Abstract
Mycobacterium tuberculosis is the causative agent of tuberculosis and has evolved an ability to survive in hostile host environments. M. tuberculosis is thought to utilize the rTCA cycle to sustain its latent growth during infection, but the enzymatic characteristics and physiological function for the key citrate lyase of the rTCA cycle, MtbCitE, in the important pathogen remain unclear. In this study, we investigated the function of MtbCitE based on its structural properties and sequence comparisons with other bacterial citrate lyase subunits. We showed that several amino acid residues were important for the citrate cleavage activity of MtbCitE. Strikingly, the citrate cleavage activity of MtbCitE was inhibited by ATP, indicating that energy metabolism might couple with the regulation of MtbCitE activity, which differed from other CitEs. More interestingly, deletion of citE from Mycobacterium bovis BCG decreased the mycobacterial survival rate under hypoxic conditions, whereas complementation with citE restored the phenotype to wild-type levels. Consistently, three key rTCA cycle enzymes were positively regulated under hypoxic conditions in mycobacteria. Therefore, we characterized a unique citrate lyase MtbCitE from M. tuberculosis and found that the CitE protein significantly contributed to mycobacterial survival under hypoxic conditions.
Highlights
Mycobacterium tuberculosis infects one-third of the total human population because it can survive within the host for a long time in a latent form
CitE contributes to mycobacterial survival under hypoxic conditions energy production, and protein acetylation
Hypoxic conditions induce the expression of key rTCA cycle genes in both M. bovis BCG and M. tuberculosis H37Ra
Summary
Mycobacterium tuberculosis infects one-third of the total human population because it can survive within the host for a long time in a latent form. Previous studies demonstrated that M. tuberculosis may switch its metabolism pathway to a less energy-efficient status to adapt to oxygen-limiting conditions, leading to low ATP concentration in hypoxic cells [3]. The reductive side of the tricarboxylic acid (TCA) cycle is an important part of this strategy, and is shared by most of the enzymes in the TCA cycle; it allows carbon fixation under anaerobic conditions [4, 5]. Citrate lyase is one of the key enzymes of the rTCA cycle [6]. Citrate lyase is a cytoplasmic enzyme that catalyzes the conversion of citrate and CoA into oxaloacetate and acetyl-CoA.
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