Analyses of methyltransferases across the pathogenicity spectrum of different mycobacterial species point to an extremophile connection

Abstract

Tuberculosis is a devastating disease, taking one human life every 20 seconds globally. We hypothesize that professional pathogens such as M.tb have acquired specific features that might assist in causing infection, persistence and transmissible pathology in their host. We have identified 121 methyltransferases (MTases) in the M.tb proteome, which use a variety of substrates - DNA, RNA, protein, intermediates of mycolic acid biosynthesis and other fatty acids - that are involved in cellular maintenance within the host. A comparative analysis of the proteome of the virulent strain H37Rv and the avirulent strain H37Ra identified 3 MTases, which displayed significant variations in terms of N-terminal extension/deletion and point mutations, possibly impacting various physicochemical properties. The cross-proteomic comparison of MTases of M.tb H37Rv with 15 different Mycobacterium species revealed the acquisition of novel MTases in a MTB complex as a function of evolution. Phylogenetic analysis revealed that these newly acquired MTases showed common roots with certain extremophiles such as halophilic and acidophilic organisms. Our results establish an evolutionary relationship of M.tb with halotolerant organisms and also the role of MTases of M.tb in withstanding the host osmotic stress, thereby pointing to their likely role in pathogenesis, virulence and niche adaptation.

Biosynthesis of mycobacterial methylmannose polysaccharides requires a unique 1- O -methyltransferase specific for 3- O -methylated mannosides

“…Methyltransferases (MTases) are important enzymes involved in the modification of a vast array of substrates but sugar methylation is much less common than methylation of protein or nucleic acids (21). Methylation of lipids, such as the mycobacterial mycolic acids, is critical for their function and structural diversity, much of which is generated by the action of SAMdependent MTases (22). SAM-dependent methylation represents a major class of biological processes and includes methyl group transfer from SAM, yielding S-adenosyl-L-homocysteine (SAH) and a methylated molecular target (23).…”

“…About 70% of the 121 MTases predicted in the M. tuberculosis genome are SAM-dependent enzymes. Twenty of the 61 MTases whose function has been identified act on RNA or DNA, 10 are involved in the methylation of mycolic acids, and the remaining participate in diverse metabolic pathways (22). Interestingly, opportunistic and nonpathogenic NTM possess 10-20% less MTases than strictly pathogenic mycobacterial species (22).…”

Proteomic profiling of integral membrane proteins associated to pathogenicity in Vibrio parahaemolyticus strains

“…However, additional factors not classified in the previous categories were also differentially accumulated. For example, the outer membrane protein assembly BamB, which participates in assembly and insertion of beta‐barrel proteins in the outer membrane , and uroporphyrin‐III methyltransferase, which is responsible for regulating the activity of NAD(P)H: glutamyl‐tRNA reductase (HemA) in the tetrapyrrole biosynthetic pathway .…”

Comprehensive analysis of protein acetyltransferases of human pathogen Mycobacterium tuberculosis

“…The following bioinformatics analysis followed previous report [17]. The Antigenic Index for all acetyltransferases was predicted through the VaxiJen v2 webserver, and the cut-off value was set 0.4 [18].…”