Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria

Abstract Tuberculosis remains a major global health threat with over 1.5 million deaths each year. Mycobacterium tuberculosis’ success story is related to a flexible metabolism, allowing growth despite restrictive conditions within the human host. Host lipids stores are a major carbon source in vivo. Their catabolism yields propionyl-CoA, which is processed by two parallel pathways, the methylmalonyl CoA pathway and the methylcitrate pathway. Both pathways are considered potential drug targets. The methylcitrate pathway is upregulated in the pathological context. However, intermediates of this pathway can be cytotoxic and Mtb’s preference for its usage remains unclear. We combine thermodynamic kinetic modeling, quantitative proteomics and time-resolved metabolomics to characterize the interplay between the two pathways and to show their functionalities in an efficient and fast propionate catabolism. We find that the methylcitrate pathway acts as a transcriptionally regulated, high capacity catabolic pathway due to its favorable thermodynamics and metabolic control distribution. In contrast, the methylmalonyl pathway is constitutively fulfilling biosynthetic tasks and can quickly detoxify propionate pulses, but is thermodynamically restricted to lower capacity.