------------------------------------
formed in the   GOODLUCK ON YOUR EVALUATIONS, BATCH 2014!  
liver and used
as a precursor
for lipid
biosynthesis

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 6