LAUSR

Biocatalysts utilize allosteric mechanisms to control selectivity, catalytic activity, and the transport of reaction components. The allosteric control of catalysis has a high potential for the development of drugs and technologies. In particular, it opens the way to specific regulation of vital enzymes with conserved active sites. Using the central metabolic enzyme UDP-glucose pyrophosphorylase from the pathogen Leishmania major (LmUGP), we demonstrate how specific allosteric inhibition sites and their links to the catalytic center can be revealed rationally, through analysis of molecular interfaces along the enzymatic reaction cycle. Two previously unknown specific allosteric inhibition sites in LmUGP were rationally identified and experimentally verified. The molecular scaffold for allosteric inhibitor targeting the pathogen’s enzyme was developed. This led to the identification of murrayamine-I as an allosteric inhibitor that selectively blocks LmUGP. The presented approach opens up the possibility of...