Dissecting the functional role of polyketide synthases in Dictyostelium discoideum

Dictyostelium discoideum exhibits the largest repository of polyketide synthase (PKS) proteins of all known genomes. However, the functional relevance of these proteins in the biology of this organism remains largely obscure. On the basis of computational, biochemical, and gene expression studies, we propose that the multifunctional Dictyostelium PKS (DiPKS) protein DiPKS1 could be involved in the biosynthesis of the differentiation regulating factor 4-methyl-5-pentylbenzene-1,3-diol (MPBD). Our cell-free reconstitution studies of a novel acyl carrier protein Type III PKS didomain from DiPKS1 revealed a crucial role of protein-protein interactions in determining the final biosynthetic product. Whereas the Type III PKS domain by itself primarily produces acyl pyrones, the presence of the interacting acyl carrier protein domain modulates the catalytic activity to produce the alkyl resorcinol scaffold of MPBD. Furthermore, we have characterized an O-methyltransferase (OMT12) from Dictyostelium with the capability to modify this resorcinol ring to synthesize a variant of MPBD. We propose that such a modification in vivo could in fact provide subtle variations in biological function and specificity. In addition, we have performed systematic computational analysis of 45 multidomain PKSs, which revealed several unique features in DiPKS proteins. Our studies provide a new perspective in understanding mechanisms by which metabolic diversity could be generated by combining existing functional scaffolds

Antiviral Agents against Flavivirus Protease: Prospect and Future Direction

Flaviviruses cause a significant amount of mortality and morbidity, especially in regions where they are endemic. A recent example is the outbreak of Zika virus throughout the world. Development of antiviral drugs against different viral targets is as important as the development of vaccines. During viral replication, a single polyprotein precursor (PP) is produced and further cleaved into individual proteins by a viral NS2B-NS3 protease complex together with host proteases. Flavivirus protease is one of the most attractive targets for development of therapeutic antivirals because it is essential for viral PP processing, leading to active viral proteins. In this review, we have summarized recent development in drug discovery targeting the NS2B-NS3 protease of flaviviruses, especially Zika, dengue, and West Nile viruses.National Institute of Allergy and Infectious DiseasesOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

<smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="place" downloadurl="http://www.5iantlavalamp.com/"> Global HIV-1 molecular epidemiology with special reference to genetic analysis of HIV-1 subtypes circulating in North India: Functional and pathogenic implications of genetic variation </smarttagtype>

424-431 HIV-1 displays extensive genetic diversity globally which poses challenge in designing a suitable antigen/immunogen to provoke desired protective immune response in host. HIV-1 mediated pathogenesis is complex and involves host genes, virus genes and other factors. A number of genetic subtypes have been identified based on sequence variations, largely in envelope region. Different genetic subtypes display variation in amino acid sequences with increasing incidence of subtype B, C, D and mosaic recombinants in India. They can potentially alter the functions of several proteins like Rev, Tat ,Vpr, Vif etc and thereby, influence HIV-1 mediated pathogenesis. Recent study has shown that LTR promoter region exhibits novel mosaic structures with segments from B/C Myanmar and India. This indicates rapid evolving nature of HIV-1 and causing epidemics due to existence of multiple subtypes in Indian region. These multiple subtypes show significant differences in various functions (gene activation, cell cycle arrest, RNA binding activities) compared to prototype subtype B genes. These differences may help in better understanding of unique features of HIV-1 epidemic in India. </smarttagtype