More than cholesterol catabolism: regulatory vulnerabilities in Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is the epitome of persistent. Mtb is the pathogen that causes tuberculosis, the leading cause of death by infection worldwide. The success of this pathogen is due in part to its clever ability to adapt to its host environment and its effective manipulation of the host immune system. A major contributing factor to the survival and virulence of Mtb is its acquisition and metabolism of host derived lipids including cholesterol. Accumulating evidence suggests that the catabolism of cholesterol during infection is highly regulated by cholesterol catabolites. We review what is known about how regulation interconnects with cholesterol catabolism. This framework provides support for an indirect approach to drug development that targets Mtb cholesterol metabolism through dysregulation of nutrient utilization pathways.

Figure 1. The regulatory network of cholesterol catabolism and utilization is a vulnerable drug target

Cholesterol metabolites induce the expression of genes in the KstR1, KstR2, and Mce3R regulons. Enzymes encoded in the KstR1 and KstR2 regulons catabolize cholesterol and are regulated by PTMs, cAMP, and mycothiol potential. The Mce3R regulon influences stress resistance and is targeted by 6-azasteroids. cAMP regulates protein acyltransferases and cAMP production is increased by small molecule V-58.

Figure 2. Post-translational Regulation of Cholesterol Catabolism

Cholesterol catabolic enzymes are post-translationally regulated by acetylation, succinylation, and redox potential. (A) The cholesterol catabolic pathway and the enzymes involved that are post-translationally regulated. (B) The different post-translational regulatory mechanisms for catabolic enzymes. The cAMP-dependent MtPat acetylates lysine and this modification is removed by NAD⁺-dependent sirtuin, CobB. CobB also functions as a desuccinylase. Disulfide formation in FadA5 regulates catalytic activity and is reversible.

Figure 3. Post-translational Regulation of Cholesterol Catabolite Metabolic Network

The thioester catabolites of cholesterol degradation are utilized in various metabolic pathways. Propionyl-CoA is consumed by the methylcitrate cycle and methylmalonyl-CoA pathway. Acetyl-CoA is a substrate for the TCA cycle and the glyoxylate cycle. Pyruvate is transformed into acetyl-CoA and succinyl-CoA is converted to succinate. Various proteins in this metabolic network have been identified as carrying marks for acetylation and succinylation.