Wernicke's encephalopathy in a chronic alcoholic is due to thiamine deficiency. Which biochemical reactions are impaired, explaining the selective vulnerability of high-metabolic-demand brain regions?

• A Pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase — all TPP-dependent — are impaired, reducing acetyl-CoA supply to TCA, alpha-ketoglutarate to succinyl-CoA, and HMP shunt flux, causing energy failure and oxidative stress ✓
• B Only transketolase is impaired in the brain, reducing NADPH and causing oxidative damage
• C Thiamine is required for ATP synthesis directly as a component of Complex V
• D Thiamine deficiency inhibits acetylcholine synthesis because TPP is required by choline acetyltransferase

Explanation

Thiamine pyrophosphate (TPP) is the cofactor for three major enzyme complexes: pyruvate dehydrogenase (pyruvate → acetyl-CoA), alpha-ketoglutarate dehydrogenase (α-KG → succinyl-CoA in TCA), and transketolase (HMP shunt). Impairment of these three enzymes together reduces glucose oxidation, impairs TCA cycle flux, and depletes NADPH, causing energy failure and oxidative stress in the metabolically active mammillary bodies, periaqueductal grey, and thalamus. Erythrocyte transketolase activity (with and without added TPP — the 'TPP effect') is a sensitive functional test for thiamine deficiency.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.