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.
| Original language | English |
|---|---|
| Pages (from-to) | 3597-3614 |
| Number of pages | 18 |
| Journal | Applied Microbiology and Biotechnology |
| Volume | 103 |
| Issue number | 9 |
| Early online date | 27 Feb 2019 |
| DOIs | |
| Publication status | Published - 2 May 2019 |
Fingerprint
Keywords
- Antibiotic exposure response
- Cytochrome P450
- Essentiality
- Mycobacterium tuberculosis
- Redox partners
- Stress response
Cite this
}
Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets? / Ortega Ugalde, S.; Boot, Maikel ; Commandeur, J.N.M.; Jennings, P.; Bitter, W.; Vos, J.C.
In: Applied Microbiology and Biotechnology, Vol. 103, No. 9, 02.05.2019, p. 3597-3614.Research output: Contribution to Journal › Article › Academic › peer-review
TY - JOUR
T1 - Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?
AU - Ortega Ugalde, S.
AU - Boot, Maikel
AU - Commandeur, J.N.M.
AU - Jennings, P.
AU - Bitter, W.
AU - Vos, J.C.
PY - 2019/5/2
Y1 - 2019/5/2
N2 - 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.
AB - 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.
KW - Antibiotic exposure response
KW - Cytochrome P450
KW - Essentiality
KW - Mycobacterium tuberculosis
KW - Redox partners
KW - Stress response
UR - http://www.scopus.com/inward/record.url?scp=85064279163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064279163&partnerID=8YFLogxK
U2 - 10.1007/s00253-019-09697-z
DO - 10.1007/s00253-019-09697-z
M3 - Article
VL - 103
SP - 3597
EP - 3614
JO - Applied Microbiology and Biotechnology
JF - Applied Microbiology and Biotechnology
SN - 0175-7598
IS - 9
ER -