ArticleBiochemistry2011
Loss of allostery and coenzyme B12 delivery by a pathogenic mutation in adenosyltransferase.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- Clinical and Genetic Characterization of Isolated Methylmalonic Acidemia in Malaysian Children: Identification of Two NovelDiagnostics (Basel, Switzerland) · 2026Article
- Conformation-gated binding underlies kinetic asymmetry and negative cooperativity in ATP:cob(I)alamin adenosyltransferase.Cell reports. Physical science · 2025Article
- Cobalt-Sulfur Coordination Chemistry Drives BJournal of the American Chemical Society · 2023Article
- Coordination Chemistry Controls Coenzyme BInorganic chemistry · 2023Article
- Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme BProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria.Human genetics · 2022Article
- Mobile loop dynamics in adenosyltransferase control binding and reactivity of coenzyme BProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Mutational and Functional Analyses of Substrate Binding and Catalysis of theBiochemistry · 2020Article
- Cofactor Editing by the G-protein Metallochaperone Domain Regulates the Radical BThe Journal of biological chemistry · 2017Article
- Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies.Clinical genetics · 2015Article
- Autoinhibition and signaling by the switch II motif in the G-protein chaperone of a radical B12 enzyme.The Journal of biological chemistry · 2013Article
- A switch III motif relays signaling between a B12 enzyme and its G-protein chaperone.Nature chemical biology · 2013Article
- Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin.The Journal of biological chemistry · 2013Review
- The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning.Biochimie · 2013Article
- On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions.BMC genomics · 2012Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
ATP-dependent cob(I)alamin adenosyltransferase (ATR) is a bifunctional protein: an enzyme that catalyzes the adenosylation of cob(I)alamin and an escort that delivers the product, adenosylcobalamin (AdoCbl or coenzyme B(12)), to methylmalonyl-CoA mutase (MCM), resulting in holoenzyme formation. Failure to assemble holo-MCM leads to methylmalonic aciduria. We have previously demonstrated that only 2 equiv of AdoCbl bind per homotrimer of ATR and that binding of ATP to the vacant active site triggers ejection of 1 equiv of AdoCbl from an adjacent site. In this study, we have mimicked in the Methylobacterium extorquens ATR, a C-terminal truncation mutation, D180X, described in a patient with methylmalonic aciduria, and characterized the associated biochemical penalties. We demonstrate that while k(cat) and K(M)(Cob(I)) for D180X ATR are only modestly decreased (by 3- and 2-fold, respectively), affinity for the product, AdoCbl, is significantly diminished (400-fold), and the negative cooperativity associated with its binding is lost. We also demonstrate that the D180X mutation corrupts ATP-dependent cofactor ejection, which leads to transfer of AdoCbl from wild-type ATR to MCM. These results suggest that the pathogenicity of the corresponding human truncation mutant results from its inability to sequester AdoCbl for direct transfer to MCM. Instead, cofactor release into solution is predicted to reduce the capacity for holo-MCM formation, leading to disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.