bioRxiv Biochemistry
bioRxiv Biochemistry
5 years ago

Evolution of chalcone isomerase from a non-catalytic ancestor

D. S., Kaltenbach, Munsberg, F. S., M., A., J. R., S. C. L., J. P., Tawfik, Rabin, Pabis, Dindo, Burke, Kamerlin, Noel
The emergence of catalysis in a non-catalytic protein scaffold is a rare, unexplored event. Chalcone isomerase (CHI), a key enzyme in plant flavonoid biosynthesis, is presumed to have evolved from a non-enzymatic ancestor related to the widely-distributed fatty-acid binding proteins (FAPs) and a plant protein family with no isomerase activity (CHILs for CHI-like). Ancestral inference confirmed that CHI evolved from a protein lacking isomerase activity. We also identified four alternative founder mutations, i.e. mutations that individually instated activity, including a mutation that is not phylogenetically traceable. Despite strong epistasis in other cases of protein evolution, the laboratory reconstructed mutational trajectory shows weak epistasis. Thus, enantioselective CHI activity can readily emerge despite a catalytically inactive starting point. X-ray crystallography, NMR, and MD simulations reveal reshaping of the active site toward a productive substrate-binding mode and repositioning of the catalytic arginine that was inherited from the ancestral fatty-acid binding proteins.

Publisher URL: http://biorxiv.org/cgi/content/short/174128v1

DOI: 10.1101/174128

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