ID   ERG9_SCHPO              Reviewed;         460 AA.
AC   P36596;
DT   01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-1994, sequence version 1.
DT   27-MAR-2024, entry version 169.
DE   RecName: Full=Squalene synthase {ECO:0000303|PubMed:8474436};
DE            Short=SQS {ECO:0000303|PubMed:8474436};
DE            Short=SS {ECO:0000303|PubMed:8474436};
DE            EC=2.5.1.21 {ECO:0000305|PubMed:8474436};
DE   AltName: Full=FPP:FPP farnesyltransferase {ECO:0000303|PubMed:8474436};
DE   AltName: Full=Farnesyl-diphosphate farnesyltransferase {ECO:0000303|PubMed:8474436};
GN   Name=erg9 {ECO:0000303|PubMed:8474436}; ORFNames=SPBC646.05c;
OS   Schizosaccharomyces pombe (strain 972 / ATCC 24843) (Fission yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC   Schizosaccharomycetes; Schizosaccharomycetales; Schizosaccharomycetaceae;
OC   Schizosaccharomyces.
OX   NCBI_TaxID=284812;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND PATHWAY.
RC   STRAIN=972 / ATCC 24843;
RX   PubMed=8474436; DOI=10.1128/mcb.13.5.2706-2717.1993;
RA   Robinson G.W., Tsay Y.H., Kienzle B.K., Smith-Monroy C.A., Bishop R.W.;
RT   "Conservation between human and fungal squalene synthetases: similarities
RT   in structure, function, and regulation.";
RL   Mol. Cell. Biol. 13:2706-2717(1993).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=972 / ATCC 24843;
RX   PubMed=11859360; DOI=10.1038/nature724;
RA   Wood V., Gwilliam R., Rajandream M.A., Lyne M.H., Lyne R., Stewart A.,
RA   Sgouros J.G., Peat N., Hayles J., Baker S.G., Basham D., Bowman S.,
RA   Brooks K., Brown D., Brown S., Chillingworth T., Churcher C.M., Collins M.,
RA   Connor R., Cronin A., Davis P., Feltwell T., Fraser A., Gentles S.,
RA   Goble A., Hamlin N., Harris D.E., Hidalgo J., Hodgson G., Holroyd S.,
RA   Hornsby T., Howarth S., Huckle E.J., Hunt S., Jagels K., James K.D.,
RA   Jones L., Jones M., Leather S., McDonald S., McLean J., Mooney P.,
RA   Moule S., Mungall K.L., Murphy L.D., Niblett D., Odell C., Oliver K.,
RA   O'Neil S., Pearson D., Quail M.A., Rabbinowitsch E., Rutherford K.M.,
RA   Rutter S., Saunders D., Seeger K., Sharp S., Skelton J., Simmonds M.N.,
RA   Squares R., Squares S., Stevens K., Taylor K., Taylor R.G., Tivey A.,
RA   Walsh S.V., Warren T., Whitehead S., Woodward J.R., Volckaert G., Aert R.,
RA   Robben J., Grymonprez B., Weltjens I., Vanstreels E., Rieger M.,
RA   Schaefer M., Mueller-Auer S., Gabel C., Fuchs M., Duesterhoeft A.,
RA   Fritzc C., Holzer E., Moestl D., Hilbert H., Borzym K., Langer I., Beck A.,
RA   Lehrach H., Reinhardt R., Pohl T.M., Eger P., Zimmermann W., Wedler H.,
RA   Wambutt R., Purnelle B., Goffeau A., Cadieu E., Dreano S., Gloux S.,
RA   Lelaure V., Mottier S., Galibert F., Aves S.J., Xiang Z., Hunt C.,
RA   Moore K., Hurst S.M., Lucas M., Rochet M., Gaillardin C., Tallada V.A.,
RA   Garzon A., Thode G., Daga R.R., Cruzado L., Jimenez J., Sanchez M.,
RA   del Rey F., Benito J., Dominguez A., Revuelta J.L., Moreno S.,
RA   Armstrong J., Forsburg S.L., Cerutti L., Lowe T., McCombie W.R.,
RA   Paulsen I., Potashkin J., Shpakovski G.V., Ussery D., Barrell B.G.,
RA   Nurse P.;
RT   "The genome sequence of Schizosaccharomyces pombe.";
RL   Nature 415:871-880(2002).
RN   [3]
RP   FUNCTION.
RX   PubMed=8586261; DOI=10.1111/j.1574-6968.1995.tb07929.x;
RA   Harmouch N., Coulon J., Bonaly R.;
RT   "Identification of 24-methylene-24,25-dihydrolanosterol as a precursor of
RT   ergosterol in the yeasts Schizosaccharomyces pombe and Schizosaccharomyces
RT   octosporus.";
RL   FEMS Microbiol. Lett. 134:147-152(1995).
RN   [4]
RP   SUBCELLULAR LOCATION, AND INTERACTION WITH POF14.
