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Ravishankar S.,Astrazeneca | Ravishankar S.,Vellore Institute of Technology | Ambady A.,Astrazeneca | Ambady A.,Gangagen Biotechnologies Pvt. Ltd. | And 5 more authors.
PLoS ONE | Year: 2016

Discovery of mupirocin, an antibiotic that targets isoleucyl-tRNA synthetase, established aminoacyl-tRNA synthetase as an attractive target for the discovery of novel antibacterial agents. Despite a high degree of similarity between the bacterial and human aminoacyltRNA synthetases, the selectivity observed with mupirocin triggered the possibility of targeting other aminoacyl-tRNA synthetases as potential drug targets. These enzymes catalyse the condensation of a specific amino acid to its cognate tRNA in an energy-dependent reaction. Therefore, each organism is expected to encode at least twenty aminoacyl-tRNA synthetases, one for each amino acid. However, a bioinformatics search for genes encoding aminoacyl-tRNA synthetases from Mycobacterium smegmatis returned multiple genes for glutamyl (GluRS), cysteinyl (CysRS), prolyl (ProRS) and lysyl (LysRS) tRNA synthetases. The pathogenic mycobacteria, namely, Mycobacterium tuberculosis and Mycobacterium leprae, were also found to possess two genes each for CysRS and LysRS. A similar search indicated the presence of additional genes for LysRS in gram negative bacteria as well. Herein, we describe sequence and structural analysis of the additional aminoacyl-tRNA synthetase genes found in M. smegmatis. Characterization of conditional expression strains of Cysteinyl and Lysyl-tRNA synthetases generated in M. smegmatis revealed that the canonical aminoacyl-tRNA synthetase are essential, while the additional ones are not essential for the growth of M. smegmatis. © 2016 Ravishankar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Jayaram S.,Institute of Bioinformatics | Jayaram S.,Manipal University India | Gupta M.K.,Institute of Bioinformatics | Gupta M.K.,Manipal University India | And 4 more authors.
Expert Review of Proteomics | Year: 2014

Glioblastoma multiforme (GBM) is one of the most aggressive and lethal forms of the primary brain tumors. With predominance of tumor heterogeneity and emergence of new subtypes, new approaches are needed to develop tissue-based markers for tumor typing or circulatory markers to serve as blood-based assays. Multi-omics data integration for GBM tissues would offer new insights on the molecular view of GBM pathogenesis useful to identify biomarker panels. On the other hand, mapping differentially expressed tissue proteins for their secretory potential through bioinformatics analysis or analysis of the tumor cell secretome or tumor exosomes would enhance our understanding of the tumor microenvironment and prospects for targeting circulatory biomarkers. In this review, the authors first present potential biomarker candidates for GBM that have been reported and then focus on plausible pipelines for multi-omic data integration to identify additional, high-confidence molecular panels for clinical applications in GBM. © 2014 Informa UK, Ltd. Source

Sirdeshmukh R.,Institute of Bioinformatics | Sirdeshmukh R.,Mazumdar Shaw Center for Translational Research
Journal of Proteomics | Year: 2015

The Draft Maps of Human Proteome published in two independent articles provide a catalogue of proteins encoded in the human genome including missing proteins, based on large scale mass spectrometric analysis. Six months later, a Tissue-based Human Proteome Map was published which includes a study of expression and distribution of human proteins across tissues and cells using specific antibodies. Independently, in an ongoing global effort - the Chromosome centric, and Biology and Disease centric Human Proteome Project (C-HPP and B/D-HPP) initiated by the Human Proteome Organization aims to study in-depth human proteins and their variants in terms of biology and disease in a chromosome centric manner. Under this initiative, a consortium formed among five Asian research teams including India aims to study Chromosome 12 encoded proteins and their disease context. Together, the group has recently published the first series of 3 papers giving the overall vision and the initial contributions. While one of the draft maps of the human proteome is largely contributed by an Indian team, Indian researchers have significant role in the other two initiatives as well. These efforts will be pursued further as more teams join and more disease and biology components get incorporated. Biological significance: This article focuses on the complexity and challenges of deciphering human proteome and contribution of Indian researchers in the human proteome projects, including the on-going C-HPP.This article is part of a Special Issue entitled: Proteomics in India. © 2015 Elsevier B.V. Source

Simple M.,Roswell Park Cancer Institute | Simple M.,Vellore Institute of Technology | Suresh A.,Mazumdar Shaw Center for Translational Research | Suresh A.,Roswell Park Cancer Institute | And 3 more authors.
Oral Oncology | Year: 2015

Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the 'Cancer stem cells' (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT. © 2015 Elsevier Ltd. All rights reserved. Source

Gupta M.K.,Institute of Bioinformatics | Gupta M.K.,Manipal University India | Jayaram S.,Institute of Bioinformatics | Jayaram S.,Manipal University India | And 10 more authors.
Journal of Proteome Research | Year: 2014

In line with the aims of the Chromosome-centric Human Proteome Project (C-HPP) to completely annotate proteins of each chromosome and biology/disease driven HPP (B/D-HPP) to decipher their relation to diseases, we have generated a nonredundant catalogue of protein-coding genes for Chromosome 12 (Chr. 12) and further annotated proteins associated with major neurological disorders. Integrating high level proteomic evidence from four major databases (neXtProt, Global Proteome Machine (GPMdb), PeptideAtlas, and Human Protein Atlas (HPA)) along with Ensembl data resource resulted in the identification of 1066 protein coding genes, of which 171 were defined as "missing proteins" based on the weak or complete absence of experimental evidence. With functional annotations using DAVID and GAD, about 40% of the proteins could be grouped as brain related with implications in cancer or neurological disorders. We used published and unpublished high confidence mass spectrometry data from our group and other literature consisting of more than 5000 proteins derived from clinical specimens from patients with human gliomas, Alzheimers disease, and Parkinsons disease and mapped it onto Chr. 12. We observed a total of 202 proteins mapping to human Chr. 12, 136 of which were differentially expressed in these disease conditions as compared to the normal. Functional grouping indicated their association with cell cycle, cell-to-cell signaling, and other important processes and networks, whereas their disease association analysis confirmed neurological diseases and cancer as the major group along with psycological disorders, with several overexpressed genes/proteins mapping to 12q13-15 amplicon region. Using multiple strategies and bioinformatics tools, we identified 103 differentially expressed proteins to have secretory potential, 17 of which have already been reported in direct analysis of the plasma or cerebrospinal fluid (CSF) from the patients and 21 of them mapped to cancer associated protein (CAPs) database that are amenable to selective reaction monitoring (SRM) assays for targeted proteomic analysis. Our analysis also reveals, for the first time, mass spectrometric evidence for two "missing proteins" from Chr. 12, namely, synaptic vesicle 2-related protein (SVOP) and IQ motif containing D (IQCD). The analysis provides a snapshot of Chr. 12 encoded proteins associated with gliomas and major neurological conditions and their secretability which can be used to drive efforts for clinical applications. © 2014 American Chemical Society. Source

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