EzCatDB: S00024

DB codeS00024
RLCP classification5.304.3380000.2135
CATH domainDomain 11.10.600.10Catalytic domain
E.C.2.5.1.1,2.5.1.10
CSA1fps
MACiEM0253

CATH domainRelated DB codes (homologues)
1.10.600.10S00026,S00027

Enzyme Name
Swiss-protKEGG

P08836P14324
Protein nameFarnesyl pyrophosphate synthetaseFarnesyl pyrophosphate synthetasedimethylallyltranstransferase
   (EC 2.5.1.1)

geranyl-diphosphate synthase
   (EC 2.5.1.1)

prenyltransferase
   (EC 2.5.1.1)

dimethylallyltransferase
   (EC 2.5.1.1)

DMAPP:IPP-dimethylallyltransferase
   (EC 2.5.1.1)

(2E,6E)-farnesyl diphosphate synthetase
   (EC 2.5.1.1)

diprenyltransferase
   (EC 2.5.1.1)

geranyl pyrophosphate synthase
   (EC 2.5.1.1)

geranyl pyrophosphate synthetase
   (EC 2.5.1.1)

trans-farnesyl pyrophosphate synthetase
   (EC 2.5.1.1)

geranyltranstransferase
   (EC 2.5.1.10)

farnesyl-diphosphate synthase
   (EC 2.5.1.10)

geranyl transferase I
   (EC 2.5.1.10)

prenyltransferase
   (EC 2.5.1.10)

farnesyl pyrophosphate synthetase
   (EC 2.5.1.10)

farnesylpyrophosphate synthetase
   (EC 2.5.1.10)

SynonymsFPP synthetase
FPS
Farnesyl diphosphate synthetase
FPP synthetase
FPS
Farnesyl diphosphate synthetase
IncludesDimethylallyltranstransferase
   EC 2.5.1.1
Geranyltranstransferase
   EC 2.5.1.10
Dimethylallyltranstransferase
   EC 2.5.1.1
Geranyltranstransferase
   EC 2.5.1.10

KEGG pathways
MAP codePathwaysE.C.
MAP00100Biosynthesis of steroids2.5.1.1,2.5.1.10
MAP00900Terpenoid biosynthesis2.5.1.1,2.5.1.10

Swiss-prot:Accession NumberP08836P14324
Entry nameFPPS_CHICKFPPS_HUMAN
ActivityDimethylallyl diphosphate + isopentenyl diphosphate = diphosphate + geranyl diphosphate.,Geranyl diphosphate + isopentenyl diphosphate = diphosphate + trans,trans-farnesyl diphosphate.Dimethylallyl diphosphate + isopentenyl diphosphate = diphosphate + geranyl diphosphate.,Geranyl diphosphate + isopentenyl diphosphate = diphosphate + trans,trans-farnesyl diphosphate.
SubunitHomodimer.Homodimer. Interacts with RSAD2. Interacts with HTLV-1 protein p13(II).
Subcellular locationCytoplasm.Cytoplasm.
Cofactor



CofactorsSubstratesProductsintermediates
KEGG-idC02148C00235C00341C00129C00013C00341C00448
E.C.
2.5.1.12.5.1.102.5.1.1,2.5.1.102.5.1.1,2.5.1.102.5.1.12.5.1.10
CompoundDivalent metalDimethylallyl diphosphateGeranyl diphosphateIsopentenyl diphosphatePyrophosphateGeranyl diphosphateTrans,trans-Farnesyl diphosphateCarbocation and eliminated pyrophosphate in transition-state
Typedivalent metal (Ca2+, Mg2+)lipid,phosphate group/phosphate ionlipid,phosphate group/phosphate ionlipid,phosphate group/phosphate ionphosphate group/phosphate ionlipid,phosphate group/phosphate ionlipid,phosphate group/phosphate ion
1fpsAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ubvAUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1ubwABound:2x_MGUnboundBound:GPPUnboundUnboundUnboundUnboundUnbound
1ubxABound:_MGUnboundAnalogue:FPPUnboundUnboundUnboundUnboundUnbound
1ubyABound:2x_MGBound:DMAUnboundUnboundUnboundUnboundUnboundUnbound
1yq7ABound:3x_MGUnboundUnboundAnalogue:PO4-PO4UnboundUnboundUnboundTransition-state-analogue:RIS
1yv5ABound:3x_MGUnboundUnboundAnalogue:PO4-PO4UnboundUnboundUnboundTransition-state-analogue:RIS
1zw5ABound:3x_MGUnboundUnboundBound:IPRUnboundUnboundUnboundTransition-state-analogue:ZOL
2f7mFUnboundUnboundUnboundAnalogue:PO4UnboundUnboundUnboundUnbound
2f89FBound:3x_MNUnboundUnboundUnboundUnboundUnboundUnboundTransition-state-analogue:210
2f8cFBound:3x_MGUnboundUnboundAnalogue:PO4UnboundUnboundUnboundTransition-state-analogue:ZOL
2f8zFBound:3x_MGUnboundUnboundBound:IPEUnboundUnboundUnboundTransition-state-analogue:ZOL
2f92FAnalogue:3x_ZNUnboundUnboundAnalogue:PO4UnboundUnboundUnboundTransition-state-analogue:AHD
2f94FAnalogue:3x_ZNUnboundUnboundAnalogue:PO4UnboundUnboundUnboundTransition-state-analogue:BFQ
2f9kFAnalogue:3x_ZNUnboundUnboundAnalogue:PO4UnboundUnboundUnboundTransition-state-analogue:ZOL

