Insights into the inhibitory mechanisms of NADH on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase.

ABSTRACT: Human NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the oxidative decarboxylation of isocitrate in the citric acid cycle. In the α₂βγ heterotetramer of NAD-IDH, the γ subunit plays the regulatory role and the β subunit the structural role. Previous biochemical data have shown that mammalian NAD-IDHs can be inhibited by NADH; however, the molecular mechanism is unclear. In this work, we show that the αβ, αγ and α₂βγ enzymes of human NAD-IDH can be inhibited by NADH, and further determine the crystal structure of the αγ heterodimer bound with an Mg²⁺ and an NADH at the active site and an NADH at the allosteric site, which resembles that of the inactive α^Mgγ heterodimer. The NADH at the active site occupies the binding site for NAD

SUBMITTER: Liu Y 

PROVIDER: S-EPMC5816668 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature