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.

Complete Genome Sequence of Ovine Mycobacterium avium subsp. paratuberculosis Strain JIII-386 (MAP-S/type III) and Its Comparison to MAP-S/type I, MAP-C, and M. avium Complex Genomes

“…Only a few genes belong to a described KEGG pathway. However, in general, the singleton gene set of the LSP S s includes different transcriptional regulators belonging to different families and two genes coding for different cytochrome P450 proteins that could influence virulence of mycobacteria [ 114 ]. In addition, genes in LSP S III comprising three methyltransferases and one desosaminyl transferase precursor are likely involved in the synthesis of a macrolide(s).…”

CYP2E1 changes the biological function of gastric cancer cells via the PI3K/Akt/mTOR signaling pathway

“…cYPs are a superfamily of proteins containing heme as a cofactor that play a crucial role in the metabolism of a diverse range of xenobiotics (7). P450 proteins play a critical role in chemical carcinogenesis by activating or inactivating carcinogens, which impacts the initiation and promotion of tumors (8).…”

Insights into gene expression responses to infections in teleosts using microarray data: a systematic review

“…2017; Ortega Ugalde et al . 2019). Cytochromes b and c are involved in the electron transport chain in the mitochondria, mainly the unidirectional electron flow along the chain, which is possible given the differential reduction potential (Chertkova et al .…”

“…Cytochromes and related proteins Cytochromes are haem-containing proteins whose characteristic mode of action involves the transfer of a single electron between the Fe(II) and Fe(III) of the haem group. In vertebrates, they are classified based on the nature and mode of binding to the said group as cytochromes a, b and c, among others (Ichiye 2013;Chertkova et al 2017;Ortega Ugalde et al 2019). Cytochromes b and c are involved in the electron transport chain in the mitochondria, mainly the unidirectional electron flow along the chain, which is possible given the differential reduction potential (Chertkova et al 2017).…”