Active-site residues
resource
literature [14], [27], [29]
pdbCatalytic residuesCofactor-binding residuesMain-chain involved in catalysiscomment
1fpsAARG 126;LYS 214;THR 215;PHE 253;GLN 254;LYS 271
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214

1ubvAARG 126;LYS 214;THR 215;PHE 253;GLN 254;       
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214
mutant F112A, F113S, K271A
1ubwAARG 126;LYS 214;THR 215;PHE 253;GLN 254;       
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214
mutant F112A, F113S, K271A
1ubxAARG 126;LYS 214;THR 215;PHE 253;GLN 254;LYS 271
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214
mutant F112A, F113S
1ubyAARG 126;LYS 214;THR 215;PHE 253;GLN 254;       
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214
mutant F112A, F113S, K271A
1yq7AARG 126;LYS 214;THR 215;PHE 253;GLN 254;LYS 271
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214

1yv5AARG 126;LYS 214;THR 215;PHE 253;GLN 254;LYS 271
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214

1zw5AARG 126;LYS 214;THR 215;PHE 253;GLN 254;LYS 271
ASP 117;ASP 121(Magnesium-1 & -2);ASP 257(Magnesium-3)
LYS 214

2f7mFARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f89FARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f8cFARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f8zFARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f92FARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f94FARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200

2f9kFARG 112;LYS 200;THR 201;PHE 239;GLN 240;LYS 257
ASP 103;ASP 107(Magnesium-1 & -2);ASP 243(Magnesium-3)
LYS 200


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]Fig. 4, p.30753-30754
[3]p.3344-3346, Fig.9
[9]Fig.4, p.999-1000
[13]p.10876
[14]

[16]Fig.5, p.15021-15023
[17]

