Pseudilins: halogenated, allosteric inhibitors of the non-mevalonate pathway enzyme IspD.
The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis have been identified as attractive targets with novel modes of action for the development of herbicides for crop protection and agents against infectious diseases. This pathway is present in many pathogenic organisms and plants, but absent in mammals. By using high-throughput screening, we identified highly halogenated marine natural products, the pseudilins, to be inhibitors of the third enzyme, IspD, in the pathway. Their activity against the IspD enzymes from Arabidopsis thaliana and Plasmodium vivax was determined in photometric and NMR-based assays. Cocrystal structures revealed that pseudilins bind to an allosteric pocket by using both divalent metal ion coordination and halogen bonding. The allosteric mode of action for preventing cosubstrate (CTP) binding at the active site was elucidated. Pseudilins show herbicidal activity in plant assays and antiplasmodial activity in cell-based assays.
Center for Integrated Protein Science Munich, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching (Germany).
Andrea
A
Kunfermann
Matthias
M
Witschel
Boris
B
Illarionov
René
R
Martin
Matthias
M
Rottmann
H Wolfgang
HW
Höffken
Michael
M
Seet
Wolfgang
W
Eisenreich
Hans-Joachim
HJ
Knölker
Markus
M
Fischer
Adelbert
A
Bacher
Michael
M
Groll
François
F
Diederich
D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D017360:Arabidopsis / Q000201:enzymology; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D054879:Halogenation; D006540:Herbicides / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008798:Mevalonic Acid / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010966:Plasmodium vivax / Q000201:enzymology; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000470:Alkaloids; D001688:Biological Products; D006540:Herbicides; D009097:Multienzyme Complexes; D010940:Plant Proteins; D015800:Protozoan Proteins; D008798:Mevalonic Acid
allosteric inhibition; antiinfectives; drug discovery; halogen bonding; herbicides; pseudilins