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5. RPA161724558016.Pdf 93 | P a g e International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 6(6): November-December 2017 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 4.018*** ICV 6.16*** Pharmaceutical Sciences REVIEW ARTICLE …………!!! “GENETICS OF MYCOBACTERIA AND ITS TRENDS IN TUBERCULOSIS: A SYSTEMATIC REVIEW” Mr. Shaikh Zuber Peermohammed*, Dr. Bhise Satish Balkrishna, Sinhgad Technical Education Society‘s (STES – SINHGAD INSTITUTE) Smt. Kashibai Navale College of Pharmacy, Kondhwa, Pune – 411048 (MS) Affiliated to Savitribai Phule Pune University (Formerly known as University of Pune.). KEYWORDS: ABSTRACT Tuberculosis has reemerged as a serious threat to human health because M.tuberculosis, of the increasing prevalence of drugresistant strains and synergetic Lipoarabinomannan, infection with HIV, prompting an urgent need for new and more efficient Mycothiol (MSH), One- treatments. Mycobacterium tuberculosis (M.tb.), an intracellular Hybrid System Vector, pathogen, is exquisitely adapted for human parasitization. Mycobacterial Ubiquitination. infection has been a major cause of death throughout human history and For Correspondence: still results in the death of about two million people globally each year. Mr. Shaikh Zuber This enduring pathogenicity suggests that Mycobacterium may use Peermohammed* unique pathogenic mechanisms during its infection process. M.tb. Address: Department of confronts a more hostile environment during infection, including Pharmacology (Doctoral restricted access to nutrients and reduced oxygen tension. Therefore, Section), Sinhgad M.tb. must possess genetic mechanisms to facilitate integrated responses Technical Education to multiple stresses encountered within the phagosome, and also to Society‘s Smt. Kashibai trigger some yet-to-be-identified switches during infection process. There Navale College of is an inherent need to understand Mycobacterial infection patterns and Pharmacy, Pune mechanisms in order to develop efficient therapeutics. The review will Affiliated to Savitribai elaborate the current evidence for strain phenotypic and genotyping Phule Pune University. variation in M.tb. The purpose of this review is to gain knowledge w.r.t certain aspects of Metabolomics of M. tuberculosis in order to determine their role in the pathogenesis of Tuberculosis (TB). Full Text Available On www.ijupbs.com 94 | P a g e International Standard Serial Number (ISSN): 2319-8141 1. INTRODUCTION: It has been estimated that one-third of world‘s population is infected with Mycobacterium tuberculosis, the causative agent of Tuberculosis. It has evolved a number of distinct strategies to survive in hostile environment of macrophages. The drugs for treatment of TB are available but the long and demanding regimens lead to erratic and incomplete treatment often resulting in development of drug resistance. Hence, the importance of identification and characterization of new drug targets cannot be overemphasized. M.tb has a unique and large repertoire of lipid associated genes and its cell wall, which is known to contain a distinct variety of lipids, plays a crucial role in its pathogenesis. The pathogen resides in the host macrophages, where it encounters various stressful conditions such as changes in pH, exposure to reactive oxygen, nitrogen intermediates, degradative enzymes and deprivation of essential nutrients. During these conditions, the lipid rich cell surface of M.tb. is often subjected to damage by host assault. In M.tb. complex (MTBC), a possible role for strain diversity in TB infection models and in clinical settings remain open questions. However, until the development of the first molecular strain- typing techniques in the early 1990s, there was a general belief that genetic diversity within MTBC was too limited to account for these differences in virulence. The highly variable outcomes in TB, which ranges from lifelong asymptomatic infection to severe extrapulmonary disease affecting multiple organs were primarily attributed to host and environmental factors. One additional difficulty in trying to link genomic diversity to phenotypic diversity in MTBC is a genetically monomorphic organism and has been the lack of appropriate tools to index genomic diversity and classify strains. [1-2] Quantitative proteomics based approaches and post-translational modification analysis can be efficiently applied to gain an insight into the molecular mechanisms involved.The measurement of the proteome and posttranslationally modified proteome dynamics using mass spectrometry, results in a widearray of information, such as significant changes in protein expression, protein abundance, the modification status, the site occupancy level, interactors, functional significance of key players, potential drug targets, etc. The potential of proteomics to investigate the involvement of post-translational modifications in bacterial pathogenesis and host–pathogen Full Text Available On www.ijupbs.com 95 | P a g e International Standard Serial Number (ISSN): 2319-8141 interactions. Development of high-resolution instruments and improvements in experimental techniques has helped expand the scope of infection biology.