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.
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Alkaloids
Alkaloids U 0600First Total Synthesis of the Neuronal Cell Protecting Carbazole Alkaloid Carbazomadurin A by Sequential Transition Metal-Catalyzed Reactions. -The title alkaloid (XIII) is obtained from isovanillic acid (I) in nine steps and 11% overall yield involving the palladium-catalyzed fusion of the three building blocks (V), (VI), and (X) as well as the oxidative cyclization of diarylamine (VII). The stereospezific construction of the trisubstituted double bond of the side chain of (XIII), (X), is achieved by employing a zirconium-catalyzed carboalumination of alkynes. Building block (VI) is synthesized from 2-bromo-6-nitrotoluene via hydrogenation, diazotization, alkylation, nitration, and reduction in six steps and 44% overall yield. -(KNOELKER*, H.-J.; KNOELL, J.; Chem.
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