title: The internal gene duplication and interrupted coding sequences in the MmpL genes of Mycobacterium tuberculosis: Towards understanding the multidrug transport in an evolutionary perspective.
abstract: The multidrug resistance has emerged as a major problem in the treatment of many of the infectious diseases. Tuberculosis (TB) is one of such disease caused by Mycobacterium tuberculosis. There is short term chemotherapy to treat the infection, but the main hurdle is the development of the resistance to antibiotics. This resistance is primarily due to the impermeable mycolic acid rich cell wall of the bacteria and other factors such as efflux of antibiotics from the bacterial cell. The MmpL (Mycobacterial Membrane Protein Large) proteins of mycobacteria are involved in the lipid transport and antibiotic efflux as indicated by the preliminary reports. We present here, comprehensive comparative sequence and structural analysis, which revealed topological signatures shared by the MmpL proteins and RND (Resistance Nodulation Division) multidrug efflux transporters. This provides evidence in support of the notion that they belong to the extended RND permeases superfamily. In silico modelled tertiary structures are in homology with an integral membrane component present in all of the RND efflux pumps. We document internal gene duplication and gene splitting events happened in the MmpL genes, which further elucidate the molecular functions of these putative transporters in an evolutionary perspective.
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Shahpur District, Kangra 176206, Himachal Pradesh, India.
authors.forename: Padmani
authors.initials: P
authors.lastname: Sandhu
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Shahpur District, Kangra 176206, Himachal Pradesh, India. Electronic address: yusuf@daad-alumni.de.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Akhter
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000737:chemistry; D016000:Cluster Analysis; D024881:Drug Resistance, Bacterial; D019143:Evolution, Molecular; D020440:Gene Duplication; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010802:Phylogeny; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D026901:Membrane Transport Proteins
keywords: Efflux pumps; MmpL genes; Multidrug resistance; Mycobacterium tuberculosis; RND transporters; Reductive evolution