geranylgeranyl diphosphate synthase | Lanosterol biosynthesis pathway | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

Top ▲

geranylgeranyl diphosphate synthase

Target id: 643

Nomenclature: geranylgeranyl diphosphate synthase

Family: Lanosterol biosynthesis pathway

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 300 1q43 GGPS1 geranylgeranyl diphosphate synthase 1 1,13
Mouse - 236 13 A1; 13 8.0 cM Ggps1 geranylgeranyl diphosphate synthase 1
Rat - 300 17q12.1 Ggps1 geranylgeranyl diphosphate synthase 1
Previous and Unofficial Names
farnesyltransferase | geranylgeranyl pyrophosphate synthase | geranylgeranyl-PP synthetase | GGDPS | GGPP synthase | GGPPS | GGPS | GGSP1 | (2E,6E)-farnesyl diphosphate synthase | Crlf3 | dimethylallyltranstransferase | farnesyltranstransferase | geranyltranstransferase | GGPPSase | GGPPS1
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human geranylgeranyl pyrophosphate synthase bound to GGPP
PDB Id:  2Q80
Ligand:  geranylgeranyl diphosphate   This ligand is endogenous
Resolution:  2.7Å
Species:  Human
References:  5
Enzyme Reaction
EC Number: 2.5.1.1 Dimethylallyl diphosphate + isopentenyl diphosphate = geranyl diphosphate + diphosphate
EC Number: 2.5.1.10 Geranyl diphosphate + isopentenyl diphosphate -> trans,trans-farnesyl diphosphate + diphosphate
EC Number: 2.5.1.29 Trans,trans-farnesyl diphosphate + isopentenyl diphosphate -> geranylgeranyl diphosphate + diphosphate
Substrates and Reaction Kinetics
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
trans,trans-farnesyl diphosphate Hs Kcat 0.2 s-1 Recombinant enzyme expressed in E coli, in vitro assay. pH 7.7, 37°C Steady state kinetics. Concentration of isopentenyl diphosphate varied between 0.2-20 micromolar; 2mM MgCl2 5
isopentenyl diphosphate Rn Km 2.9x10-6 M pKm 5.5 Recombinant wild type enzyme expressed in E coli, in vitro assay pH 7.0, 37°C, Concentrations of substrates: 20µM IPP, 5mM MgCl2 6
isopentenyl diphosphate Hs Km 3x10-6 M pKm 5.5 Recombinant enzyme expressed in E coli, in vitro assay. pH 7.7, 37°C Concentration of isopentenyl diphosphate varied between 0.2-20 micromolar; 2mM MgCl2 5
trans,trans-farnesyl diphosphate Rn Km 7.1x10-7 M pKm 6.1 Recombinant wild type enzyme expressed in E coli, in vitro assay pH 7.0, 37°C, Concentrations of substrates: 20µM FPP, 5mM MgCl2 6
trans,trans-farnesyl diphosphate Hs Km 4.2x10-6 M pKm 5.4 Recombinant enzyme expressed in E coli, in vitro assay. pH 7.7, 37°C Steady state kinetics. Concentration of isopentenyl diphosphate varied between 0.2-20 micromolar; 2mM MgCl2 5
isopentenyl diphosphate Hs Vmax 12.7 nmol/min/nmol Recombinant enzyme expressed in E coli, in vitro assay. 80ng of enzyme in assay pH 7.7, 37°C. Steady state kinetics. Concentration of isopentenyl diphosphate varied between 0.2-20 micromolar; 2mM MgCl2 5
Cofactors
Cofactor Species Comments Reference
Zn2+ Human 10
Mg2+ Human Also characterised in mice 5,10,12
Mn2+ Mouse 12

