GGPS1 Gene - Geranylgeranyl Diphosphate Synthase 1
Key enzyme in the mevalonate pathway for protein prenylation and cellular signaling
Gene Information Card
| Symbol | GGPS1 |
|---|---|
| Full Name | Geranylgeranyl Diphosphate Synthase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 1q42.3 |
| NCBI Gene ID | 9453 ncbi.nlm.nih.gov/gene/9453 |
| Ensembl ID | ENSG00000143178 |
| UniProt ID | O95749 |
| OMIM ID | 606982 |
| HGNC ID | 4249 |
| Aliases | GGPPS, GGPP synthase, geranylgeranyl pyrophosphate synthase |
Description
GGPS1 encodes geranylgeranyl diphosphate synthase 1, a key enzyme in the mevalonate pathway that catalyzes the synthesis of geranylgeranyl diphosphate (GGPP) from farnesyl diphosphate (FPP) and isopentenyl diphosphate (IPP). GGPP is essential for protein prenylation, a post-translational modification critical for membrane localization and function of small GTPases such as Rho, Rac, and Cdc42. The enzyme functions as a homodimer and is involved in cellular signaling, proliferation, and differentiation.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Spastic Paraplegia (HSP) | Loss-of-function mutations in GGPS1 impair GGPP synthesis, disrupting protein prenylation and axonal transport in motor neurons. | ClinVar; PMID: 32707084 |
| Charcot-Marie-Tooth Disease Type 2 | Missense variants in GGPS1 cause peripheral neuropathy via defective prenylation of small GTPases. | OMIM #606982; PMID: 32707084 |
| Cancer (multiple types) | Overexpression of GGPS1 in tumors promotes geranylgeranylation of oncogenic GTPases, enhancing cell proliferation and metastasis. | COSMIC; PMID: 25691885 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 38.2 | High |
| Adrenal gland | 22.5 | Medium |
| Liver | 18.7 | Medium |
| Brain (cerebellum) | 15.3 | Medium |
| Heart | 12.1 | Medium |
| Lung | 9.8 | Low |
| Kidney | 8.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 25.4 | Embryonic kidney cells; high expression |
| HeLa | 20.1 | Cervical carcinoma; moderate expression |
| HepG2 | 18.9 | Hepatocellular carcinoma; moderate expression |
| A549 | 15.2 | Lung carcinoma; moderate expression |
| K562 | 12.3 | Leukemia; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.100G>A (p.Gly34Arg) | Missense | Rare | Loss of enzymatic activity; associated with HSP |
| c.769C>T (p.Arg257Trp) | Missense | Rare | Reduced GGPP production; linked to CMT2 |
| c.1120_1121insA (p.Thr374Asnfs*12) | Frameshift | Very rare | Premature truncation; loss of function |
| c.854A>G (p.Asn285Ser) | Missense | Rare | Decreased dimer stability; pathogenic |
Mutation functional classification
Loss of Function (LOF)
Missense and frameshift mutations that reduce or abolish GGPS1 enzymatic activity, leading to decreased GGPP levels and impaired prenylation of small GTPases.
Gain of Function (GOF)
Not reported; no activating mutations have been described in GGPS1.
Dominant Negative (DN)
Some missense variants (e.g., p.Gly34Arg) may exert dominant-negative effects by forming inactive heterodimers with wild-type enzyme.
View complete mutation data：
Gene Ontology (GO)
| • geranylgeranyl diphosphate synthase activity (GO:0004337) | • isoprenoid biosynthetic process (GO:0008299) |
| • isopentenyl diphosphate biosynthetic process (mevalonate pathway) (GO:0019287) | • cytosol (GO:0005829) |
| • mitochondrion (GO:0005739) | • membrane (GO:0016020) |
Pathways
• Mevalonate pathway (KEGG: hsa00900)
• Terpenoid backbone biosynthesis (KEGG: hsa00900)
• Protein prenylation (Reactome: R-HSA-597592)
Protein Summary
The GGPS1 protein (UniProt O95749) is a 374-amino acid homodimeric enzyme localized primarily in the cytosol and mitochondria. It catalyzes the condensation of farnesyl diphosphate (FPP) with isopentenyl diphosphate (IPP) to form geranylgeranyl diphosphate (GGPP), a 20-carbon isoprenoid lipid. GGPP is a substrate for geranylgeranyltransferase I and II, which modify C-terminal cysteine residues of small GTPases (e.g., Rho, Rac, Rab) for membrane anchoring. The enzyme contains two conserved aspartate-rich motifs (DDXXD) essential for substrate binding and catalysis. Structural studies reveal a dimeric alpha-helical fold with a central active site cavity.
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