Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.

Autor:	Doan MT; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Neinast MD; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Varner EL; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Bedi KC Jr; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Bartee D; Chemical Biology Laboratory, National Cancer Institute, Frederick MD, USA., Jiang H; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Trefely S; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Xu P; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Singh JP; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Jang C; Lewis Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ, USA., Rame JE; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Brady DC; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Meier JL; Chemical Biology Laboratory, National Cancer Institute, Frederick MD, USA., Marguiles KB; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Arany Z; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Snyder NW; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA. Electronic address: NateWSnyder@temple.edu.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2022 Jun; Vol. 63 (6), pp. 100224. Date of Electronic Publication: 2022 May 11.
DOI:	10.1016/j.jlr.2022.100224
Abstrakt:	Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13 C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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