title: Betaine-homocysteine methyltransferase: zinc in a distorted barrel.
abstract: 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 A and 2.05 A. 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.
authors.affiliation: Biophysics Research Division and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Evans
authors.forename: Donald P
authors.initials: DP
authors.lastname: Huddler
authors.forename: Jiri
authors.initials: J
authors.lastname: Jiracek
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro
authors.forename: Norman S
authors.initials: NS
authors.lastname: Millian
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Garrow
authors.forename: Martha L
authors.initials: ML
authors.lastname: Ludwig
mesh_terms: D000595:Amino Acid Sequence; D050940:Betaine-Homocysteine S-Methyltransferase; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism*
chemical_list: D008780:Methyltransferases; C494548:BHMT protein, human; D050940:Betaine-Homocysteine S-Methyltransferase; D015032:Zinc