RX   PubMed=17016471; DOI=10.1038/sj.emboj.7601329;
RA   Tafforeau L., Le Blastier S., Bamps S., Dewez M., Vandenhaute J.,
RA   Hermand D.;
RT   "Repression of ergosterol level during oxidative stress by fission yeast F-
RT   box protein Pof14 independently of SCF.";
RL   EMBO J. 25:4547-4556(2006).
RN   [5]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX   PubMed=16823372; DOI=10.1038/nbt1222;
RA   Matsuyama A., Arai R., Yashiroda Y., Shirai A., Kamata A., Sekido S.,
RA   Kobayashi Y., Hashimoto A., Hamamoto M., Hiraoka Y., Horinouchi S.,
RA   Yoshida M.;
RT   "ORFeome cloning and global analysis of protein localization in the fission
RT   yeast Schizosaccharomyces pombe.";
RL   Nat. Biotechnol. 24:841-847(2006).
RN   [6]
RP   FUNCTION.
RX   PubMed=18310029; DOI=10.1099/mic.0.2007/011155-0;
RA   Iwaki T., Iefuji H., Hiraga Y., Hosomi A., Morita T., Giga-Hama Y.,
RA   Takegawa K.;
RT   "Multiple functions of ergosterol in the fission yeast Schizosaccharomyces
RT   pombe.";
RL   Microbiology 154:830-841(2008).
CC   -!- FUNCTION: Squalene synthase; part of the third module of ergosterol
CC       biosynthesis pathway that includes by the late steps of the pathway
CC       (PubMed:8474436). Erg9 produces squalene from 2 farnesyl pyrophosphate
CC       moieties (PubMed:8474436). The third module or late pathway involves
CC       the ergosterol synthesis itself through consecutive reactions that
CC       mainly occur in the endoplasmic reticulum (ER) membrane. Firstly, the
CC       squalene synthase erg9 catalyzes the condensation of 2 farnesyl
CC       pyrophosphate moieties to form squalene, which is the precursor of all
CC       steroids. Secondly, squalene is converted into lanosterol by the
CC       consecutive action of the squalene epoxidase erg1 and the lanosterol
CC       synthase erg7. The lanosterol 14-alpha-demethylase erg11/cyp1 catalyzes
CC       C14-demethylation of lanosterol to produce 4,4'-dimethyl
CC       cholesta-8,14,24-triene-3-beta-ol. In the next steps, a complex process
CC       involving various demethylation, reduction and desaturation reactions
CC       catalyzed by the C-14 reductase erg24 and the C-4 demethylation complex
CC       erg25-erg26-erg27 leads to the production of zymosterol. Erg28 likely
CC       functions in the C-4 demethylation complex reaction by tethering erg26
CC       and Erg27 to the endoplasmic reticulum or to facilitate interaction
CC       between these proteins. Then, the sterol 24-C-methyltransferase erg6
CC       catalyzes the methyl transfer from S-adenosyl-methionine to the C-24 of
CC       zymosterol to form fecosterol. The C-8 sterol isomerase erg2 catalyzes
CC       the reaction which results in unsaturation at C-7 in the B ring of
CC       sterols and thus converts fecosterol to episterol. The sterol-C5-
CC       desaturases erg31 and erg32 then catalyze the introduction of a C-5
CC       double bond in the B ring to produce 5-dehydroepisterol. The C-22
CC       sterol desaturase erg5 further converts 5-dehydroepisterol into
CC       ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double
CC       bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-
CC       3beta-ol is substrate of the C-24(28) sterol reductase erg4 to produce
CC       ergosterol (PubMed:18310029) (Probable). In the genus
CC       Schizosaccharomyces, a second route exists between lanosterol and
CC       fecosterol, via the methylation of lanosterol to eburicol by erg6,
CC       followed by C14-demethylation by erg11/cyp1 and C4-demethylation by the
CC       demethylation complex erg25-erg26-erg27 (PubMed:8586261) (Probable).
CC       {ECO:0000269|PubMed:8474436, ECO:0000305|PubMed:18310029,
CC       ECO:0000305|PubMed:8586261}.
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:0000305|PubMed:8474436};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32296;
CC         Evidence={ECO:0000305|PubMed:8474436};
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:0000305|PubMed:8474436};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32300;
CC         Evidence={ECO:0000305|PubMed:8474436};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:P29704};
CC   -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC       farnesyl diphosphate: step 1/3. {ECO:0000269|PubMed:8474436}.
CC   -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC       {ECO:0000269|PubMed:8474436}.
CC   -!- SUBUNIT: Interacts with pof14. {ECO:0000269|PubMed:17016471}.
CC   -!- INTERACTION:
CC       P36596; Q10223: pof14; NbExp=5; IntAct=EBI-1794119, EBI-1793014;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:16823372, ECO:0000269|PubMed:17016471}; Single-pass
CC       membrane protein {ECO:0000269|PubMed:16823372,
CC       ECO:0000269|PubMed:17016471}.
