{"doi":"10.1016/j.jlr.2022.100224","title":"Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species","abstract":"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 13C-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.","journal":"Journal of Lipid Research","year":2022,"id":287405,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9416,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":225540,"name":"Michael D. Neinast","orcid":"0000-0003-4032-8142","position":1,"is_corresponding":false},{"id":261601,"name":"Erika L. Varner","orcid":null,"position":2,"is_corresponding":false},{"id":236208,"name":"Kenneth Bedi","orcid":"0000-0003-3588-9324","position":3,"is_corresponding":false},{"id":260635,"name":"David Bartee","orcid":"0000-0001-8090-4242","position":4,"is_corresponding":false},{"id":563929,"name":"Helen Jiang","orcid":null,"position":5,"is_corresponding":false},{"id":237763,"name":"Sophie Trefely","orcid":"0000-0003-3816-6869","position":6,"is_corresponding":false},{"id":421460,"name":"Peining Xu","orcid":null,"position":7,"is_corresponding":false},{"id":563068,"name":"Jay Prakash Singh","orcid":"0000-0002-8113-0936","position":8,"is_corresponding":false},{"id":225539,"name":"Cholsoon Jang","orcid":"0000-0001-6651-4213","position":9,"is_corresponding":false},{"id":563072,"name":"J. Eduardo Rame","orcid":"0000-0002-2936-1702","position":10,"is_corresponding":false},{"id":255608,"name":"Donita C. Brady","orcid":"0000-0002-2786-2802","position":11,"is_corresponding":false},{"id":232494,"name":"Jordan L. Meier","orcid":"0000-0002-0537-7101","position":12,"is_corresponding":false},{"id":967900,"name":"Kenneth B. Marguiles","orcid":null,"position":13,"is_corresponding":false},{"id":225545,"name":"Zoltàn Arany","orcid":"0000-0003-1368-2453","position":14,"is_corresponding":false},{"id":237765,"name":"Nathaniel W. Snyder","orcid":"0000-0001-5643-8747","position":15,"is_corresponding":false},{"id":563069,"name":"Mary T. Doan","orcid":"0000-0001-6295-4895","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T00:30:01.051685Z","pmid":"35568254","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}