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.

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis

“…1c). Overall, the addition of B12 had little-to-no effect on BDQ inhibition of Mtb growth, supporting the role of the MCC in BDQ-mediated inhibition of Mtb growth, with previous studies demonstrating the reduced capacity and biosynthetic role of the MMCoA pathway versus the high capacity and catabolic role of the MCC 50,51 .…”

Systems-wide dissection of organic acid assimilation in Pseudomonas aeruginosa reveals a novel path to underground metabolism

“…In M. tuberculosis , this detoxification is carried out by the constitutively expressed methylmalonyl-CoA (MMCO) pathway, which can quickly react to sudden changes in propionate concentration and detoxify the cell accordingly. By contrast, the role of the M. tuberculosis 2MCC appears to be as a “professional catabolizer”, with a higher overall flux capacity than the MMCO (63). The absence of a functional MMCO in Pa means that this organism depends exclusively on the 2MCC for both the assimilation and detoxification of propionate.…”

“…tuberculosis 2MCC appears to be as a "professional catabolizer", with a higher overall flux capacity than the MMCO (63). The absence of a functional MMCO in Pa means that this organism depends exclusively on the 2MCC for both the assimilation and detoxification of propionate.…”

Systems-Wide Dissection of Organic Acid Assimilation in Pseudomonas aeruginosa Reveals a Novel Path To Underground Metabolism

“…In M. tuberculosis , this detoxification is carried out by the constitutively expressed methylmalonyl-CoA (MMCO) pathway, which can quickly react to sudden changes in propionate concentration and detoxify the cell accordingly. By contrast, the role of the M. tuberculosis 2MCC appears to be as a “professional catabolizer,” with a higher overall flux capacity than the MMCO ( 65 ). The absence of a functional MMCO in Pa means that this organism depends exclusively on the 2MCC for both the assimilation and detoxification of propionate.…”