Molecular evolutionary dynamics of cytochrome P450 monooxygenases across kingdoms: Special focus on mycobacterial P450s

Parvez, Mohammad K.; Qhanya, Lehlohonolo Benedict; Mthakathi, Ntsane Trevor; Kgosiemang, Ipeleng Kopano Rosinah; Bamal, Hans Denis; Pagadala, Nataraj Sekhar; Xie, Ting; Yang, Haoran; Chen, Hengye; Theron, Chrispian W.; Monyaki, Richie; Raselemane, Seiso Caiphus; Salewe, Vuyani; Mongale, Bogadi Lorato; Matowane, Retshedisitswe Godfrey; Abdalla, Sara Mohamed Hasaan; Booi, Wool Isaac; Wyk, Mari van; Olivier, Dedré; Boucher, Charlotte E.; Nelson, David R.; Tuszyński, Jack A.; Blackburn, Jonathan M.; Yu, Jae‐Hyuk; Mashele, Samson Sitheni; Chen, Wanping; Syed, Khajamohiddin

doi:10.1038/srep33099

Cited by 68 publications

(123 citation statements)

References 60 publications

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“…Several NSAIDs are metabolized through CYP enzymes. CYPs have also been identified in bacteria, with the highest number in mycobacteria (97). The one study reporting the effect of antipyretics on bacterial CYPs found that an induction of CYPs renders bacteria more sensitive to oxidant insults (47).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Effects of Antipyretics

Zimmermann

Curtis

2017

Antimicrob Agents Chemother

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Antipyretics are some of the most commonly used drugs. Since they are often coadministered with antimicrobial therapy, it is important to understand the interactions between these two classes of drugs. Our review is the first to summarize the antimicrobial effects of antipyretic drugs and the underlying mechanisms involved. Antipyretics can inhibit virus replication, inhibit or promote bacterial or fungal growth, alter the expression of virulence factors, change the surface hydrophobicity of microbes, influence biofilm production, affect the motility, adherence, and metabolism of pathogens, interact with the transport and release of antibiotics by leukocytes, modify the susceptibility of bacteria to antibiotics, and induce or reduce the frequency of mutations leading to antimicrobial resistance. While antipyretics may compromise the efficacy of antimicrobial therapy, they can also be beneficial, for example, in the management of biofilm-associated infections, in reducing virulence factors, in therapy of resistant pathogens, and in inducing synergistic effects. In an era where it is becoming increasingly difficult to find new antimicrobial drugs, targeting virulence factors, enhancing the efficacy of antimicrobial therapy, and reducing resistance may be important strategies.

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Section: Discussionmentioning

confidence: 99%

Antimicrobial Effects of Antipyretics

Zimmermann

Curtis

2017

Antimicrob Agents Chemother

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“…The P450 profile heat-map revealed that the P450 families CYP110 and CYP120 were found to be a co-presence in most of the cyanobacterial species ( Figure 5). Non-conservation of P450 families was also observed in Bacillus species [54], but in the Streptomyces [55] and mycobacterial species [59] quite a large number of P450 families were found to be conserved.…”

Section: Cyp110 Is the Dominant P450 Family In Cyanobacterial Speciesmentioning

confidence: 97%

“…Comparative analysis with other bacterial species revealed that cyanobacterial species have the lowest number of P450s compared to Bacillus species, Streptomyces and mycobacterial species (Table 2). Cyanobacterial species have an average of three P450s in their genomes compared to an average of four P450s in Bacillus species [54], 30 P450s in mycobacterial species [59], and 34 P450s in Streptomyces species [55] (Table 2). The species names with respect to their codes can be found in Table S2.…”

Section: Cyanobacterial Species Have Lowest Number Of P450smentioning

confidence: 99%

Comprehensive Analyses of Cytochrome P450 Monooxygenases and Secondary Metabolite Biosynthetic Gene Clusters in Cyanobacteria