[27]Fig.3, p.8527-8528
[29]p.7830-7831

references
[1]
PubMed ID8003978
JournalProtein Sci
Year1994
Volume3
Pages600-7
AuthorsChen A, Kroon PA, Poulter CD
TitleIsoprenyl diphosphate synthases: protein sequence comparisons, a phylogenetic tree, and predictions of secondary structure.
[2]
PubMed ID8940054
JournalJ Biol Chem
Year1996
Volume271
Pages30748-54
AuthorsOhnuma S, Narita K, Nakazawa T, Ishida C, Takeuchi Y, Ohto C, Nishino T
TitleA role of the amino acid residue located on the fifth position before the first aspartate-rich motif of farnesyl diphosphate synthase on determination of the final product.
[3]
PubMed ID12135472
JournalEur J Biochem
Year2002
Volume269
Pages3339-54
AuthorsLiang PH, Ko TP, Wang AH
TitleStructure, mechanism and function of prenyltransferases.
[4]
PubMed ID12769708
JournalCurr Top Med Chem
Year2003
Volume3
Pages1043-74
AuthorsKale TA, Hsieh SA, Rose MW, Distefano MD
TitleUse of synthetic isoprenoid analogues for understanding protein prenyltransferase mechanism and structure.
[5]
PubMed ID15456258
JournalJ Med Chem
Year2004
Volume47
Pages5149-58
AuthorsCheng F, Oldfield E
TitleInhibition of isoprene biosynthesis pathway enzymes by phosphonates, bisphosphonates, and diphosphates.
[6]
PubMed ID84684
JournalBiochemistry
Year1979
Volume18
Pages860-4
AuthorsBrems DN, Rilling HC
TitlePhotoaffinity labeling of the catalytic site of prenyltransferase
[7]
PubMed ID7259201
JournalArch Biochem Biophys
Year1981
Volume208
Pages508-11
AuthorsSaito A, Rilling HC
TitleThe formation of cyclic sesquiterpenes from farnesyl pyrophosphate by prenyltransferase
[8]
PubMed ID7272273
JournalBiochemistry
Year1981
Volume20
Pages3711-8
AuthorsBrems DN, Bruenger E, Rilling HC
TitleIsolation and characterization of a photoaffinity-labeled peptide from the catalytic site of prenyltransferase
[9]
PubMed ID4092833
JournalBiochem Soc Trans
Year1985
Volume13
Pages997-1003
AuthorsRilling HC
TitleThe mechanism of the condensation reactions of cholesterol biosynthesis. Fourth Morton lecture
[10]
PubMed ID3519603
JournalJ Biochem (Tokyo)
Year1986
Volume99
Pages1327-37
AuthorsFujisaki S, Nishino T, Katsuki H
TitleIsoprenoid synthesis in Escherichia coli. Separation and partial purification of four enzymes involved in the synthesis
[11]
PubMed ID2541701
JournalBiochem Biophys Res Commun
Year1989
Volume160
Pages448-52
AuthorsYoshida I, Koyama T, Ogura K
TitleFormation of a stable and catalytically active complex of the two essential components of hexaprenyl diphosphate synthase from Micrococcus luteus B-P 26
[12]
PubMed ID8411181
JournalJ Mol Biol
Year1993
Volume233
Pages787-8
AuthorsNakane H, Koyama T, Obata S, Osabe M, Takeshita A, Nishino T, Ogura K, Miki K
TitleCrystallization and preliminary X-ray diffraction studies of Bacillus stearothermophilus farnesyl diphosphate synthase expressed in Escherichia coli
[13]
CommentsX-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 20-367.
PubMed ID8086404
JournalBiochemistry
Year1994
Volume33
Pages10871-7
AuthorsTarshis LC, Yan M, Poulter CD, Sacchettini JC
TitleCrystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution
Related PDB1fps
Related Swiss-protP08836
[14]
PubMed ID7626083
JournalBiochem Biophys Res Commun
Year1995
Volume212
Pages681-6
AuthorsKoyama T, Tajima M, Nishino T, Ogura K
TitleSignificance of Phe-220 and Gln-221 in the catalytic mechanism of farnesyl diphosphate synthase of Bacillus stearothermophilus
[15]
PubMed ID8639752
JournalPlant Mol Biol
Year1996
Volume30
Pages935-46
AuthorsAdiwilaga K, Kush A
TitleCloning and characterization of cDNA encoding farnesyl diphosphate synthase from rubber tree (Hevea brasiliensis)
[16]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 20-367.
PubMed ID8986756
JournalProc Natl Acad Sci U S A
Year1996
Volume93
Pages15018-23
AuthorsTarshis LC, Proteau PJ, Kellogg BA, Sacchettini JC, Poulter CD
TitleRegulation of product chain length by isoprenyl diphosphate synthases
Related PDB1ubv,1ubw,1ubx,1uby
Related Swiss-protP08836
[17]
PubMed ID9667899
JournalCurr Opin Chem Biol
Year1997
Volume1
Pages570-8
AuthorsKellogg BA, Poulter CD
TitleChain elongation in the isoprenoid biosynthetic pathway
[18]
PubMed ID9324768
JournalScience
Year1997
Volume277
Pages1788-9
AuthorsSacchettini JC, Poulter CD
TitleCreating isoprenoid diversity
[19]
PubMed ID10825960
JournalOrg Lett
Year1999
Volume1
Pages1071-3
AuthorsLeyes AE, Baker JA, Poulter CD
TitleBiosynthesis of isoprenoids in Escherichia coli
[20]
PubMed ID10631008
JournalBiochemistry
Year2000
Volume39
Pages463-9
AuthorsKoyama T, Gotoh Y, Nishino T
TitleIntersubunit location of the active site of farnesyl diphosphate synthase
[21]
PubMed ID11112517
JournalBiochemistry
Year2000
Volume39
Pages15316-21
AuthorsStanley Fernandez SM, Kellogg BA, Poulter CD
TitleFarnesyl diphosphate synthase. Altering the catalytic site to select for geranyl diphosphate activity
[22]
PubMed ID11027152
JournalBiochemistry
Year2000
Volume39
Pages12717-22
AuthorsZhang YW, Li XY, Koyama T
TitleChain length determination of prenyltransferases
[23]
PubMed ID11142508
JournalJ Biomol NMR
Year2000
Volume18
Pages183-8
AuthorsMueller GA, Choy WY, Skrynnikov NR, Kay LE
TitleA method for incorporating dipolar couplings into structure calculations in cases of (near) axial symmetry of alignment
[24]
PubMed ID11435429
JournalJ Biol Chem
Year2001
Volume276
Pages33930-7
AuthorsMontalvetti A, Bailey BN, Martin MB, Severin GW, Oldfield E, Docampo R
TitleBisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase
[25]
PubMed ID11348105
JournalJ Org Chem
Year2001
Volume66
Pages3253-64
AuthorsTurek TC, Gaon I, Distefano MD, Strickland CL
TitleSynthesis of farnesyl diphosphate analogues containing ether-linked photoactive benzophenones and their application in studies of protein prenyltransferases
[26]
PubMed ID12086477
JournalJ Med Chem
Year2002
Volume45
Pages2894-903
AuthorsSzabo CM, Martin MB, Oldfield E
TitleAn investigation of bone resorption and Dictyostelium discoideum growth inhibition by bisphosphonate drugs
[27]
PubMed ID14672944
JournalJ Biol Chem
Year2004
Volume279
Pages8526-9
AuthorsHosfield DJ, Zhang Y, Dougan DR, Broun A, Tari LW, Swanson RV, Finn J
TitleStructural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis.
Related PDB1rqi,1rqj,1rtr
[28]
PubMed ID16698791
JournalJ Biol Chem
Year2006
Volume[Epub ahead of print]
Pages
AuthorsKavanagh KL, Dunford JE, Bunkoczi G, Russell RG, Oppermann U
TitleThe crystal structure of human geranylgeranyl pyrophosphate synthase reveals a novel hexameric arrangement and inhibitory product binding.
Related PDB2fvi
[29]
PubMed ID16684881
JournalProc Natl Acad Sci U S A
Year2006
Volume103
Pages7829-34
AuthorsKavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U
TitleThe molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.
Related PDB1yq7,1yv5,1zw5
[30]
JournalChemMedChem
Year2006
Volume1
Pages267-73
AuthorsRondeau J-M, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, Lehmann S, Ramage P, Rieffel S, Strauss A, Green JR, Jahnke W
TitleStructural basis for the exceptional in vivo efficacy of bisphosphonate drugs.
Related PDB2f7m,2f89,2f8c,2f8z,2f92,2f94,2f9k

