Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking

Froese, D. Sean; Kopec, J.; Fitzpatrick, Fiona; Schuller, M.; McCorvie, Thomas J.; Chalk, R.; Plessl, Tanja; Fettelschoss, Victoria; Fowler, Brian; Baumgartner, Matthias R.; Yue, Wyatt W.

doi:10.1074/jbc.m115.683268

Cited by 35 publications

(42 citation statements)

References 39 publications

(78 reference statements)

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“…This outcome is supported by the high proportion of truncating mutations and the loss of either protein stability or the ability to functionally interact with MUT in the case of missense mutations. These latter “loss of interaction” mutations are increasingly being found in the intracellular B 12 metabolic pathway, having already been identified in MMADHC, MMACHC (Froese et al., ) and MUT (Forny et al., ). This further points to complexation as required for proper B 12 pathway function, and future studies will clarify the residues required for physical and functional interaction, as well as how MMAB, and perhaps MCEE (methylmalonyl‐CoA epimerase), fit into this supramolecular multi‐protein machinery.…”

Section: Discussionmentioning

confidence: 92%

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

et al. 2017

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Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations. We biochemically investigated how missense mutations in MMAA in 22 patients lead to disease. About a third confer instability to the recombinant protein in bacterial and human expression systems. All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding. However, all mutations strongly decreased functional association with MUT by reducing GTPase activity stimulation upon incubation with MUT, while nine mutant proteins additionally lost the ability to physically bind MUT. Finally, all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT. This work suggests loss of functional interaction between MMAA and MUT as a disease-causing mechanism that impacts processing and assembly of a cofactor to its destination enzyme.

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Section: Discussionmentioning

confidence: 92%

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

et al. 2017

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“…Mutation of MMACHC , which occurs in patients with the cblC defect, results in decreased availability of Cbl for downstream enzymes, and the inability of cells to metabolize and therefore utilize certain Cbl forms (eg, CNCbl). Following reduction to cob(II)alamin, MMACHC‐chaperoned Cbl is then targeted to either MS or MUT by methylmalonic aciduria cblD type with homocystinuria (MMADHC), a protein which interacts with MMACHC only after MMACHC has bound and processed Cbl . MMADHC contains a mitochondrial leader sequence at its N‐terminus, and has been identified in both the cytosol and mitochondria .…”

Section: Intracellular Cobalamin Transport and Modificationmentioning

confidence: 99%

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Froese

Fowler

Baumgartner

2019

J of Inher Metab Disea

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166

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Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.

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“…Within the cytosol, the MMACHC protein binds, dealkylates, and decyanides Cbl. The MMADHC protein targets the MMACHC‐Cbl complex to process Cbl to its cofactor function sites in the cytosol and/or the mitochondria.…”

Section: Cbl‐dependent Remethylation Disorders Mthfr and Mthfd Deficmentioning

confidence: 99%

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

J of Inher Metab Disea

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This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl‐dependent remethylation. Acquired and inborn Cbl‐related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl‐dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net‐effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

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Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking

Cited by 35 publications

References 39 publications

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

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Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking

Cited by 35 publications

References 39 publications

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

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Product

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Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation