A 35-year-old farmer presents to the emergency department with acute onset of severe muscle weakness, tachycardia, and hypotension following accidental exposure to an insecticide containing inorganic arsenic. Laboratory studies show profound hypoglycemia and markedly elevated lactate levels. The structure marked **D** in the glycolysis pathway diagram is the primary target of arsenic toxicity in this patient. Which of the following best explains the mechanism by which arsenic impairs the function of this enzyme and leads to the observed metabolic derangement?

Explanation

## Why "Arsenate substitutes for inorganic phosphate..." is right The structure marked **D** (GAPDH) catalyzes the oxidation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, the only step in glycolysis that produces NADH and couples oxidation to phosphorylation. Arsenic toxicity exploits this mechanism: arsenate (AsO₄³⁻) structurally mimics inorganic phosphate (PO₄³⁻) and enters the active site of GAPDH. It forms 1-arseno-3-phosphoglycerate, which is thermodynamically unstable and hydrolyzes spontaneously without transferring its energy to ADP. This uncouples oxidation from phosphorylation, blocking ATP synthesis while glycolysis continues, leading to energy depletion, lactate accumulation, and the acute metabolic crisis observed in this patient. This is the classic mechanism of arsenic poisoning and a high-yield forensic-biochemistry fact (Harper 32e, Ch 18). ## Why each distractor is wrong - **"Arsenic directly inhibits the NAD+ binding site..."**: While GAPDH does require NAD+ as a cofactor, arsenic does not directly inhibit NAD+ binding. The mechanism is substrate-level (phosphate mimicry), not cofactor inhibition. NAD+ remains available but cannot be regenerated efficiently because the product is unstable. - **"Arsenic competitively inhibits pyruvate kinase..."**: Pyruvate kinase (marked **C**, not **D**) is not the primary target of arsenic. Although pyruvate kinase is important, the question explicitly anchors on **D** (GAPDH), and arsenic's lethal effect is through GAPDH inhibition and uncoupling of phosphorylation. - **"Arsenic chelates magnesium cofactors required for phosphofructokinase..."**: Phosphofructokinase (marked **B**, not **D**) does require Mg²⁺, but arsenic does not primarily chelate magnesium. This distractor confuses the target enzyme and the mechanism of arsenic toxicity. **High-Yield:** GAPDH is the only NADH-producing step in glycolysis and the Achilles' heel of arsenic poisoning—arsenate mimics phosphate, forms an unstable arseno-intermediate, and uncouples ATP synthesis, causing acute energy failure. [cite: Harper 32e, Ch 18 — Glycolysis and Energy Metabolism; arsenic poisoning mechanism in biochemistry and forensic toxicology]