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

Abstract

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.

Impact of lifestyle on cytochrome P450 monooxygenase repertoire is clearly evident in the bacterial phylum Firmicutes

“…3). Cyanobacterial species also had no P450 family conserved, but P450 families CYP110 and CYP120 were found to be a co-presence in www.nature.com/scientificreports/ www.nature.com/scientificreports/ most of these species 49 . the large CYP107 family was found to be conserved in Streptomyces species 46 and quite a number of P450 families were found to be conserved in mycobacterial species 47 .…”

“…Studies on the role of P450s in organism's adaptations or changes in P450 profiles according to an organism's life have been conducted on eukaryotic organisms such as fungi [34][35][36][37][38][39][40][41] , oomycetes 42 , plants 43 , and animals 44 . However, this phenomenon is scarcely reported in prokaryotes; currently data are available only for bacterial species belonging to the genera Streptomyces 45,46 , Mycobacterium 47,48 and the phylum Cyanobacteria 49 , suggesting that more research is needed to unravel P450s' role in other bacterial species. The presence of species with diverse characteristics that are adapted to diverse ecological niches, such as in Firmicutes, will enhance understanding of the role of P450s in bacterial species, especially with respect to their role in those organism's adaptations.…”

More P450s Are Involved in Secondary Metabolite Biosynthesis in Streptomyces Compared to Bacillus, Cyanobacteria, and Mycobacterium

“…Analysis of the most prevalent number of P450s revealed that 19 P450s was the prevalent number in Streptomyces species ( Table 1 ). The average number of P450s in Streptomyces species was found to be higher than in Bacillus species [ 22 ] and cyanobacterial species [ 23 ], and almost the same as in mycobacterial species [ 21 ] ( Table 2 ). A point to be noted is that the number of species greatly influences the average number of P450s and, thus, the higher the number of species in the analysis, the better and more accurate the results, as mentioned elsewhere [ 20 , 23 ].…”

“…P450s in the newly sequenced species need to be annotated as per the International P450 Nomenclature Committee rules [ 17 , 18 , 19 ] to enable researchers to use the same names for functional and evolutionary analysis of P450s. For this reason, large numbers of P450s have recently been annotated in bacterial species belonging to the genera Mycobacterium [ 21 ], Bacillus [ 22 ], Streptomyces [ 20 ], and Cyanobacteria [ 23 ]. These studies have revealed numerous P450s involved in the synthesis of different types of secondary metabolites.…”

Proteomic Insights into Starvation of Nitrogen-Replete Cells of Nostoc sp. PCC 7120 under β-N-Methylamino-L-Alanine (BMAA) Treatment

“…Another metabolically important enzyme, upregulated in the presence of BMAA, was identified as Cytochrome P450 ( all1361 ) ( Table 2 ). It is known that Cytochrome P450 monooxygenases (CYPs/P450s) is a diverse superfamily of heme-dependent enzymes that contribute to the production and diversity of various secondary metabolites and are present in all cyanobacteria [ 61 ]. These enzymes introduce oxygen into a wide range of molecules.…”