Zeeshan Ansari - Academia.edu (original) (raw)

Papers by Zeeshan Ansari

Polyketide synthases (PKSs) catalyze biosynthesis of a diverse family of pharmaceutically importa... more Polyketide synthases (PKSs) catalyze biosynthesis of a diverse family of pharmaceutically important secondary metabolites. Bioinformatics analysis of sequence and structural features of PKS proteins plays a crucial role in discovery of new natural products by genome mining, as well as in design of novel secondary metabolites by biosynthetic engineering. The availability of the crystal structures of various PKS catalytic and docking domains, and mammalian fatty acid synthase module prompted us to develop SBSPKS software which consists of three major components. Model_3D_PKS can be used for modeling, visualization and analysis of 3D structure of individual PKS catalytic domains, dimeric structures for complete PKS modules and prediction of substrate specificity. Dock_Dom_Anal identifies the key interacting residue pairs in inter-subunit interfaces based on alignment of inter-polypeptide linker sequences to the docking domain structure. In case of modular PKS with multiple open reading frames (ORFs), it can predict the cognate order of substrate channeling based on combinatorial evaluation of all possible interface contacts. NRPS-PKS provides user friendly tools for identifying various catalytic domains in the sequence of a Type I PKS protein and comparing them with experimentally characterized PKS/NRPS clusters cataloged in the backend databases of SBSPKS. SBSPKS is available at http://www.nii.ac.in/sbspks.html.

MOJ Proteomics & Bioinformatics, 2015

Many neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are result of... more Many neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are result of synucleinopathies, where neuronal cells show proteinaceous aggregates primarily formed of alpha-synuclein. Understanding the initial steps is crucial toward developing therapeutic strategies to combat these maladies. Using computational approaches, we attempted to understand the initial steps of oligomerization process of SNCA. Using predicted docked models of SNCA dimers, we identified important residues involved in the interaction of the assembly. Using combinatorial library of peptides and docking studies, we found several peptides that have better binding energies than wild type SNCA monomers. These findings will be valuable in guiding rational therapeutic interventions towards major neurodegenerative disorders involving synucleinopathies.

Anti-cancer agents in medicinal chemistry, Jan 18, 2017

Introduction Epidemiological studies indicate that diet rich in fruits and vegetables are associa... more Introduction Epidemiological studies indicate that diet rich in fruits and vegetables are associated with decreased cancer risk thereby indicating that dietary polyphenols can be potential chemo-preventive agents. The reversible nature of epigenetic modifications makes them a favorable target for cancer prevention. Polyphenols have been shown to reverse aberrant epigenetic patterns by targeting the regulatory enzymes, DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). In vitro and in silico studies of DNMTs and HDACs were planned to examine genistein's role as a natural epigenetic modifier in human cervical cancer cells, HeLa. <P></P> Methods Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein. Expression of DNMTs and HDACs was also studied. In-silico studies were performe...

