FDFT_RAT
ID FDFT_RAT Reviewed; 416 AA.
AC Q02769;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Squalene synthase;
DE Short=SQS;
DE Short=SS;
DE EC=2.5.1.21 {ECO:0000269|PubMed:9575210};
DE AltName: Full=FPP:FPP farnesyltransferase;
DE AltName: Full=Farnesyl-diphosphate farnesyltransferase;
GN Name=Fdft1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1569107; DOI=10.1016/s0021-9258(18)42489-1;
RA Shechter I., Klinger E., Rucker M.L., Engstrom R.G., Spirito J.A.,
RA Islam M.A., Boettcher B.R., Wienstein D.B.;
RT "Solubilization, purification, and characterization of a truncated form of
RT rat hepatic squalene synthetase.";
RL J. Biol. Chem. 267:8628-8635(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=1400448; DOI=10.1016/s0021-9258(19)36619-0;
RA McKenzie T.L., Jiang G., Straubhaar J.R., Conrad D.G., Shechter I.;
RT "Molecular cloning, expression, and characterization of the cDNA for the
RT rat hepatic squalene synthase.";
RL J. Biol. Chem. 267:21368-21374(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=8509416; DOI=10.1016/s0021-9258(18)31462-5;
RA Stamellos K.D., Shackelford J.E., Schechter I., Jiang G., Conrad D.G.,
RA Keller G.-A., Krisans S.K.;
RT "Subcellular localization of squalene synthase in rat hepatic cells.
RT Biochemical and immunochemical evidence.";
RL J. Biol. Chem. 268:12825-12836(1993).
RN [5]
RP CATALYTIC ACTIVITY, FUNCTION, AND MUTAGENESIS OF TYR-171; TYR-174; ARG-185;
RP GLN-283; PHE-286; PHE-288 AND GLN-293.
RX PubMed=9575210; DOI=10.1074/jbc.273.20.12515;
RA Gu P., Ishii Y., Spencer T.A., Shechter I.;
RT "Function-structure studies and identification of three enzyme domains
RT involved in the catalytic activity in rat hepatic squalene synthase.";
RL J. Biol. Chem. 273:12515-12525(1998).
RN [6]
RP DISEASE.
RX PubMed=16440058; DOI=10.1172/jci20797;
RA Mori M., Li G., Abe I., Nakayama J., Guo Z., Sawashita J., Ugawa T.,
RA Nishizono S., Serikawa T., Higuchi K., Shumiya S.;
RT "Lanosterol synthase mutations cause cholesterol deficiency-associated
RT cataracts in the Shumiya cataract rat.";
RL J. Clin. Invest. 116:395-404(2006).
CC -!- FUNCTION: Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP)
CC moieties to form squalene (PubMed:9575210). Proceeds in two distinct
CC steps. In the first half-reaction, two molecules of FPP react to form
CC the stable presqualene diphosphate intermediate (PSQPP), with
CC concomitant release of a proton and a molecule of inorganic
CC diphosphate. In the second half-reaction, PSQPP undergoes heterolysis,
CC isomerization, and reduction with NADPH or NADH to form squalene. It is
CC the first committed enzyme of the sterol biosynthesis pathway (By
CC similarity). {ECO:0000250|UniProtKB:P37268,
CC ECO:0000269|PubMed:9575210}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 (2E,6E)-farnesyl diphosphate + H(+) + NADPH = 2 diphosphate
CC + NADP(+) + squalene; Xref=Rhea:RHEA:32295, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:33019, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:175763; EC=2.5.1.21;
CC Evidence={ECO:0000269|PubMed:9575210};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32296;
CC Evidence={ECO:0000269|PubMed:9575210};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 (2E,6E)-farnesyl diphosphate + H(+) + NADH = 2 diphosphate +
CC NAD(+) + squalene; Xref=Rhea:RHEA:32299, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:33019, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:175763; EC=2.5.1.21;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32300;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADH + presqualene diphosphate = diphosphate + NAD(+) +
