Geranylgeranyl diphosphate synthase 1 (GGPS1)

Geranylgeranyl diphosphate synthase 1 (GGPS1) is an enzyme of the prenyltransferase family responsible for catalyzing the synthesis of geranylgeranyl diphosphate (GGPP) from farnesyl diphosphate and isopentenyl diphosphate. GGPP is essential for the post-translational geranylgeranylation of proteins, notably small GTPases such as members of the Ras family, which are involved in signal transduction, cytoskeletal dynamics, and intracellular transport. GGPS1 is ubiquitously expressed in human tissues, with highest expression in the testis, and plays critical physiological roles across multiple organ systems. Dysfunction or mutations in GGPS1 are linked to various diseases including muscular dystrophy, congenital hearing loss, ovarian insufficiency, and have been implicated in pathologies such as cancer, liver disease, diabetes, and pulmonary disease. Therapeutically, GGPS1 is targeted by bisphosphonate drugs, commonly used in osteoporosis treatment, which can lead to adverse effects including atypical fractures, especially in individuals with certain GGPS1 mutations. The enzyme's role in regulating prenylation highlights its significance in metabolic and signalling networks, making it a relevant target for drug development and a potential biomarker for disease state and treatment response.

Other names

Geranylgeranyl pyrophosphate synthaseGGPP synthaseGGPPSase(2E,6E)-farnesyl diphosphate synthaseDimethylallyltranstransferaseFarnesyl diphosphate synthaseFarnesyltranstransferaseGeranyltranstransferaseGGPPSMDHLOMUDHLOV

Inhibition of GGPP synthesis (prevents protein prenylation, affects signalling). Bisphosphonates bind and inhibit the active site, reducing enzyme activity, affecting osteoclast function and bone remodeling. Modulation of prenylation can disrupt Ras/Rho GTPase signalling relevant to cancer/insulin resistance.