ERG6_CANAL
ID ERG6_CANAL Reviewed; 376 AA.
AC O74198; A0A1D8PJE1; Q5AJG1;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2017, sequence version 2.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=Sterol 24-C-methyltransferase {ECO:0000303|PubMed:9593144};
DE Short=SCMT {ECO:0000305};
DE Short=SMT {ECO:0000303|PubMed:9593144};
DE EC=2.1.1.41 {ECO:0000269|PubMed:20946868};
DE AltName: Full=Delta(24)-sterol C-methyltransferase {ECO:0000305};
DE AltName: Full=Ergosterol biosynthesis protein 6 {ECO:0000303|PubMed:9593144};
GN Name=ERG6 {ECO:0000303|PubMed:9593144}; OrderedLocusNames=CAALFM_C302150CA;
GN ORFNames=CaO19.1631, CaO19.9199;
OS Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida.
OX NCBI_TaxID=237561;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9593144; DOI=10.1128/aac.42.5.1160;
RA Jensen-Pergakes K.L., Kennedy M.A., Lees N.D., Barbuch R., Koegel C.,
RA Bard M.;
RT "Sequencing, disruption, and characterization of the Candida albicans
RT sterol methyltransferase (ERG6) gene: drug susceptibility studies in erg6
RT mutants.";
RL Antimicrob. Agents Chemother. 42:1160-1167(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=15123810; DOI=10.1073/pnas.0401648101;
RA Jones T., Federspiel N.A., Chibana H., Dungan J., Kalman S., Magee B.B.,
RA Newport G., Thorstenson Y.R., Agabian N., Magee P.T., Davis R.W.,
RA Scherer S.;
RT "The diploid genome sequence of Candida albicans.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:7329-7334(2004).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=17419877; DOI=10.1186/gb-2007-8-4-r52;
RA van het Hoog M., Rast T.J., Martchenko M., Grindle S., Dignard D.,
RA Hogues H., Cuomo C., Berriman M., Scherer S., Magee B.B., Whiteway M.,
RA Chibana H., Nantel A., Magee P.T.;
RT "Assembly of the Candida albicans genome into sixteen supercontigs aligned
RT on the eight chromosomes.";
RL Genome Biol. 8:RESEARCH52.1-RESEARCH52.12(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=24025428; DOI=10.1186/gb-2013-14-9-r97;
RA Muzzey D., Schwartz K., Weissman J.S., Sherlock G.;
RT "Assembly of a phased diploid Candida albicans genome facilitates allele-
RT specific measurements and provides a simple model for repeat and indel
RT structure.";
RL Genome Biol. 14:RESEARCH97.1-RESEARCH97.14(2013).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=11847103; DOI=10.1093/emboj/21.4.546;
RA Cruz M.C., Goldstein A.L., Blankenship J.R., Del Poeta M., Davis D.,
RA Cardenas M.E., Perfect J.R., McCusker J.H., Heitman J.;
RT "Calcineurin is essential for survival during membrane stress in Candida
RT albicans.";
RL EMBO J. 21:546-559(2002).
RN [6]
RP INDUCTION.
RX PubMed=15820985; DOI=10.1093/jac/dki088;
RA Copping V.M.S., Barelle C.J., Hube B., Gow N.A.R., Brown A.J.P., Odds F.C.;
RT "Exposure of Candida albicans to antifungal agents affects expression of
RT SAP2 and SAP9 secreted proteinase genes.";
RL J. Antimicrob. Chemother. 55:645-654(2005).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, AND PATHWAY.
RX PubMed=20946868; DOI=10.1016/j.abb.2010.10.008;
RA Ganapathy K., Kanagasabai R., Nguyen T.T., Nes W.D.;
RT "Purification, characterization and inhibition of sterol C24-
RT methyltransferase from Candida albicans.";
RL Arch. Biochem. Biophys. 505:194-201(2011).
RN [8]
RP INDUCTION.
RX PubMed=21592964; DOI=10.1074/jbc.m111.233569;
RA Singh R.P., Prasad H.K., Sinha I., Agarwal N., Natarajan K.;
RT "Cap2-HAP complex is a critical transcriptional regulator that has dual but
RT contrasting roles in regulation of iron homeostasis in Candida albicans.";
RL J. Biol. Chem. 286:25154-25170(2011).
RN [9]
RP INDUCTION.
RX PubMed=22265407; DOI=10.1016/j.cell.2011.10.048;
RA Nobile C.J., Fox E.P., Nett J.E., Sorrells T.R., Mitrovich Q.M.,
RA Hernday A.D., Tuch B.B., Andes D.R., Johnson A.D.;
RT "A recently evolved transcriptional network controls biofilm development in
RT Candida albicans.";
RL Cell 148:126-138(2012).
RN [10]
RP INDUCTION.
RX PubMed=22406769; DOI=10.1016/j.fgb.2012.02.006;
RA Kamthan M., Mukhopadhyay G., Chakraborty N., Chakraborty S., Datta A.;
RT "Quantitative proteomics and metabolomics approaches to demonstrate N-
RT acetyl-D-glucosamine inducible amino acid deprivation response as
RT morphological switch in Candida albicans.";
RL Fungal Genet. Biol. 49:369-378(2012).
