Human cystathionine β-synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the CXXC motif seen in the crystal structure of the truncated enzyme

Elevated levels of homocysteine, a sulfur-containing amino acid, are correlated with increased risk for cardiovascular diseases and Alzheimers disease and with neural tube defects. The only route for the catabolic removal of homocysteine in mammals begins with the pyridoxal phosphate- (PLP-) dependent β-replacement reaction catalyzed by cystathionine β-synthase. The enzyme has a b-type heme with unusual spectroscopic properties but as yet unknown function. The human enzyme has a modular organization and can be cleaved into an N-terminal catalytic core, which retains both the heme and PLP-binding sites and is highly active, and a C-terminal regulatory domain, where the allosteric activator S-adenosylmethionine is presumed to bind. Studies with the isolated recombinant enzyme and in transformed human liver cells indicate that the enzyme is ∼2-fold more active under oxidizing conditions. In addition to heme, the enzyme contains a CXXC oxidoreductase motif that could, in principle, be involved in redox sensin...