Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: implications for drug design.
Typanosoma cruzi, the causative agent of Chagas disease, has recently been shown to be sensitive to the action of the bisphosphonates currently used in bone resorption therapy. These compounds target the mevalonate pathway by inhibiting farnesyl diphosphate synthase (farnesyl pyrophosphate synthase, FPPS), the enzyme that condenses the diphosphates of C5 alcohols (isopentenyl and dimethylallyl) to form C10 and C15 diphosphates (geranyl and farnesyl). The structures of the T. cruzi FPPS (TcFPPS) alone and in two complexes with substrates and inhibitors reveal that following binding of the two substrates and three Mg2+ ions, the enzyme undergoes a conformational change consisting of a hinge-like closure of the binding site. In this conformation, it would be possible for the enzyme to bind a bisphosphonate inhibitor that spans the sites usually occupied by dimethylallyl diphosphate (DMAPP) and the homoallyl moiety of isopentenyl diphosphate. This observation may lead to the design of new, more potent anti-trypanosomal bisphosphonates, because existing FPPS inhibitors occupy only the DMAPP site. In addition, the structures provide an important mechanistic insight: after its formation, geranyl diphosphate can swing without leaving the enzyme, from the product site to the substrate site to participate in the synthesis of farnesyl diphosphate.
Gabelli
Sandra B
SB
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
McLellan
Jason S
JS
Montalvetti
Andrea
A
Oldfield
Eric
E
Docampo
Roberto
R
Amzel
L Mario
LM
D019386:Alendronate / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D012968:Etidronic Acid / Q000031:analogs & derivatives; D051228:Geranyltranstransferase / Q000737:chemistry* / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D000068296:Risedronic Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014344:Trypanocidal Agents / Q000737:chemistry; D014349:Trypanosoma cruzi / Q000201:enzymology*
D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D051228:Geranyltranstransferase; D008274:Magnesium; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate