Describe the HMP shunt with its reactions and significance. Explain the importance of NADPH and add a note on G6PD deficiency.

Definition

• The tissues listed all have either active lipid synthesis or a high oxidative stress load — which is exactly what NADPH is needed for

The Two Phases

A. Oxidative (irreversible) phase

Glucose-6-phosphate → glucose-6-phosphate dehydrogenase (G6PD) — rate-limiting; NADPH produced → 6-Phosphogluconolactone → Lactonase → 6-Phosphogluconate → 6-Phosphogluconate dehydrogenase — NADPH + CO2 → ribulose-5-phosphate

• 2 NADPH are produced per glucose-6-phosphate
• G6PD is regulated by the NADP+:NADPH ratio — NADPH inhibits it, so the pathway runs only when NADPH is being consumed

B. Non-oxidative (reversible) phase

• Ribulose-5-phosphate is converted to ribose-5-phosphate (isomerase) or xylulose-5-phosphate (epimerase)
• Transketolase transfers 2-carbon units; requires thiamine pyrophosphate
• Transaldolase transfers 3-carbon units; no coenzyme
• These interconvert sugars of 3, 4, 5, 6 and 7 carbons, ultimately yielding fructose-6-phosphate and glyceraldehyde-3-phosphate, which rejoin glycolysis
• Because it is reversible, the cell can make ribose without making NADPH, or the reverse, according to need

Functions of Nadph

Functions of Ribose-5-phosphate

• Synthesis of nucleotides — ATP, GTP, NAD, FAD, CoA
• Synthesis of DNA and RNA (as deoxyribose, via ribonucleotide reductase)
• Essential in rapidly dividing tissues — bone marrow, gut mucosa, tumours

Significance in the Red Blood Cell

RBC constantly exposed to oxygen → free radicals → Glutathione peroxidase destroys H2O2, becoming GSSG → Glutathione reductase needs NADPH to regenerate GSH → NADPH comes only from the HMP shunt in the RBC → Without it: haemoglobin and membrane proteins oxidised → Heinz bodies → haemolysis

• The RBC has no other source of NADPH, having no mitochondria and no malic enzyme activity of consequence — which is why G6PD deficiency shows itself there first

Regulation and Interaction with Other Pathways

• The reversibility of the non-oxidative phase is what makes this flexibility possible — the cell is never forced to make one product to obtain the other
• G6PD is the control point, governed by the NADP+:NADPH ratio rather than by hormones
• Insulin induces G6PD in the fed state, linking the shunt to lipogenesis

Applied Aspects

• G6PD deficiency — the commonest enzymopathy in the world, affecting about 400 million people; X-linked; acute haemolysis on exposure to oxidant drugs, fava beans or infection
• Chronic granulomatous disease — defective NADPH oxidase → neutrophils engulf but cannot kill catalase-positive organisms → recurrent abscesses. Diagnosed by the NBT or DHR test
• Thiamine deficiency impairs transketolase — the basis of the erythrocyte transketolase activity test for thiamine status
• Wernicke–Korsakoff syndrome is associated with a transketolase variant of low thiamine affinity in some patients
• Tumours up-regulate the HMP shunt for both NADPH and ribose — a target for anticancer drugs
• Adrenal cortex and gonads have very high shunt activity — steroid hydroxylations consume NADPH heavily
• The lactating mammary gland runs the pathway hard to supply NADPH for milk fat synthesis
• Ribose-5-phosphate for nucleotide synthesis makes the pathway essential in bone marrow and any regenerating tissue
• Sepsis and chronic infection deplete NADPH through the respiratory burst, which can unmask borderline G6PD deficiency