Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate- independent isoprenoid biosynthesis.
The YgbP protein of Escherichia coli encodes the enzyme 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) synthetase, a member of the cytidyltransferase family of enzymes. CDP-ME is an intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, algae, the plant plastids and the malaria parasite. Because vertebrates synthesize isoprenoid precursors using a mevalonate pathway, CDP-ME synthetase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal and antimalarial drugs. The high-resolution structures of E. coli CDP-ME synthetase in the apo form and complexed with both CTP-Mg2+ and CDP-ME-Mg2+ reveal the stereochemical principles underlying both substrate and product recognition as well as catalysis in CDP-ME synthetase. Moreover, these complexes represent the first experimental structures for any cytidyltransferase with both substrates and products bound.
Richard
S B
SB
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Bowman
M E
ME
Kwiatkowski
W
W
Kang
I
I
Chow
C
C
Lillo
A M
AM
Cane
D E
DE
Noel
J P
JP
D001051:Apoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D003565:Cytidine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D003570:Cytidine Triphosphate / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D015195:Drug Design; D004896:Erythritol / Q000031:analogs & derivatives* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D008798:Mevalonic Acid / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013403:Sugar Phosphates / Q000378:metabolism
C114232:2-C-methylerythritol 4-phosphate; C400182:4-diphosphocytidyl-2-C-methylerythritol; D001051:Apoenzymes; D011106:Polyisoprenyl Phosphates; D013403:Sugar Phosphates; D003565:Cytidine Diphosphate; D003570:Cytidine Triphosphate; C400183:4-diphosphocytidyl-2-C--methylerythritol synthase; D009713:Nucleotidyltransferases; D004896:Erythritol; D008798:Mevalonic Acid