# The metallophosphoesterase Rv0805 regulates carbon flux and cell envelope homeostasis during growth of mycobacteria in propionate

## TL;DR

This study shows that the enzyme Rv0805 helps mycobacteria process propionate, a byproduct of cholesterol, and maintain cell structure, which is crucial for their survival in the host.

## Contribution

The study identifies Rv0805 as a key regulator linking propionate metabolism and cell envelope integrity in mycobacteria.

## Key findings

- Loss of Rv0805 impairs propionate uptake and alters cell envelope lipid composition.
- Rv0805 is essential for carbon flux through the methylcitrate cycle during propionate metabolism.
- Vitamin B12 supplementation rescues growth by restoring metabolic balance in Rv0805-deficient mycobacteria.

## Abstract

Mycobacterium tuberculosis relies on host-derived lipids, including cholesterol, for intracellular survival, generating propionyl-CoA—a metabolite that must be efficiently assimilated to prevent toxicity. The metallophosphoesterase Rv0805 is required for optimal growth on cholesterol, and an Rv0805 knockout strain exhibits impaired ability to colonize the murine lung. However, the mechanisms underlying the essential role of Rv0805 under host-relevant conditions remain unclear. The deletion of the rv0805 ortholog (bcg_0857) in Mycobacterium bovis BCG reveals that both its catalytic activity and membrane localization are essential for growth on propionate, a by-product of cholesterol metabolism. Loss of Rv0805 impaired propionate uptake, altered cell envelope lipid composition with an accumulation of methyl-branched lipids, and reduced carbon flux through the methylcitrate cycle, ultimately depleting key central carbon metabolites required for growth. Vitamin B12 supplementation activated the methylmalonyl pathway, restoring metabolic balance and rescuing growth. These findings demonstrate that Rv0805 links propionate metabolism with cell envelope integrity, identifying its activity and localization as metabolic vulnerabilities that could be exploited for tuberculosis therapy.

Rv0805 links propionate metabolism with cell envelope homeostasis in mycobacteria, and its loss uncovers a metabolic vulnerability that could be exploited to restrict mycobacterial survival in lipid-rich host microenvironments.