Molecular targets of the nitrogen containing bisphosphonates: the molecular pharmacology of prenyl synthase inhibition.
The nitrogen containing bisphosphonates (N-BP) are the drug of choice for treating disease characterised by resorption of bone such as osteoporosis and metastatic bone disease. The overall mechanism of action is achieved through a combination of precise targeting to the bone environment and an extremely potent inhibition of a vital enzyme in an essential metabolic pathway. This targeting to bone is achieved through the phosphate-carbon-phosphate backbone of the drug which gives a high affinity for bone mineral. Once bound to bone the N-BP can be internalised by osteoclasts as they resorb bone where the drug can then interact with its molecular target. The enzyme target of these drugs, FPP synthase, is at a branch point in the mevalonate pathway. This pathway is principally used for the manufacture of cholesterol but also many other biochemicals including farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These prenyl groups are used in the post-transcriptional modification of proteins such as small GTPases that require a lipid membrane anchor to function. The main cellular effect of the blockade of FPP synthase by N-BP is to prevent protein prenylation resulting in disruption to vital signalling pathways and loss of osteoclast function. This review will examine the biochemistry of FPP synthase, inhibition by the N-BP and and other potential uses of prenyl synthase inhibitors.
Dunford
J E
JE
Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Science, The Botnar Research Centre, University of Oxford, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK. james.dunford@ndorms.ox.ac.uk
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy; D001862:Bone Resorption / Q000188:drug therapy; D020134:Catalytic Domain; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009584:Nitrogen / Q000737:chemistry; D010024:Osteoporosis / Q000188:drug therapy; D017368:Protein Prenylation / Q000187:drug effects; D013329:Structure-Activity Relationship
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D004122:Dimethylallyltranstransferase; D051228:Geranyltranstransferase; D009584:Nitrogen