Loading…
Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase
Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartat...
Saved in:
Published in: | Biochemical and biophysical research communications 2018-03, Vol.497 (3), p.835-842 |
---|---|
Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.
•A novel inhibitor of the malarial ATC is described.•X-ray data show that it binds close to the active site.•Kinetic analysis of the mode of inhibition is presented.•An allosteric mechanism of inhibition is proposed.•An initial structure activity relationship is described. |
---|---|
ISSN: | 0006-291X 1090-2104 |
DOI: | 10.1016/j.bbrc.2018.02.112 |