Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?

S. Ortega Ugalde; Maikel  Boot; J.N.M. Commandeur; P. Jennings; W. Bitter; J.C. Vos

doi:10.1007/s00253-019-09697-z

Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?

S. Ortega Ugalde, Maikel Boot, J.N.M. Commandeur, P. Jennings, W. Bitter, J.C. Vos

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

This review covers the current knowledge of the cytochrome P450 enzymes (CYPs) of the human pathogen Mycobacterium tuberculosis (Mtb) and their endogenous redox partners, focusing on their biological function, expression, regulation, involvement in antibiotic resistance, and suitability for exploitation as antitubercular targets. The Mtb genome encodes twenty CYPs and nine associated redox partners required for CYP catalytic activity. Transposon insertion mutagenesis studies have established the (conditional) essentiality of several of these enzymes for in vitro growth and host infection. Biochemical characterization of a handful of Mtb CYPs has revealed that they have specific physiological functions in bacterial virulence and persistence in the host. Analysis of the transcriptional response of Mtb CYPs and redox partners to external insults and to first-line antibiotics used to treat tuberculosis showed a diverse expression landscape, suggesting for some enzymes a potential role in drug resistance. Combining the knowledge about the physiological roles and expression profiles indicates that, at least five Mtb CYPs, CYP121A1, CYP125A1, CYP139A1, CYP142A1, and CYP143A1, as well as two ferredoxins, FdxA and FdxC, can be considered promising novel therapeutic targets.

Language	English
Pages	3597-3614
Number of pages	18
Journal	Applied Microbiology and Biotechnology
Volume	103
Issue number	9
Early online date	27 Feb 2019
DOIs	10.1007/s00253-019-09697-z 10.1007/s00253-019-09697-z
Publication status	Published - 2 May 2019

Fingerprint

Mycobacterium tuberculosis

Cytochrome P-450 Enzyme System

Oxidation-Reduction

Pharmaceutical Preparations

Ferredoxins

Enzymes

Microbial Drug Resistance

Drug Resistance

Mutagenesis

Virulence

Tuberculosis

Genome

Anti-Bacterial Agents

Growth

Infection

Therapeutics

Keywords

Antibiotic exposure response
Cytochrome P450
Essentiality
Mycobacterium tuberculosis
Redox partners
Stress response

Cite this

Ortega Ugalde, S., Boot, M., Commandeur, J. N. M., Jennings, P., Bitter, W., & Vos, J. C. (2019). Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets? Applied Microbiology and Biotechnology, 103(9), 3597-3614. https://doi.org/10.1007/s00253-019-09697-z, https://doi.org/10.1007/s00253-019-09697-z

Ortega Ugalde, S. ; Boot, Maikel ; Commandeur, J.N.M. ; Jennings, P. ; Bitter, W. ; Vos, J.C. / Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?. In: Applied Microbiology and Biotechnology. 2019 ; Vol. 103, No. 9. pp. 3597-3614.

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title = "Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?",

abstract = "This review covers the current knowledge of the cytochrome P450 enzymes (CYPs) of the human pathogen Mycobacterium tuberculosis (Mtb) and their endogenous redox partners, focusing on their biological function, expression, regulation, involvement in antibiotic resistance, and suitability for exploitation as antitubercular targets. The Mtb genome encodes twenty CYPs and nine associated redox partners required for CYP catalytic activity. Transposon insertion mutagenesis studies have established the (conditional) essentiality of several of these enzymes for in vitro growth and host infection. Biochemical characterization of a handful of Mtb CYPs has revealed that they have specific physiological functions in bacterial virulence and persistence in the host. Analysis of the transcriptional response of Mtb CYPs and redox partners to external insults and to first-line antibiotics used to treat tuberculosis showed a diverse expression landscape, suggesting for some enzymes a potential role in drug resistance. Combining the knowledge about the physiological roles and expression profiles indicates that, at least five Mtb CYPs, CYP121A1, CYP125A1, CYP139A1, CYP142A1, and CYP143A1, as well as two ferredoxins, FdxA and FdxC, can be considered promising novel therapeutic targets.",

keywords = "Antibiotic exposure response, Cytochrome P450, Essentiality, Mycobacterium tuberculosis, Redox partners, Stress response",

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Ortega Ugalde, S, Boot, M, Commandeur, JNM , Jennings, P , Bitter, W & Vos, JC 2019, 'Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?', Applied Microbiology and Biotechnology, vol. 103, no. 9, pp. 3597-3614. https://doi.org/10.1007/s00253-019-09697-z, https://doi.org/10.1007/s00253-019-09697-z