Methemoglobin (MetHb) contains iron in the Fe³⁺ state. Which enzyme system normally reduces MetHb back to functional Hb, and what electron donor does it use?

• A Glutathione reductase using NADPH from the pentose phosphate pathway
• B Cytochrome b5 reductase (diaphorase I) using NADH generated by glycolysis, reducing cytochrome b5 which then reduces MetHb ✓
• C Methemoglobin reductase using ascorbate as the direct electron donor
• D Catalase using hydrogen peroxide as an oxidant to regenerate Fe²⁺ in hemoglobin

Explanation

Normally, MetHb (Fe³⁺) is continuously formed (~1–3%) and reduced back by NADH-cytochrome b5 reductase (also called diaphorase I). NADH from glycolysis reduces cytochrome b5 (a small heme protein in the RBC membrane), which then donates an electron to MetHb Fe³⁺, reducing it to Fe²⁺. This system handles the physiologic methemoglobin load. A secondary pathway using NADPH-methemoglobin reductase is present but requires methylene blue as a cofactor and is the basis for methylene blue treatment of acquired MetHb toxicity (from nitrites, dapsone). Ascorbate is a minor, non-enzymatic pathway.

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

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