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BPH-608 Hs Inhibition 7.2 pKi 3
pKi 7.2 (Ki 6x10-8 M) [3]
BPH-675 Hs Inhibition 7.2 pKi 3
pKi 7.2 (Ki 7x10-8 M) [3]
BPH-629 Hs Inhibition 7.0 pKi 3
pKi 7.0 (Ki 1.1x10-7 M) [3]
BPH-676 Hs Inhibition 7.0 pKi 3
pKi 7.0 (Ki 1.1x10-7 M) [3]
geranylgeranyl diphosphate Hs Feedback inhibition 4.6 pKi 5
pKi 4.6 (2.5x10-5 M) [5]
Description: recombinant human protein expressed in E coli, in vitro assay
Conditions: The concentration of GGPP varied between 0.4-40µM. pH 7.7, 37°C
BPH-742 Hs Inhibition 7.0 pIC50 4
pIC50 7.0 (IC50 1x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
(2E, 6E)-farnesylbisphosphonate Hs Inhibition 7.0 pIC50 11
pIC50 7.0 (IC50 1x10-7 M) [11]
Description: Inhibition of GST-tagged human recombinant GGDPS expressed in BL21 gold bacteria
Conditions: Concentrations of substrates: 20µM FPP, 40µM IPP in 35µL buffer. pH 7.5, 37°C
3-azageranylgeranyl diphosphate Hs Inhibition 6.8 pIC50 9
pIC50 6.8 (IC50 1.4x10-7 M) [9]
Description: Inhibitory activity against the human recombinant geranylgeranyl diphosphate synthase (GGPPSase).
Conditions: Concentration of substrates: 25µM GPP or FPP, addition of 1.5µL of a 0.35mM solution of IPP. pH 7.9, 37°C
compound 14 [PMID: 18800762] Hs Inhibition 6.6 pIC50 4
pIC50 6.6 (IC50 2.8x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
BPH-715 Hs Inhibition 6.6 pIC50 4
pIC50 6.6 (IC50 2.8x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
compound 12 [PMID: 12014956] Hs Inhibition 6.5 pIC50 9
pIC50 6.5 (IC50 3.1x10-7 M) [9]
Description: Inhibitory activity against the human recombinant geranylgeranyl diphosphate synthase (GGPPSase).
Conditions: Concentration of substrates: 25µM GPP or FPP, addition of 1.5µL of a 0.35mM solution of IPP. pH 7.9, 37°C
compound 16 [PMID: 18800762] Hs Inhibition 6.5 pIC50 4
pIC50 6.5 (IC50 3.5x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH, 7.9, 37°C. Concentration of substrate: 25µM FPP or GPP
digeranyl bisphosphonate Hs Inhibition 6.0 – 6.7 pIC50 4,10
pIC50 6.7 (IC50 2x10-7 M) [10]
Description: recombinant human protein expressed in BL21 gold bacteria, purified, in vitro assay
Conditions: pH 7.5, 37°C. Substrate concentrations: 20µM FPP, 40µM IPP and 207micro;M GPP.
pIC50 6.0 [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
compound 19 [PMID: 18800762] Hs Inhibition 6.2 pIC50 4
pIC50 6.2 (IC50 5.9x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
BPH-252 Hs Inhibition 6.1 – 6.2 pIC50 4,9
pIC50 6.2 (IC50 7.1x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
pIC50 6.1 (IC50 7.2x10-7 M) [9]
Description: Inhibitory activity against the human recombinant geranylgeranyl diphosphate synthase (GGPPSase).
Conditions: Concentration of substrates: 25µM GPP or FPP, addition of 1.5µL of a 0.35mM solution of IPP. pH 7.9, 37°C
BPH-628 Hs Inhibition 6.1 pIC50 3-4
pIC50 6.1 (IC50 7.2x10-7 M) [3]
Description: Inhibition of human GGPPS; radiometric assay
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM GPP or FPP.
pIC50 6.1 (IC50 7.2x10-7 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
compound 11 [PMID: 18800762] Hs Inhibition 5.6 pIC50 4
pIC50 5.6 [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
minodronic acid Hs Inhibition 4.0 – 6.2 pIC50 4,8
pIC50 6.2 (IC50 6.7x10-7 M) [8]
Description: Inhibition of GGPPS after 10 mins using [14C]IPP as substrate by liquid scintillation counting
Conditions: Concentration of substrates: 50µM IPP, 50µM FPP.
pIC50 4.0 [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
compound 47 [PMID: 18800762] Hs Inhibition 4.6 pIC50 4
pIC50 4.6 (IC50 2.754x10-5 M) [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP
compound 51 [PMID: 18800762] Hs Inhibition 4.1 pIC50 4
pIC50 4.1 [4]
Description: Inhibition of human recombinant geranylgeranyl diphosphate synthase
Conditions: pH 7.0, 37°C. Concentration of substrate: 25µM FPP or GPP

Some of the inhibitors above have been selected as representative structures from sets of stucturally similar compounds with bioactivity data at this target on ChEMBLdb.

