Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system

Abstract

The Mycobacterium tuberculosis genome encodes twenty cytochrome P450 enzymes, most or all of which appear to have specific physiological functions rather than being devoted to the removal of xenobiotics. However, in many cases their specific functions remain obscure. Considerable spectroscopic, biophysical, crystallographic, and catalytic information is available on nine of these cytochrome P450 enzymes, although gaps exist in our knowledge of even these enzymes. The available evidence indicates that at least three of the better-characterized enzymes are promising targets for antituberculosis drug discovery. This review summarizes the information on the nine relatively well-characterized cytochrome P450 enzymes, with a particular emphasis on CYP121, CYP125, and CYP142 from Mycobacterium tuberculosis and Mycobacterium smegmatis.

Keywords: Azole drugs; Cholesterol degradation; Cytochrome P450; Enzyme inhibitors; Mycobacterium tuberculosis.

Fig. 1

The three sequential reactions of the cholesterol biosynthetic pathway catalyzed by CYP51.

Fig. 2

Intramolecular crosslinking of the L-Tyr-L-Tyr cyclodipeptide catalyzed by CYP121A1.

Fig. 3

Structure of the sulfolipid S881 and the role of CYP128A1 in its formation.

Fig. 4

Schematic model of the CYP124A1 active site illustrating why a methyl-branched hydrocarbon terminus, in which one methyl is bound in the lipophilic cavity and the other is presented for oxidation, is a good substrate, whereas an unbranched chain terminus, in which binding of the methyl in the lipophilic cavity prevents its presentation for oxidation, is not.

Fig. 5

Phagocytosis of M. bovis BCG by two macrophage cell lines (J774, BMM) before and after cholesterol depletion of the macrophages. In panel A the phagocytosis by the control (black bars) and depleted (light bars) is compared. In panel B the bars indicate phagocytosis in cholesterol depleted cells as a percentage of that observed in control cells. Reprinted with permission from (61).

Fig. 6

Stereoscopic view of cholest-4-en-3-one bound in the active site of CYP125A1. Reprinted with permission from (16)

Fig. 7

Side products detected in the oxidation of cholest-4-en-3-one by M. tuberculosis CYP125A1. The side-products, shown in blue, are boxed and are denoted by the labels M1–M5. The mechanisms proposed for their formation from the aldehyde intermediate are indicated.

Fig. 8

Comparison of the surfaces of CYP125A1 and CYP142A2 illustrating capping of the CYP125A1, but not CYP142A2, active site channel by peptide segments in CYP125A1 not present in CYP142A2.

Fig. 9

Oxidation of 16,26-dihydroxycholesterol (the “triol”) to its 3-keto-4-ene derivative.

Fig. 10

Structures of two terminally difluorinated sterols that inhibit the growth of M. tuberculosis.