Khumalo

Nzuza

Padayachee

et al. 2020

IJMS

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The prokaryotic phylum Cyanobacteria are some of the oldest known photosynthetic organisms responsible for the oxygenation of the earth. Cyanobacterial species have been recognised as a prosperous source of bioactive secondary metabolites with antibacterial, antiviral, antifungal and/or anticancer activities. Cytochrome P450 monooxygenases (CYPs/P450s) contribute to the production and diversity of various secondary metabolites. To better understand the metabolic potential of cyanobacterial species, we have carried out comprehensive analyses of P450s, predicted secondary metabolite biosynthetic gene clusters (BGCs), and P450s located in secondary metabolite BGCs. Analysis of the genomes of 114 cyanobacterial species identified 341 P450s in 88 species, belonging to 36 families and 79 subfamilies. In total, 770 secondary metabolite BGCs were found in 103 cyanobacterial species. Only 8% of P450s were found to be part of BGCs. Comparative analyses with other bacteria Bacillus, Streptomyces and mycobacterial species have revealed a lower number of P450s and BGCs and a percentage of P450s forming part of BGCs in cyanobacterial species. A mathematical formula presented in this study revealed that cyanobacterial species have the highest gene-cluster diversity percentage compared to Bacillus and mycobacterial species, indicating that these diverse gene clusters are destined to produce different types of secondary metabolites. The study provides fundamental knowledge of P450s and those associated with secondary metabolism in cyanobacterial species, which may illuminate their value for the pharmaceutical and cosmetics industries.

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“…Thus the larger genome of M. marinum provides both increased redundancy, with a smaller percentage of essential genes than M. tuberculosis, but also increased adaptability. This is part of a common trend, where the number of CYP genes in Mycobacterium species decreases as the organism environment changes from soil living mycobacteria (average of 50 CYPs) to a human pathogen (average of 19) [17].…”

Section: Introductionmentioning

confidence: 98%

Structural and functional characterisation of the cytochrome P450 enzyme CYP268A2 fromMycobacterium marinum

Child

Naumann

Bruning

et al. 2018

Biochemical Journal

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Members of the cytochrome P450 monooxygenase family CYP268 are found across a broad range of species including the pathogens, ,, and CYP268A2, from, which is the first member of this family to be studied, was purified and characterised. CYP268A2 was found to bind a variety of substrates with high affinity, including branched and straight chain fatty acids (C10-C12), acetate esters, and aromatic compounds. The enzyme was also found to bind phenylimidazole inhibitors but not larger azoles, such as ketoconazole. The monooxygenase activity of CYP268A2 was efficiently reconstituted using heterologous electron transfer partner proteins. CYP268A2 hydroxylated geranyl acetate and s-pseudoionone at a terminal methyl group to yield (,)-8-hydroxy-3,7-dimethylocta-2,6-dien-1-yl acetate and (,,)-11-hydroxy-6,10-dimethylundeca-3,5,9-trien-2-one, respectively. The X-ray crystal structure of CYP268A2 was solved to a resolution of 2.0 Å with -pseudoionone bound in the active site. The overall structure was similar to that of the related phytanic acid monooxygenase CYP124A1 enzyme from, which shares 41% sequence identity. The active site is predominantly hydrophobic, but includes the Ser99 and Gln209 residues which form hydrogen bonds with the terminal carbonyl group of the pseudoionone. The structure provided an explanation on why CYP268A2 shows a preference for shorter substrates over the longer chain fatty acids which bind to CYP124A1 and the selective nature of the catalysed monooxygenase activity.

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Molecular evolutionary dynamics of cytochrome P450 monooxygenases across kingdoms: Special focus on mycobacterial P450s

Cited by 68 publications

References 60 publications

Antimicrobial Effects of Antipyretics

Antimicrobial Effects of Antipyretics

Comprehensive Analyses of Cytochrome P450 Monooxygenases and Secondary Metabolite Biosynthetic Gene Clusters in Cyanobacteria

Structural and functional characterisation of the cytochrome P450 enzyme CYP268A2 fromMycobacterium marinum

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