Potential Drug Targets in the Mycobacterium Tuberculosis Cytochrome P450 System

Overview

Journal J Inorg Biochem

Specialty Biochemistry

Date 2018 Jan 21

PMID 29352597

Citations 20

Authors

Paul R Ortiz de Montellano

Affiliations

Soon will be listed here.

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.

Citing Articles

Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review.

Abdelmonem B, Abdelaal N, Anwer E, Rashwan A, Hussein M, Ahmed Y Biomedicines. 2024; 12(7).

PMID: 39062040 PMC: 11275228. DOI: 10.3390/biomedicines12071467.

Structure-Function Analysis of the Essential P450 Drug Target, CYP121A1.

Padayachee T, Lamb D, Nelson D, Syed K Int J Mol Sci. 2024; 25(9).

PMID: 38732102 PMC: 11084333. DOI: 10.3390/ijms25094886.

In Situ Structural Observation of a Substrate- and Peroxide-Bound High-Spin Ferric-Hydroperoxo Intermediate in the P450 Enzyme CYP121.

Nguyen R, Davis I, Dasgupta M, Wang Y, Simon P, Butryn A J Am Chem Soc. 2023; 145(46):25120-25133.

PMID: 37939223 PMC: 10799213. DOI: 10.1021/jacs.3c04991.

Effects of second-line anti-tuberculosis drugs on the intestinal microbiota of patients with rifampicin-resistant tuberculosis.

Wu C, Yi H, Hu Y, Luo D, Tang Z, Wen X Front Cell Infect Microbiol. 2023; 13:1127916.

PMID: 37187470 PMC: 10178494. DOI: 10.3389/fcimb.2023.1127916.

The implication of Mycobacterium tuberculosis-mediated metabolism of targeted xenobiotics.

Singh V, Dziwornu G, Chibale K Nat Rev Chem. 2023; 7(5):340-354.

PMID: 37117810 PMC: 10026799. DOI: 10.1038/s41570-023-00472-3.

References

Onderko E, Silakov A, Yosca T, Green M . Characterization of a selenocysteine-ligated P450 compound I reveals direct link between electron donation and reactivity. Nat Chem. 2017; 9(7):623-628. DOI: 10.1038/nchem.2781. View

Ahmad Z, Sharma S, Khuller G . The potential of azole antifungals against latent/persistent tuberculosis. FEMS Microbiol Lett. 2006; 258(2):200-3. DOI: 10.1111/j.1574-6968.2006.00224.x. View

Abuhammad A . Cholesterol metabolism: a potential therapeutic target in Mycobacteria. Br J Pharmacol. 2016; 174(14):2194-2208. PMC: 5481656. DOI: 10.1111/bph.13694. View

Becher R, Wirsel S . Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens. Appl Microbiol Biotechnol. 2012; 95(4):825-40. DOI: 10.1007/s00253-012-4195-9. View

Matsuura K, Yoshioka S, Tosha T, Hori H, Ishimori K, Kitagawa T . Structural diversities of active site in clinical azole-bound forms between sterol 14alpha-demethylases (CYP51s) from human and Mycobacterium tuberculosis. J Biol Chem. 2004; 280(10):9088-96. DOI: 10.1074/jbc.M413042200. View

Zampieri D, Mamolo M, Vio L, Banfi E, Scialino G, Fermeglia M . Synthesis, antifungal and antimycobacterial activities of new bis-imidazole derivatives, and prediction of their binding to P450(14DM) by molecular docking and MM/PBSA method. Bioorg Med Chem. 2007; 15(23):7444-58. DOI: 10.1016/j.bmc.2007.07.023. View

McLean K, Warman A, Seward H, Marshall K, Girvan H, Cheesman M . Biophysical characterization of the sterol demethylase P450 from Mycobacterium tuberculosis, its cognate ferredoxin, and their interactions. Biochemistry. 2006; 45(27):8427-43. DOI: 10.1021/bi0601609. View

Bellamine A, Mangla A, Dennis A, Nes W, Waterman M . Structural requirements for substrate recognition of Mycobacterium tuberculosis 14 alpha-demethylase: implications for sterol biosynthesis. J Lipid Res. 2001; 42(1):128-36. View

Vasilevskaya A, Yantsevich A, Sergeev G, Lemish A, Usanov S, Gilep A . Identification of Mycobacterium tuberculosis enzyme involved in vitamin D and 7-dehydrocholesterol metabolism. J Steroid Biochem Mol Biol. 2016; 169:202-209. DOI: 10.1016/j.jsbmb.2016.05.021. View

10.

Ouellet H, Johnston J, de Montellano P . The Mycobacterium tuberculosis cytochrome P450 system. Arch Biochem Biophys. 2009; 493(1):82-95. PMC: 2812603. DOI: 10.1016/j.abb.2009.07.011. View

11.

Sassetti C, Rubin E . Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A. 2003; 100(22):12989-94. PMC: 240732. DOI: 10.1073/pnas.2134250100. View

12.

Hudson S, Surade S, Coyne A, McLean K, Leys D, Munro A . Overcoming the limitations of fragment merging: rescuing a strained merged fragment series targeting Mycobacterium tuberculosis CYP121. ChemMedChem. 2013; 8(9):1451-6. PMC: 4281926. DOI: 10.1002/cmdc.201300219. View

13.

Driscoll M, McLean K, Cheesman M, Jowitt T, Howard M, Carroll P . Expression and characterization of Mycobacterium tuberculosis CYP144: common themes and lessons learned in the M. tuberculosis P450 enzyme family. Biochim Biophys Acta. 2010; 1814(1):76-87. DOI: 10.1016/j.bbapap.2010.05.015. View

14.

Podust L, Ouellet H, von Kries J, de Montellano P . Interaction of Mycobacterium tuberculosis CYP130 with heterocyclic arylamines. J Biol Chem. 2009; 284(37):25211-9. PMC: 2757224. DOI: 10.1074/jbc.M109.017632. View

15.

Jackson C, Lamb D, Kelly D, Kelly S . Bactericidal and inhibitory effects of azole antifungal compounds on Mycobacterium smegmatis. FEMS Microbiol Lett. 2000; 192(2):159-62. DOI: 10.1111/j.1574-6968.2000.tb09375.x. View

16.

Ouellet H, Johnston J, de Montellano P . Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis. Trends Microbiol. 2011; 19(11):530-9. PMC: 3205253. DOI: 10.1016/j.tim.2011.07.009. View

17.

Johnston J, Singh A, Clary A, Chen C, Hayes P, Chow S . Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1. Bioorg Med Chem. 2012; 20(13):4064-81. PMC: 3376231. DOI: 10.1016/j.bmc.2012.05.003. View

18.

Dornevil K, Davis I, Fielding A, Terrell J, Ma L, Liu A . Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from proceeds through a catalytic shunt pathway. J Biol Chem. 2017; 292(33):13645-13657. PMC: 5569305. DOI: 10.1074/jbc.M117.794099. View

19.

McLean K, Marshall K, Richmond A, Hunter I, Fowler K, Kieser T . Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiology (Reading). 2002; 148(Pt 10):2937-2949. DOI: 10.1099/00221287-148-10-2937. View

20.

Kavanagh M, Chenge J, Zoufir A, McLean K, Coyne A, Bender A . Fragment Profiling Approach to Inhibitors of the Orphan M. tuberculosis P450 CYP144A1. Biochemistry. 2017; 56(11):1559-1572. DOI: 10.1021/acs.biochem.6b00954. View