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Lookup NU author(s): Dr Thomas McCorvieORCiD, Professor Wyatt YueORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. Vitamin B12 (cobalamin, Cbl) is required as a cofactor by two human enzymes, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylmalonyl-CoA mutase (MMUT). Within the body, a vast array of transporters, enzymes and chaperones are required for the generation and delivery of these cofactor forms. How they perform these functions is dictated by the structure and interactions of the proteins involved, the molecular bases of which are only now being elucidated. In this review, we highlight recent insights into human Cbl metabolism and address open questions in the field by employing a protein structure and interactome based perspective. We discuss how three very similar proteins—haptocorrin, intrinsic factor and transcobalamin—exploit slight structural differences and unique ligand receptor interactions to effect selective Cbl absorption and internalisation. We describe recent advances in the understanding of how endocytosed Cbl is transported across the lysosomal membrane and the implications of the recently solved ABCD4 structure. We detail how MMACHC and MMADHC cooperate to modify and target cytosolic Cbl to the client enzymes MTR and MMUT using ingenious modifications to an ancient nitroreductase fold, and how MTR and MMUT link with their accessory enzymes to sustainably harness the supernucleophilic potential of Cbl. Finally, we provide an outlook on how future studies may combine structural and interactome based approaches and incorporate knowledge of post-translational modifications to bring further insights.
Author(s): McCorvie TJ, Ferreira D, Yue WW, Froese DS
Publication type: Review
Publication status: Published
Journal: Journal of Inherited Metabolic Disease
Year: 2023
Volume: 46
Issue: 3
Pages: 406-420
Print publication date: 01/05/2023
Online publication date: 21/01/2023
Acceptance date: 19/01/2023
ISSN (print): 0141-8955
ISSN (electronic): 1573-2665
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/jimd.12593
DOI: 10.1002/jimd.12593
PubMed id: 36680553
