Comparative Analysis, Structural Insights, and Substrate/Drug Interaction of CYP128A1 in Mycobacterium tuberculosis

Abstract

<jats:p>Cytochrome P450 monooxygenases (CYPs/P450s) are well known for their role in organisms’ primary and secondary metabolism. Among 20 P450s of the tuberculosis-causing Mycobacterium tuberculosis H37Rv, CYP128A1 is particularly important owing to its involvement in synthesizing electron transport molecules such as menaquinone-9 (MK9). This study employs different in silico approaches to understand CYP128 P450 family’s distribution and structural aspects. Genome data-mining of 4250 mycobacterial species has revealed the presence of 2674 CYP128 P450s in 2646 mycobacterial species belonging to six different categories. Contrast features were observed in the CYP128 gene distribution, subfamily patterns, and characteristics of the secondary metabolite biosynthetic gene cluster (BGCs) between M. tuberculosis complex (MTBC) and other mycobacterial category species. In all MTBC species (except one) CYP128 P450s belong to subfamily A, whereas subfamily B is predominant in another four mycobacterial category species. Of CYP128 P450s, 78% was a part of BGCs with CYP124A1, or together with CYP124A1 and CYP121A1. The CYP128 family ranked fifth in the conservation ranking. Unique amino acid patterns are present at the EXXR and CXG motifs. Molecular dynamic simulation studies indicate that the CYP128A1 bind to MK9 with the highest affinity compared to the azole drugs analyzed. This study provides comprehensive comparative analysis and structural insights of CYP128A1 in M. tuberculosis.</jats:p>

In Silico Analysis of P450s and Their Role in Secondary Metabolism in the Bacterial Class Gammaproteobacteria

“…Recent studies from our laboratory focusing on bacterial species revealed that the lifestyle of an organism plays a key role in shaping P450 content vis à vis P450s helping microbes to adapt to ecological niches. However, these studies were limited to few groups of bacterial species belonging to the genera Streptomyces [ 49 , 50 ] and Mycobacterium [ 51 , 52 , 53 ] and from the phyla Cyanobacteria [ 54 ] and Firmicutes [ 55 , 56 ]. Furthermore, to date, a comparative analysis of P450s in the Gammaproteobacterial species has not been reported.…”

An Unprecedented Number of Cytochrome P450s Are Involved in Secondary Metabolism in Salinispora Species

“…A point to be noted is that, among bacterial species, species belonging to the phylum Actinobacteria have the highest average number of P450s ( Table 1 ). This indicates selective enrichment of P450s in these species due to their adaptation to ecological niches vis a vis P450s, helping them adapt to diverse ecological niches described elsewhere [ 58 , 74 , 75 ]. Salinispora species P450s, along with P450-fragments, are presented in Table S2 .…”

“…If a P450 family is conserved or few P450 families are co-presence, these families play an important role in a species’s primary- or secondary-metabolism. Previous studies showed that this type of P450s prominently plays a role in secondary metabolism, helping species adapt to diverse ecological niches [ 58 , 59 , 72 , 74 , 75 ]. The importance of P450 families that are conserved and co-presence in Salinispora species is discussed in detail in the next section.…”

In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles

“…This phenomenon of grouping P450s from species with similar life style/adaption to similar ecological niches was observed in some bacterial [35][36][37] and fungal species [38][39][40]. This indicates that after speciation, lifestyle/ecological niches played a key role in changing/preserving the amino acid content, as observed for different P450s families in bacteria [35][36][37] and fungi [38][39][40]. 1).…”