CC squalene; Xref=Rhea:RHEA:22228, ChEBI:CHEBI:15378, ChEBI:CHEBI:15440,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57310, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945; Evidence={ECO:0000250|UniProtKB:P37268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22229;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADPH + presqualene diphosphate = diphosphate + NADP(+)
CC + squalene; Xref=Rhea:RHEA:22232, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:33019, ChEBI:CHEBI:57310,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000269|PubMed:9575210};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22233;
CC Evidence={ECO:0000269|PubMed:9575210};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 (2E,6E)-farnesyl diphosphate = diphosphate + presqualene
CC diphosphate; Xref=Rhea:RHEA:22672, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57310, ChEBI:CHEBI:175763;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22673;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P37268};
CC -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC farnesyl diphosphate: step 1/3. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:8509416}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- DISEASE: Note=Defects in Lss and Fdft1 are the cause of Shumiya
CC cataract rat (SCR). This strain develop mature cataracts at around 11
CC weeks of age, exhibiting opacity from the perinuclear zone to the
CC cortical intermediate layer. Cholesterol levels in cataractous lenses
CC decreased to about 57% of normal. Cholesterol insufficiency may cause
CC the deficient proliferation of lens epithelial cells in Shumiya
CC cataract rats, resulting in the loss of homeostatic epithelial cell
CC control of the underlying fiber cells and ultimately cataractogenesis.
CC {ECO:0000269|PubMed:16440058}.
CC -!- SIMILARITY: Belongs to the phytoene/squalene synthase family.
CC {ECO:0000305}.
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DR EMBL; M95591; AAA42179.1; -; mRNA.
DR EMBL; BC081810; AAH81810.1; -; mRNA.
DR PIR; A45105; A45105.
DR RefSeq; NP_062111.1; NM_019238.2.
DR AlphaFoldDB; Q02769; -.
DR SMR; Q02769; -.
DR STRING; 10116.ENSRNOP00000029808; -.
DR BindingDB; Q02769; -.
DR ChEMBL; CHEMBL3815; -.
DR DrugCentral; Q02769; -.
DR GuidetoPHARMACOLOGY; 645; -.
DR jPOST; Q02769; -.
DR PaxDb; Q02769; -.
DR PRIDE; Q02769; -.
DR Ensembl; ENSRNOT00000032089; ENSRNOP00000029808; ENSRNOG00000021314.
DR GeneID; 29580; -.
DR KEGG; rno:29580; -.
DR UCSC; RGD:61834; rat.
DR CTD; 2222; -.
DR RGD; 61834; Fdft1.
DR eggNOG; KOG1459; Eukaryota.
DR GeneTree; ENSGT00390000016034; -.
DR HOGENOM; CLU_031981_0_2_1; -.
DR InParanoid; Q02769; -.
DR OMA; RFWPKEI; -.
DR OrthoDB; 563702at2759; -.
DR PhylomeDB; Q02769; -.
DR TreeFam; TF105316; -.
DR BRENDA; 2.5.1.21; 5301.
DR Reactome; R-RNO-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00767; UER00751.
DR PRO; PR:Q02769; -.
DR Proteomes; UP000002494; Chromosome 15.
DR Bgee; ENSRNOG00000021314; Expressed in liver and 20 other tissues.
DR Genevisible; Q02769; RN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0004310; F:farnesyl-diphosphate farnesyltransferase activity; IDA:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0051996; F:squalene synthase activity; IBA:GO_Central.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IMP:RGD.
DR GO; GO:0045338; P:farnesyl diphosphate metabolic process; IMP:RGD.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IEA:UniProtKB-KW.
DR CDD; cd00683; Trans_IPPS_HH; 1.
DR Gene3D; 1.10.600.10; -; 1.
DR InterPro; IPR008949; Isoprenoid_synthase_dom_sf.
