1qm4
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METHIONINE ADENOSYLTRANSFERASE COMPLEXED WITH A L-METHIONINE ANALOGOUS
OverviewOverview
Most of the transmethylation reactions use the same methyl donor, S-adenosylmethionine (SAM), that is synthesised from methionine and ATP by, methionine adenosyltransferase (MAT). In mammals, two MAT enzymes have, been detected, one ubiquitous and another liver specific. The liver enzyme, exists in two oligomeric forms, a tetramer (MAT I) and a dimer (MAT III), MAT I being the one that shows a higher level of affinity for methionine, but a lower SAM synthesis capacity. We have solved the crystal structure, of rat liver MAT I at 2.7 A resolution, complexed with a methionine, analogue: l-2-amino-4-methoxy-cis-but-3-enoic acid (l-cisAMB). The enzyme, consists of four identical subunits arranged in two tight dimers that are, related by crystallographic 2-fold symmetry. The crystal structure shows, the positions of the relevant cysteine residues in the chain, and that, Cys35 and Cys61 are perfectly oriented for forming a disulphide link. This, result leads us to propose a hypothesis to explain the control of MAT, I/III exchange and hence, the effects observed on activity. We have, identified the methionine-binding site into the active-site cavity, for, the first time. The l-cisAMB inhibitor is stacked against Phe251 aromatic, ring in a rather planar conformation, and its carboxylate group, coordinates a Mg(2+), which, in turn, is linked to Asp180. The essential, role of the involved residues in MAT activity has been confirmed by, site-directed mutagenesis. Phe251 is exposed to solvent and is located in, the beginning of the flexible loop Phe251-Ala260 that is connecting the, N-terminal domain to the central domain. We postulate that a, conformational change may take place during the enzymatic reaction and, this is possibly the reason of the unusual two-step mechanism involving, tripolyphosphate hydrolysis. Other important mechanistic implications are, discussed on the light of the results. Moreover, the critical role that, certain residues identified in this study may have in methionine, recognition opens further possibilities for rational drug design.
About this StructureAbout this Structure
1QM4 is a Single protein structure of sequence from Rattus norvegicus with SO4, MG, K and AMB as ligands. Active as Methionine adenosyltransferase, with EC number 2.5.1.6 Full crystallographic information is available from OCA.
ReferenceReference
The crystal structure of tetrameric methionine adenosyltransferase from rat liver reveals the methionine-binding site., Gonzalez B, Pajares MA, Hermoso JA, Alvarez L, Garrido F, Sufrin JR, Sanz-Aparicio J, J Mol Biol. 2000 Jul 7;300(2):363-75. PMID:10873471
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