In the HMP (pentose phosphate) shunt, glucose-6-phosphate dehydrogenase catalyzes the rate-limiting step. Which metabolite most potently inhibits this enzyme, and what is the physiological consequence in oxidative stress?

• A NADH inhibits G6PD; high glycolytic flux suppresses the shunt
• B ATP inhibits G6PD; low energy states activate the shunt for pentose synthesis
• C NADPH inhibits G6PD; in oxidative stress, NADPH depletion (due to demand) relieves this inhibition, activating the shunt ✓
• D Oxidized glutathione (GSSG) inhibits G6PD; reduced glutathione levels cannot be restored

Explanation

G6PD is product-inhibited by NADPH. Under normal conditions, high NADPH keeps the shunt relatively quiescent. During oxidative stress, NADPH is rapidly consumed to regenerate GSH (via glutathione reductase) to neutralize H2O2. The fall in NADPH removes product inhibition, dramatically increasing G6PD activity and NADPH regeneration. In G6PD-deficient patients, this compensatory acceleration cannot occur, leading to GSH depletion, Heinz body formation, and hemolytic crisis.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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