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Prof Viyatprajna Acharya, profile picture
Uploaded byProf Viyatprajna Acharya
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6 HMP SHUNT- alternate glucose oxidation pathway

How glucose is shunted to this minor pathway and what is its metabolic and clinical significance.

Health & Medicine◦
Related topics:
Vitamin C Overview•
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HMP SHUNT (Hexose Monophosphate shunt pathway) Prof DR. VIYATPRAJNA ACHARYA, MD, PhD Medical Biochemist
Learning objectives  What is PPP?  Why PPP?  Regulation of the pathway  Physiological significance  Clinical significance
HEXOSE MONOPHOSPHATE SHUNT  Synonym:  Pentose phosphate pathway (PPP)  Direct oxidative pathway  Phosphogluconate oxidative pathway  Dickens- Horecker pathway
Alternate glucose metabolic pathway  More anabolic than catabolic  NO ATP generation  NO ATP consumption  Ideal for tissues needing reducing power rather than energy  Gives metabolic flexibility to tissues  Can provide intermediates of glycolysis- Fructose-6-P, G-3-P  Can fulfill NADPH demand, Nucleotide demand, Energy demand
 10% glucose enters the pathway  RBC & Liver- 30% metabolism  Site: Cytoplasm  Location: L2 EAST Liver Lactating mammary gland Erythrocytes Adrenal cortex Skin Testes  Rapidly dividing cells, tumour cells, bone marrow, skin & intestinal mucosa- use PPP for generating nucleic acids and ATP, NADH, FADH2, Coenzyme A  Rest tissues use it for NADPH production- free radical scavenging and reductive biosynthesis
Overview I. Oxidative phase Hexose → Pentose II. Non-oxidative phase Pentose → Hexose
Oxidative phase
 Glucose-6-P dehydrogenase- Rate limiting enzyme  Requires NADP+  NADPH is a competitive inhibitor of G6PD  Inherited deficiency- X-linked disorder  Leads to Haemolysis  Drug induced hemolysis – Sulfamethoxazole, Furandantin Primaquin Acetaminophen  Favism – toxic glycosides of Fava beans-↓GSH level
Reduced GSH • SOD- Superoxide dismutase also requires NADPH • Free radical scavengers • Keep iron in Hb in ferrous (reduced form)- prevent MetHb formation
Free radical scavenging enzymes. GSH: glutathione.
Generation of reactive oxygen species in macrophages
Deficiency of G6PD advantageous too!!!  Malaria  Malarial parasite requires reduced GSH  Lack of G6PD- failure to thrive for malaria parasite
Non-oxidative phase
TPP TPP
SIGNIFICANCE OF PPP I. Provides NADPH- Reductive synthesis of FA FA chain elongation Cholesterol NT dNTP synthesis Steroid hormone synthesis
 NADH -reducing reactions in catabolic pathways, e.g. pyruvate to lactate.  Enters the electron transport chain- ATP is generated. • NADPH is used for reductive biosynthetic reactions • NADPH is not entering the electron transport chain; and NADPH will not generate ATP. NADP differs from NAD in having an additional phosphate group. These two coenzymes are specific for enzymes; They are not interchangeable. NAD and NADP are Different
II. NADPH required in detoxification reactions— a. Reduction of oxidized GSH b. Detoxification of drugs by Monooxygenases c. Cyt P 450 hydroxylation of aromatic compound d. Steroids, alcohols & drugs  Maintain the transparency of lens  Bactericidal activity of macrophages
Generation of pentoses Ribose -5-P –Biosynthesis of nucleotides Route for interconversion of pentoses and hexoses
Regulation of PPP  G6PD  NADPH decreases activity of G6PD  Fed state→ NADPH/ NADP ↓ + ratio ↓ PPP stimulated  Starvation & DM- ↓ PPP
CLINICAL SIGNIFICANCE  TPP coenzyme for Transketolase  Thiamine deficiency- RBC transketolase activity measured  Transketolase deficiency- Wernicke’s Korsakoff encephalopathy- Alcoholics or genetic deficiency  G6PD deficiency
It provides UDP-glucuronic acid, which is the active form of glucuronic acid. It is used for the following purposes: • Conjugation of bilirubin • Conjugation of steroids • Conjugation of various drugs which will make them more water soluble and more easily excretable. • Synthesis of glycosaminoglycans (GAG). Site The pathway is operating mainly in liver. Glucuronic Acid Pathway
Vitamin C Synthesis in Lower Animals The enzyme L-gulonolactone oxidase is absent in human beings, primates, guinea pigs and bats. Hence ascorbic acid cannot be synthesized by human beings. Essential Pentosuria It is an inborn error of metabolism. In the pathway, L- xylulose is converted to D-xylulose by two enzymes, xylitol dehydrogenase and xylulose reductase. Absence of any of these enzymes leads to pentosuria. L-xylulose is excreted in urine and gives a positive Benedict’s test. Barbiturates, aminopyrine, etc. will induce uronic acid pathway and will increase xylulosuria in such patients. This condition does not produce any harm; but it should be differentiated from diabetes mellitus.
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