GGPS1: Human Geranylgeranyl pyrophosphate synthase
PDB Code: 2Q80
Geranylgeranyl pyrophosphate synthase (GGPPS, EC 22.214.171.124) is an enzyme in the mevalonate pathway beyond the key branch point characterised by Farnesyl pyrophosphate synthase. GGPPS is an Mg2+ dependent homohexameric enzyme that catalyses the production of the C20 all- trans -geranylgeranyl pyrophosphate from the condensation of C15 farnesyl pyrophosphate and C5 isopentenyl pyrophosphate although the enzyme can also utilise C10 geranyl pyrophosphate as a substrate. The enzyme is thought to be cytosolic and is expressed mainly in brain, testes, spleen, liver and kidney. The C20 product, GGPP is mainly used for the post-translational modification of proteins with a C-terminal CAAX motif such as the small GTPases Rho, Rac, Cdc42, Rabs etc, and also nuclear lamins. The C terminal addition of GGPP to these proteins is absolutely essential for the correct subcellular localisation and regulation. The small GTPases are a crucial part of many major cellular processes such as subcellular transport, cytoskeletal organisation, cell motility and growth - all of which are deeply involved in many pathological conditions thus giving GGPP synthase potential as a drug target.
GGPP synthase is also of interest as a possible target of the nitrogen containing bisphosphonates which are currently the main therapeutic approach for the treatment of disease characterised by bone loss.
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