comments
According to the literature [3] & [9], the reaction of this enzyme proceeds via an ionization-condensation-elimination mechanism.
This enzyme catalyzes the following reactions sequentially:
(A) Elimination of phosphate group from DMAPP (leading to the formation of carbocation and pyrophosphate):
This reaction is rupture of the carbon-oxygen bond of the allylic diphosphate to form a ion pair between the pyrophosphate leaving group and the allylic carboncation.
(B) Addition polymerization between the carbocation intermediate and IPP:
This reaction is alkylation of the C3-C4 double bond of IPP by the carbocation to form a second carbocationic intermediate, leading to stereospecific abstraction of a proton from C2 of the isopentenl unit to produce a new allylic diphosphate.
According to the literature [27] & [29], the reaction proceeds as follows:
(A) Elimination of phosphate group from DMAPP (leading to the formation of carbocation and pyrophosphate):
(A1) The developing negative charge on the eliminated group, pyrophosphate, is stabilized by three magnesium ions, which are bound to acidic residues, along with Arg126, Lys214 and Lys271.
(A2) The mainchain carbonyl group of Lys214, the sidechains of Thr215 and Gln254 stabilize the developing positive charge on the leaving group, allylic group, leading to the formation of carbocation.
(A3) This elimination reaction occurs by E1-like mechanism.

createdupdated
2003-11-122009-03-11


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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