Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis

Abstract

The ability of science and medicine to control the pathogen Mycobacterium tuberculosis (Mtb) requires an understanding of the complex host environment within which it resides. Pathological and biological evidence overwhelmingly demonstrate how the mammalian steroid cholesterol is present throughout the course of infection. Better understanding Mtb requires a more complete understanding of how it utilizes molecules like cholesterol in this environment to sustain the infection of the host. Cholesterol uptake, catabolism and broader utilization are important for maintenance of the pathogen in the host and it has been experimentally validated to contribute to virulence and pathogenesis. Cholesterol is catabolized by at least three distinct sub-pathways, two for the ring system and one for the side chain, yielding dozens of steroid intermediates with varying biochemical properties. Our ability to control this worldwide infectious agent requires a greater knowledge of how Mtb uses cholesterol to its advantage throughout the course of infection. Herein, the current state of knowledge of cholesterol metabolism by Mtb is reviewed from a biochemical perspective with a focus on the metabolic genes and pathways responsible for cholesterol steroid catabolism.

Keywords: Catabolism; enzyme; metabolism; nutrition; pathway; persistence.

Figure 1

Cholesterol numbering scheme.

Figure 2

The commerically developed biological/chemical conversion of progesterone to hydrocortisone, pioneered by The Upjohn Company. The biological 11α-hydroxylation of progesterone was carried out by the fungus Rhizopus nigricans, followed by several chemical steps to ultimately give hydrocortisone.

Figure 3. Steroid ring degradation in bacteria

HSD: 3β-hydroxysteroid dehydrogenase; ChoE: cholesterol oxidase; KstD: ketosteroid dehydrogenase; KshA/B: 3-ketosteroid 9α-hydroxylase; HsaA/B: 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione 4-monooxygenase; HsaC: 3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione 4,5-dioxygenase; HsaD: 4,5-9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate hydrolase; HsaE: 2-hydroxyhexa-2,4-dienoate hydratase; HsaF: 4-hydroxy-2-oxohexanoate aldolase; HsaG: propanal dehydrogenase. Abbreviations of compound names: AD: 4-androstenedione; ADD: 1,4-androstenedione; 9OHADD: 9-hydroxy-androsta-1,4-diene-3,17-dione; 3-HSA: 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; 3,4-DSHA: 3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; 4,9-DSHA: 4,5–9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oic acid; HIP: 3aα-H-4α(3′-propanoyl-CoA)-7aβ-methylhexa-hydroindane-1,5-dione; HDD: 2-hydroxy-hexa-2,4-dienoic acid.

Figure 4

Steroid side chain degradation is initiated by Cyp125, and alternatively Cyp142. A FadD acyl-CoA ligase activates the resultant steroid carboxylic acid through esterification with CoA. The steroid side chain is truncated via three cycles of β-oxidation to yield acetyl-CoA, two units of propionyl-CoA, and a 3,17-dione steroid. The individual steps in the classical β-oxidation pathway are shown for the second cycle with solid arrows. Recently proposed alternate steps via an aldehyde (Holert et al., 2013a, Holert et al., 2013b) are shown as dashed arrows. The individual steps catalyzed in the third cycle are shown in Figure 5. Steps are labeled with specific enzyme names (see Table), if known.

Figure 5

The igr operon in Mtb. The β-oxidation chemistry catalyzed by the igr-operon encoded enzymes.

Figure 6

Cholesterol catabolism generates acetyl-CoA, propionyl-CoA, and pyruvate, which are fed into the metabolic pathways shown. PDIM: phthiocerol dimycoserate; SL-1: sulfolipid-1.