Direct anabolic three carbon metabolism to a six carbon metabolite occurs in human heart and in vivo across mouse tissues

Abstract Anabolic metabolism of carbon in mammals is mediated via the one and two carbon carriers S-adenosyl methionine and acetyl-coenzyme A (acetyl-CoA). In contrast, anabolic metabolism using three carbon units via propionyl-CoA is not thought to occur. Mammals are primarily thought to oxidize 3-carbon units by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. We found that this may not be absolute and that in mammals one non-oxidative fate of two units of propionyl-CoA is to condense to a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). Using ex vivo isotope tracing, we found that 2M2PE-CoA formed in human myocardial tissue incubated with propionate. In whole-body in vivo stable isotope tracing with infusion of 13C-labeled valine achieving steady state, 2M2PE-CoA formed via propionyl-CoA in multiple murine tissues including heart, kidney, and to a lesser degree in brown adipose tissue, liver, and tibialis anterior muscle. These results confirm the in vivo existence of at least one anabolic three to six carbon reaction conserved in humans and mice that utilizes three carbons via propionate. Highlights - Ex vivo metabolism of propionate in the human heart includes anabolism of 3-carbon to a 6-carbon metabolite - In vivo fate of valine across mouse organs includes formation of a 6-carbon metabolite from propionyl-CoA - In both cases, this reaction occurred at physiologically relevant concentrations of propionate and valine