HMP Shunt Pathway

Objective

At the end of this lecture, student will be able to

• Explain different steps in HMP shunt

• Explain the importance of HMP shunt

Hexose monophosphate pathway or HMP Shunt Pathway

• HMP shunt/ pentose phosphate pathway/phosphogluconate pathway

• An alternative pathway to glycolysis and TCA cycle for oxidation of glucose

• More anabolic in nature, i.e. biosynthesis of NADPH and pentoses

• Starts with G-6-P & no ATP is directly utilized or produced

• Enzymes are located in cytosol

• Tissues such as liver, adipose tissue, adrenal gland, erythrocytes, testes and lactating mammary gland are highly active in HMP shunt

• Reactions of the pathway: is divided into 2 phases, oxidative & Non- oxidative

1. Oxidative pathway

• G-6-P dehydrogenase is an NADP dependent enzyme that converts G-6-P to 6-phospho gluconolactone

• Gluconolactone hydrolase to hydrolysed 6-phosphogluconolactate to 6-phosphogluconate

• Synthesis of NADPH is catalysed by 6-phosphogluconate dehydrogenase to produce 3 keto 6-phosphogluconate which then undergoes decarboxylation to give ribulose-5-phosphate

• G6PD regulates HMP shunt, it catalyse an irreversible reaction

• NADPH competitively inhibits G6PD

2. Non-oxidative phase:

• Here, the reactions are concerned with the interconversion of three, four, five and seven carbon monosaccharides

• Ribulose-5-phosphate epimerse acted upon ribulose-5-phosphate to produce xylulose-5-phosphate, while ribose-5-phosphate ketoisomerase converts ribulose-5-phosphate to ribose-5-phosphate

• Enzyme transketolase catalyses the transfer of 2 carbon moiety from xylulose 5-phosphate to ribose 5-phosphate to give a 3-carbon glyceraldehyde 3-phosphate and 7-carbon sedoheptulose 7- phosphate

• Transketolase is dependent on the coenzyme TPP & Mg2+ ions

• Transaldolase brings about the transfer of 3-carbon fragment from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to give fructose 6-phosphate and four carbon erythrose 4-phosphate

• Transketolase acts on xylulose 5-phosphate and transfers a 2-carbon fragment (glyceraldehyde) from it to erythrose 4-phosphate to generate fructose 6-phosphate and glyceraldehyde 3-phosphate

• Fructose 6-phosphate & glyceraldehyde 3-phosphate can be further catabolized through glycolysis and TCA cycle

• Glucose may also be synthesized from these two compounds

The overall reaction may be represented as

6 Glucose-6-phosphate+ 12 NADP⁺+ 6H₂O → 6CO₂ +12 NADPH + 12H⁺ + 5 Glucose-6-phosphat

Significance of HMP pathway

• Generating 2 imp products, Pentoses &  NADPH needed for  the biosynthetic reactions and other functions

Importance of pentoses: i.e. ribose-5-phosphate

• Useful for the synthesis of nucleic acids (RNA & DNA)

• Synthesis of many nucleotides (ATP, NAD+, FAD and CoA)

Importance of NADPH

• Biosynthesis of fatty acids and steroids

• Synthesis of certain amino acids involving the enzyme glutamate dehydrogenase

3. Continuous production of H2O2 in the living cells which damage unsaturated lipids, proteins and DNA

• This is, however,  prevented to a large  extent through antioxidant reactions involving NADPH

• Glutathione mediated reduction of H2O2

• Glutathione (reduced, GSH) detoxifies H2O2, peroxidase catalyses this reaction & NADPH is responsible for regeneration of reduced glutathione from the oxidized one

4. Microsomal cytochrome P450 system in liver brings about the detoxification of drugs and foreign compounds by hydroxylation reactions involving NADPH

5. Phagocytises is the engulfment of foreign particles, requires NADPH

6. NADPH produced in erythrocytes has special functions to perform; lt maintains the concentration of reduced glutathione, which is essentially required to preserve the integrity of RBC membrane

7. NADPH is also necessary to keep the ferrous iron (Fe²⁺) of hemoglobin in the reduced state so that accumulation of methemoglobin (Fe³⁺) is prevented

Glucose G-phosphate dehydrogenase deficiency:

• More severe in RBC

• ↓se activity of G6PD impairs the synthesis of NADPH in RBC, which results in the accumulation of methemoglobin and peroxides in erythrocytes leading to hemolysis

• The drugs such as primaquine (antimalarial), acetanilide (antipyretic), sulfamethoxazole (antibiotic) or ingestion of fava beans (favism) produce hemolytic jaundice in these patients

• G6PD deficiency is associated with resistance to malaria (caused by

Wernicke-Korsakoff syndrome

• Genetic disorder associated with HMP shunt

• Inactivation of transketolase activity that reduces its affinity with TPP is the biochemical lesion

• Symptoms include mental disorder, loss of memory and partial paralysis

Summary

• An alternative pathway to glycolysis and TCA cycle for oxidation of glucose

• Reactions of the pathway is divided into 2 phases, oxidative & Non- oxidative

• Generate 2 imp products pentoses and ribose-5-phosphate

• Ribose-5-phosphate is ueful for the synthesis of nucleic acids

• NADPH is useful in biosynthesis of fatty acids and steroids

• G6PD deficiency leads to RBC hemolysis and wernicke-korsakoff syndrome

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