Journal
STRUCTURE
Volume 10, Issue 9, Pages 1159-1171Publisher
CELL PRESS
DOI: 10.1016/S0969-2126(02)00796-7
Keywords
homocysteine; zinc; methyltransfer(beta/alpha)(8) barrel; thiolate ligands; signature sequences
Funding
- NCRR NIH HHS [RR07707] Funding Source: Medline
- NIDDK NIH HHS [DK52501] Funding Source: Medline
- NIGMS NIH HHS [GM16429] Funding Source: Medline
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Betaine-homocysteine methyl transferase (BHMT) catalyzes the synthesis of methionine from betaine and homocysteine (Hcy), utilizing a zinc ion to activate Hcy. BHMT is a key liver enzyme that is important for homocysteine homeostasis. X-ray structures of human BHMT in its oxidized (Zn-free) and reduced (Zn-replete) forms, the latter in complex with the bisubstrate analog, S(delta-carboxybutyl)-L-homocysteine, were determined at resolutions of 2.15 Angstrom and 2.05 Angstrom. BHMT is a (beta/alpha)(8) barrel that is distorted to construct the substrate and metal binding sites. The zinc binding sequences G-V/L-N-C and G-G-C-C are at the C termini of strands beta6 and beta8. Oxidation to the Cys217-Cys299 disulfide and expulsion of Zn are accompanied by local rearrangements. The structures identify Hcy binding fingerprints and provide a prototype for the homocysteine S-methyltransferase family.
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