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 24-JAN-2024, entry version 160. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PhosphoSitePlus; Q02769; -. DR jPOST; Q02769; -. DR PaxDb; 10116-ENSRNOP00000029808; -. DR Ensembl; ENSRNOT00000032089.5; ENSRNOP00000029808.3; ENSRNOG00000021314.5. DR Ensembl; ENSRNOT00065052092; ENSRNOP00065042871; ENSRNOG00065030182. DR GeneID; 29580; -. DR KEGG; rno:29580; -. DR UCSC; RGD:61834; rat. DR AGR; RGD:61834; -. 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 OrthoDB; 5487739at2759; -. 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 cell types or tissues. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. 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; Farnesyl Diphosphate Synthase; 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 NCBIfam; TIGR01559; squal_synth; 1. DR PANTHER; PTHR11626; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; 1. DR PANTHER; PTHR11626:SF2; SQUALENE SYNTHASE; 1. DR Pfam; PF00494; SQS_PSY; 1. DR SFLD; SFLDS00005; Isoprenoid_Synthase_Type_I; 1. DR SFLD; SFLDG01018; Squalene/Phytoene_Synthase_Lik; 1. DR SUPFAM; SSF48576; Terpenoid synthases; 1. DR PROSITE; PS01044; SQUALEN_PHYTOEN_SYN_1; 1. DR PROSITE; PS01045; SQUALEN_PHYTOEN_SYN_2; 1. DR Genevisible; Q02769; RN. 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 //