The terminal heme synthetic enzyme, coproheme decarboxylase, negatively regulates heme uptake in Mycobacterium tuberculosis.

Heme is an essential cofactor and dietary source of iron for the obligate human pathogen, Mycobacterium tuberculosis (Mtb). Consequently, heme is required for Mtb growth and pathogenicity, and strategies to limit heme represent a promising therapeutic approach. Although Mtb can both make and scavenge heme, it was previously found that de novo synthesized heme is substantially more bioavailable and metabolically active than exogenously scavenged heme. These findings provided a strong justification to target the terminal heme biosynthetic enzyme, coproheme decarboxylase (ChdC), in the development of antimycobacterial therapies. Herein, we sought to characterize heme homeostasis in a ΔchdC deletion mutant in Mtb. Surprisingly, we found that ablation of ChdC in Mtb and Mycobacterium smegmatis resulted in the enhanced accumulation and bioavailability of exogenously scavenged heme compared with WT or mutants lacking glutamyl tRNA reductase, the first enzyme in the heme synthetic pathway. Moreover, we found that Mtb has a preference for scavenging reduced ferrous heme and exhibits a heme reductase activity that is inhibited by ChdC. We further found that ChdC expression is downregulated when iron is limiting, which in turn increases both heme import and bioavailability. Such a mechanism may serve to protect cells from heme toxicity while trying to meet the nutritional demand for iron. Importantly, our results also suggest that caution must be taken if targeting ChdC because of feedback mechanisms that lead to enhanced heme scavenging in response to ChdC ablation.