Molecular Cell, 2005

ever, the molecular components of biosynthetic machinery involved in the synthesis of these compl... more ever, the molecular components of biosynthetic machinery involved in the synthesis of these complex Mohd. Zeeshan Ansari, Rashmi Tickoo, lipids have not been elucidated. Vijayalakshmi Sridharan, Debasisa Mohanty, The tremendous efforts in recent years have demonand Rajesh S. Gokhale* strated that a number of mycobacterial lipids are National Institute of Immunology biosynthesized by the combined action of fatty acid Aruna Asaf Ali Marg synthases (FASs) and polyketide synthases (PKSs) New Delhi 110 067 (Camacho et al., 2001; Cox et al., 1999; Kolattukudy et India al., 1997; Sirakova et al., 2001). Whereas FASs are known to catalyze the biosynthesis of fatty acids, PKSs usually produce secondary metabolites that are a rich Summary source of commercially important therapeutic agents (Hopwood, 1997; Khosla, 2000). Traditionally, these Mycobacterium tuberculosis cell envelope is a treamultienzymatic assemblies have been studied indepensure house of biologically active lipids of fascinating dently, and their modes of interaction to produce hybrid molecular architecture. Although genetic studies have molecules of fatty acids and polyketides have not been alluded to an array of genes in biosynthesis of cominvestigated (Gokhale and Tuteja, 2001; Kolattukudy et plex lipids, their mechanistic, structural, and bioal., 1997; Minnikin et al., 2002). In mycobacteria, several chemical principles have not been investigated. Here, PKS disruption mutants display altered lipid profiles, we have dissected the molecular logic underlying the some of which also exhibit attenuation in their virulence biosynthesis of a virulence lipid phthiocerol dimycoproperties (Sirakova et al., 2001; Dubey et al., 2002). cerosate (PDIM). Cell-free reconstitution studies dem-Genetic studies have identified an array of PKS onstrate that polyketide synthases, which are usually genes that are required for biosynthesis of PDIMs and involved in the biosynthesis of secondary metaboglycosylated phenolphthiocerol esters, which are surlites, are responsible for generating complex lipids in face-exposed lipids unique to the virulent strains of mycobacteria. We show that PapA5 protein directly mycobacteria. The pks7, pks10, pks12, ppsA-E, and transfers the protein bound mycocerosic acid ana-pks15/1 mutant strains of M. tuberculosis are deficient logs on phthiocerol to catalyze the final esterification in phthiocerol derivatives and yield strains with attenustep. Based on precise identification of biological ated growth in the murine model (Kolattukudy et al., functions of proteins from Pps cluster, we have ratio-1997; Rousseau et al., 2003; Sirakova et al., 2003a, nally produced a nonmethylated variant of mycocero-2003b). Most of the genes proposed to be involved in sate esters. Apart from elucidating mechanisms that PDIM biosynthesis can be classified in two large clusgenerate chemical heterogeneity with PDIMs, this ters. The pps locus consists of three transcriptional study also presents an attractive approach to explore units with 15 open reading frames and encompasses host-pathogen interactions by altering mycobacterial w50 kbp of the genome. The enzymic activity for three surface coat. of these proteins from pps cluster has been elucidated. We recently characterized FadD26 protein as fatty acyl

Proceedings of the National Academy of Sciences, 2006

Nucleic Acids Research, 2010

BMC Bioinformatics, 2008

Background Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal pep... more Background Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance for natural product based drug discovery, identification of novel secondary metabolite natural products by genome mining has been an area of active research. A number of different tailoring enzymes catalyze a variety of chemical modifications to the polyketide or nonribosomal peptide backbone of these secondary metabolites to enhance their structural diversity. Therefore, development of powerful bioinformatics methods for identification of these tailoring enzymes and assignment of their substrate specificity is crucial for deciphering novel secondary metabolites by genome mining. Results In this work, we have carried out a comprehensive bioinformatics analysis of methyltransferase (MT) domains present ...

BMC …, 2008

Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthe... more Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance ...

Proceedings of the …, 2006

Mycobactins are a family of membrane-associated siderophores required for Mycobacterium tuberculo... more Mycobactins are a family of membrane-associated siderophores required for Mycobacterium tuberculosis to adapt to its intracellular habitat. These lipophilic siderophores have been recently shown to directly acquire intracellular iron through lipid trafficking. Despite tremendous ...

NRPS-PKS is web-based software for analysing large multi-enzymatic, multi-domain megasynthases th... more NRPS-PKS is web-based software for analysing large multi-enzymatic, multi-domain megasynthases that are involved in the biosynthesis of pharmaceutically important natural products such as cyclosporin, rifamycin and erythromycin. NRPS-PKS has been developed based on a comprehensive analysis of the sequence and structural features of several experimentally characterized biosynthetic gene clusters. The results of these analyses have been organized as four integrated searchable databases for elucidating domain organization and substrate specificity of nonribosomal peptide synthetases and three types of polyketide synthases. These databases work as the backend of NRPS-PKS and provide the knowledge base for predicting domain organization and substrate specificity of uncharacterized NRPS/PKS clusters. Benchmarking on a large set of biosynthetic gene clusters has demonstrated that, apart from correct identification of NRPS and PKS domains, NRPS-PKS can also predict specificities of adenylation and acyltransferase domains with reasonably high accuracy. These features of NRPS-PKS make it a valuable resource for identification of natural products biosynthesized by NRPS/PKS gene clusters found in newly sequenced genomes. The training and test sets of gene clusters included in NRPS-PKS correlate information on 307 open reading frames, 2223 functional protein domains, 68 starter/extender precursors and their specific recognition motifs, and also the chemical structure of 101 natural products from four different families. NRPS-PKS is a unique resource which provides a user-friendly interface for correlating chemical structures of natural products with the domains and modules in the corresponding nonribosomal peptide synthetases or polyketide synthases. It also provides guidelines for domain/module swapping as well as site-directed mutagenesis experiments to engineer biosynthesis of novel natural products. NRPS-PKS can be accessed at http://www.nii.res.in/nrps-pks.html.