DR InterPro; IPR002060; Squ/phyt_synthse.
DR InterPro; IPR006449; Squal_synth-like.
DR InterPro; IPR019845; Squalene/phytoene_synthase_CS.
DR InterPro; IPR044844; Trans_IPPS_euk-type.
DR InterPro; IPR033904; Trans_IPPS_HH.
DR PANTHER; PTHR11626; PTHR11626; 1.
DR Pfam; PF00494; SQS_PSY; 1.
DR SFLD; SFLDG01018; Squalene/Phytoene_Synthase_Lik; 1.
DR SUPFAM; SSF48576; SSF48576; 1.
DR TIGRFAMs; TIGR01559; squal_synth; 1.
DR PROSITE; PS01044; SQUALEN_PHYTOEN_SYN_1; 1.
DR PROSITE; PS01045; SQUALEN_PHYTOEN_SYN_2; 1.
PE 1: Evidence at protein level;
KW Cholesterol biosynthesis; Cholesterol metabolism; Disease variant;
KW Endoplasmic reticulum; Isoprene biosynthesis; Lipid biosynthesis;
KW Lipid metabolism; Magnesium; Membrane; Metal-binding;
KW Multifunctional enzyme; NAD; NADP; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transferase; Transmembrane; Transmembrane helix.
FT CHAIN 1..416
FT /note="Squalene synthase"
FT /id="PRO_0000067445"
FT TRANSMEM 284..304
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 384..404
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 52
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 77
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 80
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 83
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 84
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 218
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 315
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT BINDING 317
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P37268"
FT MUTAGEN 171
FT /note="Y->F,S,W: Completely abolishes formation of PSPP or
FT squalene from FPP."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 174
FT /note="Y->F,S,W: Has little effect on the total squalene
FT synthase activity."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 185
FT /note="R->G: Does not affect squalene synthase activity."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 283
FT /note="Q->E,N: Retains partial activity of the first
FT reaction. Retains partial activity of the second reaction."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 286
FT /note="F->D,R: Completely eliminates the activities of both
FT the first and the second reactions."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 286
FT /note="F->Y,W,L: Retains partial activity of the first
FT reaction. Retains partial activity of the second reaction."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 288
FT /note="F->D,R: Completely eliminates the activities of both
FT the first and the second reactions."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 288
FT /note="F->L: Retains partial activity of the first
FT reaction. Completely eliminates the activity of the second
FT reaction."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 288
FT /note="F->Y,W,L: Retains partial activity of the first
FT reaction. Retains partial activity of the second reaction."
FT /evidence="ECO:0000269|PubMed:9575210"
FT MUTAGEN 293
FT /note="Q->N,E: Retains partial activity of the first
FT reaction. Retains partial activity of the second reaction."
FT /evidence="ECO:0000269|PubMed:9575210"
SQ SEQUENCE 416 AA; 48106 MW; F4BC4D09C9F72169 CRC64;
MEFVKCLGHP EEFYNLLRFR MGGRRNFIPK MDRNSLSNSL KTCYKYLDQT SRSFAAVIQA
LDGDIRHAVC VFYLILRAMD TVEDDMAISV EKKIPLLRNF HTFLYEPEWR FTESKEKHRV
VLEDFPTISL EFRNLAEKYQ TVIADICHRM GCGMAEFLNK DVTSKQDWDK YCHYVAGLVG
IGLSRLFSAS EFEDPIVGED TECANSMGLF LQKTNIIRDY LEDQQEGRQF WPQEVWGKYV
KKLEDFVKPE NVDVAVKCLN ELITNALQHI PDVITYLSRL RNQSVFNFCA IPQVMAIATL
AACYNNHQVF KGVVKIRKGQ AVTLMMDATN MPAVKAIIYQ YIEEIYHRVP NSDPSASKAK
QLISNIRTQS LPNCQLISRS HYSPIYLSFI MLLAALSWQY LSTLSQVTED YVQREH
