Heme degradation (heme -> biliverdin -> bilirubin)

Heme (iron-protoporphyrin IX), released chiefly from senescent-erythrocyte hemoglobin, is both an essential cofactor and, when free, a pro-oxidant; its controlled catabolism recovers iron, produces the signalling gas carbon monoxide, and generates the antioxidant bile pigments. Degradation proceeds in two enzymatic steps. First, heme oxygenase — the highly inducible, cytoprotective HMOX1 (HO-1/HSP32) and the constitutive HMOX2 (HO-2, an oxygen sensor in brain and vasculature) — uses molecular O2 and electrons from NADPH--cytochrome P450 reductase to oxidatively cleave the alpha-methene bridge of heme, releasing biliverdin IX-alpha, carbon monoxide (CO) and free ferrous iron (Fe2+); this is the rate-limiting step, and the iron is recaptured by ferritin while CO acts as a vasodilatory/anti-inflammatory messenger. Second, biliverdin reductase reduces the green biliverdin to the yellow, lipophilic, potently antioxidant bilirubin: the cytosolic NAD(P)H-dependent BLVRA acts on the major IX-alpha isomer (and additionally moonlights as a signalling kinase/scaffold), while the broad-specificity NADPH flavin reductase BLVRB reduces the IX-beta isomer (prominent in fetal heme catabolism) as well as flavins and other substrates. Bilirubin is subsequently glucuronidated (UGT1A1) for biliary excretion. Inherited defects cause severe systemic inflammation with hemolysis (HMOX1 deficiency) and green jaundice / hyperbiliverdinemia (BLVRA deficiency).