ID   ERG6_YEAST              Reviewed;         383 AA.
AC   P25087; D6VZG6;
DT   01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 4.
DT   27-MAR-2024, entry version 202.
DE   RecName: Full=Sterol 24-C-methyltransferase ERG6 {ECO:0000303|PubMed:6363386};
DE            Short=SCMT {ECO:0000303|PubMed:6363386};
DE            EC=2.1.1.41 {ECO:0000269|PubMed:6363386};
DE   AltName: Full=Delta(24)-sterol C-methyltransferase ERG6 {ECO:0000305};
DE   AltName: Full=Ergosterol biosynthetic protein 6 {ECO:0000303|PubMed:6363386};
GN   Name=ERG6 {ECO:0000303|PubMed:6363386};
GN   Synonyms=ISE1, LIS1 {ECO:0000303|PubMed:8038180}, SED6
GN   {ECO:0000303|PubMed:8203167}; OrderedLocusNames=YML008C;
GN   ORFNames=YM9571.10C;
OS   Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX   NCBI_TaxID=559292;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8203167; DOI=10.1002/yea.320100213;
RA   Hardwick K.G., Pelham H.R.B.;
RT   "SED6 is identical to ERG6, and encodes a putative methyltransferase
RT   required for ergosterol synthesis.";
RL   Yeast 10:265-269(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8038180; DOI=10.1016/0005-2736(94)90339-5;
RA   Welihinda A.A., Beavis A.D., Trumbly R.J.;
RT   "Mutations in LIS1 (ERG6) gene confer increased sodium and lithium uptake
RT   in Saccharomyces cerevisiae.";
RL   Biochim. Biophys. Acta 1193:107-117(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169872;
RA   Bowman S., Churcher C.M., Badcock K., Brown D., Chillingworth T.,
RA   Connor R., Dedman K., Devlin K., Gentles S., Hamlin N., Hunt S., Jagels K.,
RA   Lye G., Moule S., Odell C., Pearson D., Rajandream M.A., Rice P.,
RA   Skelton J., Walsh S.V., Whitehead S., Barrell B.G.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome XIII.";
RL   Nature 387:90-93(1997).
RN   [4]
RP   GENOME REANNOTATION.
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=24374639; DOI=10.1534/g3.113.008995;
RA   Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA   Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA   Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT   "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL   G3 (Bethesda) 4:389-398(2014).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-258.
RX   PubMed=2060792; DOI=10.1016/0378-1119(91)90238-7;
RA   Hussain M., Lenard J.;
RT   "Characterization of PDR4, a Saccharomyces cerevisiae gene that confers
RT   pleiotropic drug resistance in high-copy number: identity with YAP1,
RT   encoding a transcriptional activator.";
RL   Gene 101:149-152(1991).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=6363386; DOI=10.1128/jb.157.2.475-483.1984;
RA   McCammon M.T., Hartmann M.A., Bottema C.D., Parks L.W.;
RT   "Sterol methylation in Saccharomyces cerevisiae.";
RL   J. Bacteriol. 157:475-483(1984).
RN   [7]
RP   ACETYLATION AT SER-2.
RX   PubMed=9298649; DOI=10.1002/elps.1150180810;
RA   Garrels J.I., McLaughlin C.S., Warner J.R., Futcher B., Latter G.I.,
RA   Kobayashi R., Schwender B., Volpe T., Anderson D.S., Mesquita-Fuentes R.,
RA   Payne W.E.;
RT   "Proteome studies of Saccharomyces cerevisiae: identification and
RT   characterization of abundant proteins.";
RL   Electrophoresis 18:1347-1360(1997).
RN   [8]
RP   LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX   PubMed=14562106; DOI=10.1038/nature02046;
RA   Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA   O'Shea E.K., Weissman J.S.;
RT   "Global analysis of protein expression in yeast.";
RL   Nature 425:737-741(2003).
RN   [9]
RP   FUNCTION, AND INTERACTION WITH ERG28.
RX   PubMed=15522820; DOI=10.1016/j.bbalip.2004.08.001;
RA   Mo C., Valachovic M., Bard M.;
RT   "The ERG28-encoded protein, Erg28p, interacts with both the sterol C-4
RT   demethylation enzyme complex as well as the late biosynthetic protein, the
RT   C-24 sterol methyltransferase (Erg6p).";
RL   Biochim. Biophys. Acta 1686:30-36(2004).
RN   [10]
RP   FUNCTION, AND INTERACTION WITH ERG28.
RX   PubMed=15995173; DOI=10.1194/jlr.m500153-jlr200;
RA   Mo C., Bard M.;
RT   "Erg28p is a key protein in the yeast sterol biosynthetic enzyme complex.";
RL   J. Lipid Res. 46:1991-1998(2005).