[3] 2. A phylogenetic framework for strain classification: Although DNA sequence data allows inferring robust phylogenetic structures, delineating biologically meaningful groupings within a continuous spectrum of genotypic diversity is not easy, and to some extent arbitrary. Nevertheless, defining such boundaries within species is important for the purpose of strain classification. The difficulty of determining biologically meaningful groupings within related bacteria arises at multiple taxonomic levels. For example, there is still no widely accepted species concept for bacteria, and species demarcation has been based on measures of genome similarity, phenotypic or ecological clustering. MTBC is an example for which the concept of ―ecotype‖ has been proposed to define the various (sub)- species within MTBC. Related concepts at lower taxonomic levels include terms such as ―lineage‖, ―sub-lineage‖, ―family‖, ―clade‖, and ―cluster‖. Larger numbers of MTBC genomes will be necessary to properly define the various sub-lineages and strain families comprised within six main lineages. It has been earlier demonstrated that exposure to acidic pH results in the upregulation of the mymA operon of M.tb. (Rv3083-Rv3089). The functional loss of the mymA operon leads to alterations in colony morphology, cell wall structure, mycolic acid composition and drug sensitivity and results in markedly reduced intracellular survival of M.tb. in macrophages. Besides, mymA mutant of M.tb. shows a drastic reduction (800 fold) in its ability to survive as compared to the parental strain. To gain further insight into functioning of mymA operon, a potential target for developing antitubercular drugs, it is necessary to characterize its gene products. FadD13, last gene of mymA operon, encodes a Fatty Acyl- CoA Synthetase and are ubiquitously distributed from bacteria to mammalian systems and catalyze activation of various fatty acids by converting them into fattyacyl-CoA thioesters. Mechanistically, these proteins carry out the catalysis in two steps involving fatty acids, ATP and CoA. In the first step, the fatty acid and the ATP react to form the fatty acyl-AMP intermediate with the release of pyrophosphate. The fatty acyl group is then transferred to the thiol group of the CoA acceptor to form fatty acyl-CoA with the concomitant release of AMP. The cytosol of Full Text Available On www.ijupbs.com 96 | P a g e International Standard Serial Number (ISSN): 2319-8141 mammalian cells contains a large multifunctional homodimeric protein (called FAS I) which contains all of enzymatic activities in the pathway whereas the mycobacteria have a different FAS I. The FAS I pathways are closely related in that high resolution structures can often be superimposed on that of the cognate domain of the FAS I proteins.[4-6] 3. Structural Components/ Composition of Mycobacteria: 3.1 Enoyl-acyl carrier protein (ACP) Reductases: Enoyl-ACP reductases catalyze the reduction of a trans-2-acyl-ACP (an enoyl-ACP) to the fully saturated acyl-ACP species (note that trans-2-butyryl-ACP is often called crotonyl-ACP). The reductant is either NADH or NADPH, although in one case a reduced flavin (FMNH2) is used as an intermediate in the reduction. The pyridine nucleotide reduction of double bond is thought to proceed by conjugate addition of a hydride ion from NADH or NADPH to carbon 3 of trans-2- acyl group with intermediate formation of an enzyme-stabilized enolate anion on the C1 carbonyl oxygen. Collapse of enolate via protonation at C2 would yield saturated product with the C2 proton being derived from hydroxyl group of an active site tyrosine side chain. The tyrosine proton is replenished from solvent via a proton wire involving Lys163 and ribose hydroxyl groups plus a chain of water molecules. The pyridine nucleotide cofactor hydride ion utilized by M.tb. enoyl-ACP reductases (FabI and InhA, respectively) is the 4S hydrogen whereas the mammalian type I synthase uses the 4R hydrogen. The trans-2 unsaturated acyl chain is linked to ACP via a thioester linkage that is required for enolization. ACP is a key feature of fatty acid synthetic pathway in that all of intermediates are covalently bound to this small, very acidic and extremely soluble protein. The carboxyl groups of the fatty acyl intermediates are
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