Curation and analysis of Polyketide Metabolism in Mycobacterium tuberculosis
Kumari Sonal, Institute of Genomics and Integrative Biology, Delhi, India
Anurag Passi, Council of Scientific and Industrial Research, Delhi, India
Vikas Kumar, Goethe University, Frankfurt, Germany
Priti Vishnoi, Institute of Genomics and Integrative Biology, Delhi, India
Keya Mukherjee, Institute of Genomics and Integrative Biology, Delhi, India
OSDD Consortium, Council of Scientific and Industrial Research, Delhi, India
Anshu Bhardwaj, Council of Scientific and Industrial Research, Delhi, India
Background
Polyketides Synthases (PKS) are a class of proteins which catalyze the synthesis and assembly of complex lipids and are responsible for the survival and virulence of Mycobacterium tuberculosis, the causal organism on tuberculosis. PKSs make phthiocerol dimycocerosates (DIMs), mycolic acid and phenolic glycolipids (PGLs) which are the most important component in the mycobacterial cell wall, making it as a central pathway in biosynthesis of mycobacterial lipids [1]. In our work, we developed the metabolic network of PKS genes by systematically curating annotations from literature. Major annotation and pathway databases like Tuberculist, TBDB, KEGG and BioCyc do not have consolidated annotations for this set of proteins e.g. 10 and 8 hypothetical genes in TBDB and tuberculist are provided with more suitable annotations. Annotation and curation was done as part of the Connect2Decode program of Open Source Drug Discovery (OSDD) project of CSIR, India.
Method
We collated information from literature regarding reactions of all 26 genes annotated as PKSs. Of these, 22 PKSs are studied in detail with specific reactions reported for each one of them. We have also included sulfotransferase (stf0) which is not a PKS but the precursor for the start of PKS biosynthetic pathway.
Result and Conclusion
A metabolic map of PKS comprising of 66 nodes and 21 edges is generated in SBML using Cell Designer. This SBML file is analyzed with Cytoscape using the Network Analyzer plugin taking 0.5-0.7 betweeness centrality, as a threshold for drug target analysis. Further literature analysis of the PKS genes highlight the importance of five genes as essential for Mtb growth, survival or virulence. One of these is also reported as a validated drug target (Rv3800c) [2]. In addition, this particular pathway is absent from humans and none of its proteins have any homologs in humans making it a unique target in therapeutic intervention.
References
1. Siméone R. Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis. FEBS J. 2010 Jun; 277(12):2715-25.
2. Sassetti CM. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003 Apr; 48(1):77-84.
(presenting author: Kumari Sonal)