RN   [11]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=18407956; DOI=10.1074/mcp.m700468-mcp200;
RA   Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.;
RT   "A multidimensional chromatography technology for in-depth phosphoproteome
RT   analysis.";
RL   Mol. Cell. Proteomics 7:1389-1396(2008).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19779198; DOI=10.1126/science.1172867;
RA   Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.;
RT   "Global analysis of Cdk1 substrate phosphorylation sites provides insights
RT   into evolution.";
RL   Science 325:1682-1686(2009).
RN   [13]
RP   FUNCTION.
RX   PubMed=29773647; DOI=10.1074/jbc.ra118.001781;
RA   Ward D.M., Chen O.S., Li L., Kaplan J., Bhuiyan S.A., Natarajan S.K.,
RA   Bard M., Cox J.E.;
RT   "Altered sterol metabolism in budding yeast affects mitochondrial iron-
RT   sulfur (Fe-S) cluster synthesis.";
RL   J. Biol. Chem. 293:10782-10795(2018).
RN   [14]
RP   REVIEW ON ERGOSTEROL BIOSYNTHESIS.
RX   PubMed=32679672; DOI=10.3390/genes11070795;
RA   Jorda T., Puig S.;
RT   "Regulation of ergosterol biosynthesis in Saccharomyces cerevisiae.";
RL   Genes (Basel) 11:0-0(2020).
CC   -!- FUNCTION: Sterol 24-C-methyltransferase; part of the third module of
CC       ergosterol biosynthesis pathway that includes the late steps of the
CC       pathway (PubMed:6363386). ERG6 catalyzes the methyl transfer from S-
CC       adenosyl-methionine to the C-24 of zymosterol to form fecosterol
CC       (PubMed:6363386). The third module or late pathway involves the
CC       ergosterol synthesis itself through consecutive reactions that mainly
CC       occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene
CC       synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate
CC       moieties to form squalene, which is the precursor of all steroids.
CC       Squalene synthase is crucial for balancing the incorporation of
CC       farnesyl diphosphate (FPP) into sterol and nonsterol isoprene
CC       synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the
CC       stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is
CC       considered to be a rate-limiting enzyme in steroid biosynthesis. Then,
CC       the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3
CC       oxidosqualene to lanosterol, a reaction that forms the sterol core. In
CC       the next steps, lanosterol is transformed to zymosterol through a
CC       complex process involving various demethylation, reduction and
CC       desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also
CC       known as CYP51) catalyzes C14-demethylation of lanosterol to produce
CC       4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for
CC       ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15
CC       double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-
CC       dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is
CC       substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which
CC       ERG25 catalyzes the three-step monooxygenation required for the
CC       demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes
CC       the oxidative decarboxylation that results in a reduction of the 3-
CC       beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is
CC       responsible for the reduction of the keto group on the C-3. ERG28 has a
CC       role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the
CC       endoplasmic reticulum and ERG29 regulates the activity of the iron-
CC       containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-
CC       methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-
CC       methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol
CC       isomerase ERG2 catalyzes the reaction which results in unsaturation at
CC       C-7 in the B ring of sterols and thus converts fecosterol to episterol.
CC       The sterol-C5-desaturase ERG3 then catalyzes 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:32679672). {ECO:0000269|PubMed:6363386,
CC       ECO:0000303|PubMed:32679672}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=S-adenosyl-L-methionine + zymosterol = fecosterol + H(+) + S-
CC         adenosyl-L-homocysteine; Xref=Rhea:RHEA:21128, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:17038, ChEBI:CHEBI:18252, ChEBI:CHEBI:57856,
CC         ChEBI:CHEBI:59789; EC=2.1.1.41;
CC         Evidence={ECO:0000269|PubMed:6363386};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21129;
CC         Evidence={ECO:0000269|PubMed:6363386};
CC   -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis; ergosterol from
CC       zymosterol: step 1/5. {ECO:0000269|PubMed:6363386}.
CC   -!- SUBUNIT: Interacts with ERG28. {ECO:0000269|PubMed:15522820,
CC       ECO:0000269|PubMed:15995173}.
CC   -!- INTERACTION:
CC       P25087; P25087: ERG6; NbExp=3; IntAct=EBI-6567, EBI-6567;
CC   -!- SUBCELLULAR LOCATION: Microsome {ECO:0000269|PubMed:6363386}.
CC       Mitochondrion {ECO:0000269|PubMed:6363386}.
CC   -!- DISRUPTION PHENOTYPE: Abolishes the production of ergosterol.
CC       {ECO:0000269|PubMed:6363386}.
CC   -!- MISCELLANEOUS: Present with 53800 molecules/cell in log phase SD
CC       medium. {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC       superfamily. Erg6/SMT family. {ECO:0000255|PROSITE-ProRule:PRU01022}.
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DR   EMBL; X74249; CAA52308.1; -; Genomic_DNA.
DR   EMBL; S72460; AAB31378.1; -; Genomic_DNA.
DR   EMBL; Z49810; CAA89944.1; -; Genomic_DNA.
