The common homocystinuria-associated P1173L variant of human methionine synthase impairs reductive methylation.

ABSTRACT: Human methionine synthase (MTR) is a cobalamin-dependent enzyme that catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. The enzyme is susceptible to oxidative inactivation and is repaired by methionine synthase reductase (MTRR) in the presence of NADPH and S-adenosylmethionine (AdoMet). The P1173L missense mutation is the most common clinical variant of MTR and causes homocystinuria, an inborn error of metabolism that is associated with aggressive occlusive cardiovascular diseases. In this study, we report that co-expression of MTR with the B₁₂ chaperone MMADHC helps overcome prior challenges with soluble expression of full-length human MTR. Kinetic analysis reveals that wild-type and P1173L MTR exhibit c

SUBMITTER: Guha A 

PROVIDER: S-EPMC12272874 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature