Biochemistry

Abstract

CANCELLED | CS-1-5 - Type III PKS and biodiversity of plant secondary metabolites: Can we manipulate it for the production of novel molecules?

Sunday, July 15
2:23 PM - 2:43 PM

This presentation has been CANCELLED.


Type III Polyketide synthases (PKSs) forms a group of ‘fascinating biosynthetic enzymes’ involved in the biosynthesis of varied polyketides with numerous applications in pharmaceutical industry. These enzymes catalyze the production of various secondary metabolites in plants such as chalcones, acridones, quinolones, curcuminoids etc. Structurally, they are homodimeric proteins, where the active site in each monomeric subunit iteratively catalyzes the priming, extension and cyclization reactions to produce an array of plant secondary metabolites. The simple structure, catalytic versatility and wide-ranging substrate specificity of type III PKSs make them as one of the best candidates for the engineering of biocatalysts. They can accept a number of unnatural substrates and produces novel structural scaffolds with intense therapeutic potential.


In our studies we have identified and characterized a quinolone and acridone forming type III PKS from Indian Bael tree (Aegle marmelos Correa) (AmQNS). The reaction involves decarboxylative condensation of malonyl-CoA with N-methylanthraniloyl-CoA to form an intermediate, which spontaneously cyclize by amide formation to yield 4-hydroxy- 2(1H)-quinolone. AmQNS can also synthesize benzalacetone by using p-coumaroyl-CoA as starter substrate. Modeling and structural analysis suggested that the CoA-binding tunnel and the catalytic triad (C-H-N) are maintained in AmQNS, with minute alterations (CHS-conserved residues Thr132, Ser133, and Phe265 are replaced by Ser132, Ala133, and Val265, respectively) in the functionally important region. Kinetic studies revealed that the catalytic efficiency of AmQNS to accept larger acyl-CoA’s are several fold higher than that for smaller substrates. The catalytic and structural significance of active site residues were investigated through site-directed mutagenesis. Modeling studies suggested that AmQNS might have emerged by the gain of function (by the substitution of two active site residues) mutation from a structural homolog ‘chalcone synthase (CHS), a type III protein’ and provided an insight into the enzymatic mechanism that could be used to produce pharmaceutically significant products.


 

Soniya V. Eppurath

Scientist F
Rajiv Gandhi Centre for Biotechnology

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