CC   -!- MISCELLANEOUS: In Aspergillus, the biosynthesis pathway of the sterol
CC       precursors leading to the prevalent sterol ergosterol differs from
CC       yeast. The ringsystem of lanosterol in S.cerevisiae is firstly
CC       demethylised in three enzymatic steps leading to the intermediate
CC       zymosterol and secondly a methyl group is added to zymosterol by the
CC       sterol 24-C-methyltransferase to form fecosterol. In Aspergillus,
CC       lanosterol is firstly transmethylated by the sterol 24-C-
CC       methyltransferase leading to the intermediate eburicol and secondly
CC       demethylated in three steps to form fecosterol. In the genus
CC       Schizosaccharomyces, 2 routes exist from lanosterol to erposterol: the
CC       classical one via zymosterol and the second one via the formation of
CC       eburicol followed by demethylation. {ECO:0000269|PubMed:8586261}.
CC   -!- SIMILARITY: Belongs to the phytoene/squalene synthase family.
CC       {ECO:0000305}.
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DR   EMBL; L06071; AAA35343.1; -; mRNA.
DR   EMBL; CU329671; CAA22809.1; -; Genomic_DNA.
DR   PIR; B48057; B48057.
DR   PIR; T40581; T40581.
DR   RefSeq; NP_595363.1; NM_001021271.2.
DR   AlphaFoldDB; P36596; -.
DR   SMR; P36596; -.
DR   BioGRID; 277625; 6.
DR   IntAct; P36596; 3.
DR   MINT; P36596; -.
DR   STRING; 284812.P36596; -.
DR   iPTMnet; P36596; -.
DR   MaxQB; P36596; -.
DR   PaxDb; 4896-SPBC646-05c-1; -.
DR   EnsemblFungi; SPBC646.05c.1; SPBC646.05c.1:pep; SPBC646.05c.
DR   GeneID; 2541110; -.
DR   KEGG; spo:SPBC646.05c; -.
DR   PomBase; SPBC646.05c; erg9.
DR   VEuPathDB; FungiDB:SPBC646.05c; -.
DR   eggNOG; KOG1459; Eukaryota.
DR   HOGENOM; CLU_031981_2_1_1; -.
DR   InParanoid; P36596; -.
DR   OMA; GEACQLM; -.
DR   PhylomeDB; P36596; -.
DR   Reactome; R-SPO-191273; Cholesterol biosynthesis.
DR   UniPathway; UPA00767; UER00751.
DR   UniPathway; UPA00768; -.
DR   PRO; PR:P36596; -.
DR   Proteomes; UP000002485; Chromosome II.
DR   GO; GO:0005783; C:endoplasmic reticulum; IGI:PomBase.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:PomBase.
DR   GO; GO:0042175; C:nuclear outer membrane-endoplasmic reticulum membrane network; IDA:PomBase.
DR   GO; GO:0004310; F:farnesyl-diphosphate farnesyltransferase activity; IGI:PomBase.
DR   GO; GO:0051996; F:squalene synthase activity; IBA:GO_Central.
DR   GO; GO:0006696; P:ergosterol biosynthetic process; IGI:PomBase.
DR   GO; GO:0045338; P:farnesyl diphosphate metabolic process; IBA:GO_Central.
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.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum; Isoprene biosynthesis; Lipid biosynthesis;
KW   Lipid metabolism; Magnesium; Membrane; Multifunctional enzyme; NADP;
KW   Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW   Sterol biosynthesis; Sterol metabolism; Transferase; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..460
FT                   /note="Squalene synthase"
FT                   /id="PRO_0000067451"
FT   TRANSMEM        425..445
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   460 AA;  53321 MW;  BAEE7F24B6CE5D25 CRC64;
     MSLANRIEEI RCLCQYKLWN DLPSYGEDEN VPQNIRRCYQ LLDMTSRSFA VVIKELPNGI
     REAVMIFYLV LRGLDTVEDD MTLPLDKKLP ILRDFYKTIE VEGWTFNESG PNEKDRQLLV
     EFDVVIKEYL NLSEGYRNVI SNITKEMGDG MAYYASLAEK NDGFSVETIE DFNKYCHYVA
     GLVGIGLSRL FAQSKLEDPD LAHSQAISNS LGLFLQKVNI IRDYREDFDD NRHFWPREIW
     SKYTSSFGDL CLPDNSEKAL ECLSDMTANA LTHATDALVY LSQLKTQEIF NFCAIPQVMA
     IATLAAVFRN PDVFQTNVKI RKGQAVQIIL HSVNLKNVCD LFLRYTRDIH YKNTPKDPNF
     LKISIECGKI EQVSESLFPR RFREMYEKAY VSKLSEQKKG NGTQKAILND EQKELYRKDL
     QKLGISILFV FFIILVCLAV IFYVFNIRIH WSDFKELNLF
//