Click here for a summary of the ChEMBL bioactivity data 


Tissue Distribution
Testis
Expression level:  High
Species:  Human
Technique:  Western blot
References:  1
Pancreas, kidney, muscle, liver, lung, placenta, brain, heart, peripheral leukocytes, colon, small intestine, ovary, prostate, thymus, spleen
Expression level:  Low
Species:  Human
Technique:  Western blot
References:  1
Brain, liver, heart, thymus, testis, ovary
Species:  Rat
Technique:  RT-PCR
References:  7
Liver, brain, spleen, testis, kidney
Species:  Rat
Technique:  Unspecified
References:  2
General Comments
Geranylgeranyl diphosphate synthase has two binding sites, one binding substrate geranyl diphosphate and the other trans,trans-farnesyl diphosphate. This is reflective of its dual functionality and multiple EC number allocation [4].

References

Show »

1. Ericsson J, Greene JM, Carter KC, Shell BK, Duan DR, Florence C, Edwards PA. (1998) Human geranylgeranyl diphosphate synthase: isolation of the cDNA, chromosomal mapping and tissue expression. J. Lipid Res., 39 (9): 1731-9. [PMID:9741684]

2. Ericsson J, Runquist M, Thelin A, Andersson M, Chojnacki T, Dallner G. (1993) Distribution of prenyltransferases in rat tissues. Evidence for a cytosolic all-trans-geranylgeranyl diphosphate synthase. J. Biol. Chem., 268 (2): 832-8. [PMID:8419360]

3. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y et al.. (2007) Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc. Natl. Acad. Sci. U.S.A., 104 (24): 10022-7. [PMID:17535895]

4. K-M Chen C, Hudock MP, Zhang Y, Guo RT, Cao R, No JH, Liang PH, Ko TP, Chang TH, Chang SC et al.. (2008) Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J. Med. Chem., 51 (18): 5594-607. [PMID:18800762]

5. Kavanagh KL, Dunford JE, Bunkoczi G, Russell RG, Oppermann U. (2006) The crystal structure of human geranylgeranyl pyrophosphate synthase reveals a novel hexameric arrangement and inhibitory product binding. J. Biol. Chem., 281 (31): 22004-12. [PMID:16698791]

6. Matsumura Y, Kidokoro T, Miyagi Y, Marilingaiah NR, Sagami H. (2007) The carboxyl-terminal region of the geranylgeranyl diphosphate synthase is indispensable for the stabilization of the region involved in substrate binding and catalysis. J. Biochem., 142 (4): 533-7. [PMID:17846065]

7. Matsumura Y, Kuzuguchi T, Sagami H. (2004) Relationship between intron 4b splicing of the rat geranylgeranyl diphosphate synthase gene and the active enzyme expression level. J. Biochem., 136 (3): 301-12. [PMID:15598886]

8. McKenna CE, Kashemirov BA, Błazewska KM, Mallard-Favier I, Stewart CA, Rojas J, Lundy MW, Ebetino FH, Baron RA, Dunford JE et al.. (2010) Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid. J. Med. Chem., 53 (9): 3454-64. [PMID:20394422]

9. Szabo CM, Matsumura Y, Fukura S, Martin MB, Sanders JM, Sengupta S, Cieslak JA, Loftus TC, Lea CR, Lee HJ et al.. (2002) Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. J. Med. Chem., 45 (11): 2185-96. [PMID:12014956]

10. Wiemer AJ, Tong H, Swanson KM, Hohl RJ. (2007) Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem. Biophys. Res. Commun., 353 (4): 921-5. [PMID:17208200]

11. Wiemer AJ, Yu JS, Lamb KM, Hohl RJ, Wiemer DF. (2008) Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. Bioorg. Med. Chem., 16 (1): 390-9. [PMID:17905588]

12. Yoshida T, Asanuma M, Grossmann L, Fuse M, Shibata T, Yonekawa T, Tanaka T, Ueno K, Yasuda T, Saito Y et al.. (2006) Geranylgeranyl-pyrophosphate (GGPP) synthase is down-regulated during differentiation of osteoblastic cell line MC3T3-E1. FEBS Lett., 580 (22): 5203-7. [PMID:16978613]

13. Zhao Y, Yu L, Gao J, Fu Q, Hua Y, Zhang H, Zhao S. (2000) cDNA cloning, chromosome mapping and expression characterization of human geranylgeranyl pyrophosphate synthase. Sci. China, C, Life Sci., 43 (6): 613-22. [PMID:18726356]

Contributors

Show »

How to cite this page

Select citation format: