Differential utilization of vitamin B 12 -dependent and independent pathways for propionate metabolism across human cells.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Propionates*/metabolism ; Propionates*/pharmacology ; Vitamin B 12*/metabolism ; Methylmalonyl-CoA Mutase*/metabolism ; Methylmalonyl-CoA Mutase*/genetics; Humans ; Citric Acid Cycle ; Fibroblasts/metabolism ; Colon/metabolism
    • Abstract:
      Propionic acid links the oxidation of branched-chain amino acids and odd-chain fatty acids to the TCA cycle. Gut microbes ferment complex fiber remnants, generating high concentrations of short chain fatty acids, acetate, propionate and butyrate, which are shared with the host as fuel sources. Analysis of vitamin B 12 -dependent propionate utilization in skin biopsy samples has been used to characterize and diagnose underlying inborn errors of cobalamin (or B 12 ) metabolism. In these cells, the B 12 -dependent enzyme, methylmalonyl-CoA mutase (MMUT), plays a central role in funneling propionate to the TCA cycle intermediate, succinate. Our understanding of the fate of propionate in other cell types, specifically, the involvement of the β-oxidation-like and methylcitrate pathways, is limited. In this study, we have used [ 14 C]-propionate tracing in combination with genetic ablation or inhibition of MMUT, to reveal the differential utilization of the B 12 -dependent and independent pathways for propionate metabolism in fibroblast versus colon cell lines. We demonstrate that itaconate can be used as a tool to investigate MMUT-dependent propionate metabolism in cultured cell lines. While MMUT gates the entry of propionate carbons into the TCA cycle in fibroblasts, colon-derived cell lines exhibit a quantitatively significant or exclusive reliance on the β-oxidation-like pathway. Lipidomics and metabolomics analyses reveal that propionate elicits pleiotropic changes, including an increase in odd-chain glycerophospholipids, and perturbations in the purine nucleotide cycle and arginine/nitric oxide metabolism. The metabolic rationale and the regulatory mechanisms underlying the differential reliance on propionate utilization pathways at a cellular, and possibly tissue level, warrant further elucidation.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: beta-oxidation; cobalamin; glycerophospholipids; itaconate; odd-chain fatty acids; propionate; vitamin B(12)
    • Accession Number:
      0 (Propionates)
      P6YC3EG204 (Vitamin B 12)
      EC 5.4.99.2 (Methylmalonyl-CoA Mutase)
      JHU490RVYR (propionic acid)
    • Publication Date:
      Date Created: 20240811 Date Completed: 20241008 Latest Revision: 20241008
    • Publication Date:
      20241008
    • Accession Number:
      PMC11408853
    • Accession Number:
      10.1016/j.jbc.2024.107662
    • Accession Number:
      39128713