DR   EMBL; X53830; CAA37826.1; -; Genomic_DNA.
DR   EMBL; BK006946; DAA09890.1; -; Genomic_DNA.
DR   PIR; S42003; S42003.
DR   RefSeq; NP_013706.1; NM_001182363.1.
DR   AlphaFoldDB; P25087; -.
DR   SMR; P25087; -.
DR   BioGRID; 35161; 632.
DR   DIP; DIP-3816N; -.
DR   IntAct; P25087; 16.
DR   MINT; P25087; -.
DR   STRING; 4932.YML008C; -.
DR   iPTMnet; P25087; -.
DR   MaxQB; P25087; -.
DR   PaxDb; 4932-YML008C; -.
DR   PeptideAtlas; P25087; -.
DR   EnsemblFungi; YML008C_mRNA; YML008C; YML008C.
DR   GeneID; 855003; -.
DR   KEGG; sce:YML008C; -.
DR   AGR; SGD:S000004467; -.
DR   SGD; S000004467; ERG6.
DR   VEuPathDB; FungiDB:YML008C; -.
DR   eggNOG; KOG1269; Eukaryota.
DR   HOGENOM; CLU_039068_5_3_1; -.
DR   InParanoid; P25087; -.
DR   OMA; NGIATMM; -.
DR   OrthoDB; 275921at2759; -.
DR   BioCyc; MetaCyc:MONOMER3O-188; -.
DR   BioCyc; YEAST:MONOMER3O-188; -.
DR   BRENDA; 2.1.1.41; 984.
DR   SABIO-RK; P25087; -.
DR   UniPathway; UPA00768; UER00760.
DR   BioGRID-ORCS; 855003; 1 hit in 10 CRISPR screens.
DR   PRO; PR:P25087; -.
DR   Proteomes; UP000002311; Chromosome XIII.
DR   RNAct; P25087; Protein.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:SGD.
DR   GO; GO:0005811; C:lipid droplet; IDA:SGD.
DR   GO; GO:0005741; C:mitochondrial outer membrane; HDA:SGD.
DR   GO; GO:0005739; C:mitochondrion; HDA:SGD.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0003838; F:sterol 24-C-methyltransferase activity; IDA:SGD.
DR   GO; GO:0006696; P:ergosterol biosynthetic process; IDA:UniProt.
DR   GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR   CDD; cd02440; AdoMet_MTases; 1.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR   InterPro; IPR013216; Methyltransf_11.
DR   InterPro; IPR030384; MeTrfase_SMT.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   InterPro; IPR013705; Sterol_MeTrfase_C.
DR   PANTHER; PTHR44068:SF1; HYPOTHETICAL LOC100005854; 1.
DR   PANTHER; PTHR44068; ZGC:194242; 1.
DR   Pfam; PF08241; Methyltransf_11; 1.
DR   Pfam; PF08498; Sterol_MT_C; 1.
DR   SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
DR   PROSITE; PS51685; SAM_MT_ERG6_SMT; 1.
DR   SWISS-2DPAGE; P25087; -.
PE   1: Evidence at protein level;
KW   Acetylation; Endoplasmic reticulum; Lipid biosynthesis; Lipid metabolism;
KW   Methyltransferase; Microsome; Mitochondrion; Phosphoprotein;
KW   Reference proteome; S-adenosyl-L-methionine; Steroid biosynthesis;
KW   Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:9298649"
FT   CHAIN           2..383
FT                   /note="Sterol 24-C-methyltransferase ERG6"
FT                   /id="PRO_0000124799"
FT   MOD_RES         2
FT                   /note="N-acetylserine"
FT                   /evidence="ECO:0000269|PubMed:9298649"
FT   MOD_RES         99
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956"
FT   CONFLICT        380
FT                   /note="E -> EE (in Ref. 2; AAB31378)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   383 AA;  43431 MW;  C3A2B6DF2C14ED63 CRC64;
     MSETELRKRQ AQFTRELHGD DIGKKTGLSA LMSKNNSAQK EAVQKYLRNW DGRTDKDAEE
     RRLEDYNEAT HSYYNVVTDF YEYGWGSSFH FSRFYKGESF AASIARHEHY LAYKAGIQRG
     DLVLDVGCGV GGPAREIARF TGCNVIGLNN NDYQIAKAKY YAKKYNLSDQ MDFVKGDFMK
     MDFEENTFDK VYAIEATCHA PKLEGVYSEI YKVLKPGGTF AVYEWVMTDK YDENNPEHRK
     IAYEIELGDG IPKMFHVDVA RKALKNCGFE VLVSEDLADN DDEIPWYYPL TGEWKYVQNL
     ANLATFFRTS YLGRQFTTAM VTVMEKLGLA PEGSKEVTAA LENAAVGLVA GGKSKLFTPM
     MLFVARKPEN AETPSQTSQE ATQ
//