The group of Markos Koutmos at the University of Michigan, Ann Arbor, determined the crystal structure of full-length cobalamin-dependent methionine synthase. Methionine synthase (MS) is central to one-carbon metabolism, serving as the enzymatic link between the folate and methionine metabolic cycles. Defects in MS result in severe pathologies including megaloblastic anemia, and substantial birth abnormalities, such as neural tube defects. MS itself has been subject to decades of studies attempting to structurally and biochemically characterize its ability to achieve three distinct methylations using dynamic domain rearrangements, yet despite all this, the full-length structure of MS has so far eluded capture. Using a thermophilic homolog, the full-length structure of MS was captured, providing a structural and functional model for this dynamic enzyme. Additionally, cobalamin/cofactor-loading was captured in crystallo, revealing insights into holoenzyme formation. Through these findings, the researchers laid the groundwork for unraveling the mechanisms by which MS orchestrates large-scale domain rearrangements that enable chemically diverse methylations.
 |
Figure: The first structure of a full-length cobalamin-dependent methionine synthase from Thermus thermophilus (tMS) is shown on the left, colored by domain (yellow: Homocysteine binding domain (Hcy), green: Folate binding domain (Fol), pink: Cap, red: Cobalamin binding domain (Cob), blue: Activation domain (Act)). The Cobalamin binding domain (Cob) reveals restructuring upon cobalamin binding in crystallo (insets). |
Citation: Mendoza, J, Purchal, M, Yamada, K, Koutmos, M, Structure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo, Nat. Commun. 14, 6365 (2023). DOI: 10.1038/s41467-023-42037-4
GM/CA @ APS
