Structure of 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase involved in mevalonate-independent biosynthesis of isoprenoids.
Isoprenoids are biosynthesized from isopentenyl diphosphate and the isomeric dimethylallyl diphosphate via the mevalonate pathway or a mevalonate-independent pathway that was identified during the last decade. The non-mevalonate pathway is present in many bacteria, some algae and in certain protozoa such as the malaria parasite Plasmodium falciparum and in the plastids of higher plants, but not in mammals and archaea. Therefore, these enzymes have been recognised as promising drug targets. We report the crystal structure of Escherichia coli 2C- methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), which converts 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate into 2C-methyl-d-erythritol 2,4-cyclodiphosphate and CMP in a Mg-dependent reaction. The protein forms homotrimers that tightly bind one zinc ion per subunit at the active site, which helps to position the substrate for direct attack of the 2-phosphate group on the beta-phosphate.
Steinbacher
Stefan
S
Abteilung für Strukturforschung, Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, Martinsried, D-82152, Germany. steinbac@biochem.mpg.de
Kaiser
Johannes
J
Wungsintaweekul
Juraithip
J
Hecht
Stefan
S
Eisenreich
Wolfgang
W
Gerhardt
Stefan
S
Bacher
Adelbert
A
Rohdich
Felix
F
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002384:Catalysis; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003568:Cytidine Monophosphate / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins; D008798:Mevalonic Acid / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019761:Phosphorus-Oxygen Lyases; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D055672:Static Electricity; D015032:Zinc / Q000378:metabolism
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D011106:Polyisoprenyl Phosphates; D019761:Phosphorus-Oxygen Lyases; C400181:ISPF protein, E coli; D003568:Cytidine Monophosphate; D015032:Zinc; D008798:Mevalonic Acid