Tuesday, October 9 2018
15:30 - 16:30

Alladi Ramakrishnan Hall

Genome-Enabled Molecular Synthesis Unraveling New Natural Product Pathways in Cyanobacteria and Marine Actinomycetes

Rajesh Viswanathan

Biology and Chemistry, IISER Tirupati

Natural products remain as a significant resource of chemically diverse drug discovery leads. Marine actinomycetes and soil cyanobacteria are prolific producers of complex natural products. These organisms biochemically encode for chemical transformations that assemble these complex natural products through novel enzymatic machinery. My laboratory has applied organic synthesis of natural products to complement recent genome sequencing efforts for microbial organisms belonging to the actinomycete genus (Nocardiopsis) and soil cyanobacterial genus (Fischerella). Sequencing and assembly of the Nocardiopsis sp. CMB-M0232 genome yielded a ∼6.4 Mbp draft with >5500 open reading frames (ORFs). The biosynthesis of diketopiperazine family of natural products involved a cryptic cyclo dipeptide synthase (CDPS) machinery (NozA and NcdA) for selectively dimerizing L-tryptophan through the recruitment of aminoacyl-tRNA substrates. This was non-intuitive, because predominantly most L-Trp derived diketopiperazine natural product biosynthesis involve a non-ribosomal peptide synthetase (NRPS) assembly. Product of this biosynthetic step (cyclo-L-Trp-L-Trp DKP) serves as a crucial intermediate (albeit an unknown isomerization event) to the construction of nocardioazines A and B. Steps leading to the construction of the nocardioazines involve regio- and stereoselective indole-C3 prenylation, indole-C3-methylation (each with concomitant ring formations) and follow-up tailoring oxidations and N-methylation chemistries. Using synthesis and mass spectrometry, we reconstructed these steps and verified the order of each biochemical event, thus adding functional validity to the genes identified in their biosynthetic cluster. The second family of alkaloids, with novel biochemical mechanisms arising out of genome sequencing efforts involve the cyanobacterial indole alkaloids belonging to the hapalindole class of natural products. This biosynthetic machinery involves promiscuous isonitrile synthase, alpha-keto glutarate-dependent
oxygenases and prenyltransferase with novel pericyclic reactions implicated in their assembly. Synthetic mimicry of prenyltransfer and pericyclic steps from the cyanobacterial and actinomycete pathways have connections to those observed in ergot alkaloid biosynthesis, compelling us to revise literature from past 30 years or so.

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