2 research outputs found
Decoding Allosteric Networks in Biocatalysts: Rational Approach to Therapies and Biotechnologies
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 using central metabolic enzymes with highly conserved active sites
as allosteric drug targets, thus solving the cross-reactivity problem.
In particular, it paves the ways to antimicrobial treatments
Total Syntheses of Murrayamine E, I, and K
We describe efficient synthetic routes
to murrayamine A (mukoenine
C), <i>O</i>-methylmurrayamine A, mahanine, <i>O</i>-methylmahanine, and murrayamine D and the first total syntheses
of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction
of the carbazole framework and an annulation of the pyran ring, which
is either catalyzed by phenylboronic acid or promoted by a Lewis acid