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:9593144, PubMed:20946868). ERG6 catalyzes the methyl
CC transfer from S-adenosyl-methionine to the C-24 of zymosterol to form
CC fecosterol (PubMed:9593144, PubMed:20946868). The third module or late
CC pathway involves the ergosterol synthesis itself through consecutive
CC reactions that mainly occur in the endoplasmic reticulum (ER) membrane.
CC Firstly, the squalene synthase ERG9 catalyzes the condensation of 2
CC farnesyl pyrophosphate moieties to form squalene, which is the
CC precursor of all steroids. Squalene synthase is crucial for balancing
CC the incorporation of farnesyl diphosphate (FPP) into sterol and
CC nonsterol isoprene synthesis. Secondly, the squalene epoxidase ERG1
CC catalyzes the stereospecific oxidation of squalene to (S)-2,3-
CC epoxysqualene, which is considered to be a rate-limiting enzyme in
CC steroid biosynthesis. Then, the lanosterol synthase ERG7 catalyzes the
CC cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that
CC forms the sterol core. In the next steps, lanosterol is transformed to
CC zymosterol through a complex process involving various demethylation,
CC reduction and desaturation reactions. The lanosterol 14-alpha-
CC demethylase ERG11 (also known as CYP51) catalyzes C14-demethylation of
CC lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol,
CC which is critical for ergosterol biosynthesis. The C-14 reductase ERG24
CC reduces the C14=C15 double bond of 4,4-dimethyl-cholesta-8,14,24-
CC trienol to produce 4,4-dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-
CC cholesta-8,24-dienol is substrate of the C-4 demethylation complex
CC ERG25-ERG26-ERG27 in which ERG25 catalyzes the three-step
CC monooxygenation required for the demethylation of 4,4-dimethyl and
CC 4alpha-methylsterols, ERG26 catalyzes the oxidative decarboxylation
CC that results in a reduction of the 3-beta-hydroxy group at the C-3
CC carbon to an oxo group, and ERG27 is responsible for the reduction of
CC the keto group on the C-3. ERG28 has a role as a scaffold to help
CC anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and ERG29
CC regulates the activity of the iron-containing C4-methylsterol oxidase
CC ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes the
CC methyl transfer from S-adenosyl-methionine to the C-24 of zymosterol to
CC form fecosterol. The C-8 sterol isomerase ERG2 catalyzes the reaction
CC which results in unsaturation at C-7 in the B ring of sterols and thus
CC converts fecosterol to episterol. The sterol-C5-desaturase ERG3 then
CC catalyzes the introduction of a C-5 double bond in the B ring to
CC produce 5-dehydroepisterol. The C-22 sterol desaturase ERG5 further
CC converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol
CC by forming the C-22(23) double bond in the sterol side chain. Finally,
CC ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28)
CC sterol reductase ERG4 to produce ergosterol (Probable).
CC {ECO:0000269|PubMed:20946868, ECO:0000269|PubMed:9593144, ECO:0000305}.
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:20946868};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21129;
CC Evidence={ECO:0000269|PubMed:20946868};
CC -!- ACTIVITY REGULATION: Substrate analogs 25-azalanosterol and 24(R,S),25-
CC epiminolanosterol act as inhibitors. {ECO:0000269|PubMed:20946868}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=55 uM for zymosterol {ECO:0000269|PubMed:20946868};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis; ergosterol from
CC zymosterol: step 1/5. {ECO:0000269|PubMed:20946868}.
CC -!- INDUCTION: Expression is induced in the presence of fluconazole and up-
CC regulated in azole-resistant strain (PubMed:15820985). Expression is
CC positively regulated by the transcription regulator HAP43
CC (PubMed:21592964). Expression is also induced by N-acetyl-D-glucosamine
CC (PubMed:22406769). Expression is repressed during spider biofilm
CC formation (PubMed:22265407). {ECO:0000269|PubMed:15820985,
CC ECO:0000269|PubMed:21592964, ECO:0000269|PubMed:22265407,
CC ECO:0000269|PubMed:22406769}.
CC -!- DISRUPTION PHENOTYPE: Does not affect the susceptibility to azoles
CC (PubMed:9593144). Leads to hypersensitivity to cyclosporin A (CsA) and
CC FK506, inhibitors of the protein phosphatase calcineurin
CC (PubMed:11847103). {ECO:0000269|PubMed:11847103,
CC ECO:0000269|PubMed:9593144}.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. Erg6/SMT family. {ECO:0000305}.
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DR EMBL; AF031941; AAC26626.1; -; Genomic_DNA.
DR EMBL; CP017625; AOW28252.1; -; Genomic_DNA.
DR RefSeq; XP_721708.2; XM_716615.2.
DR AlphaFoldDB; O74198; -.
DR SMR; O74198; -.
DR BioGRID; 1219749; 1.
DR STRING; 237561.O74198; -.
DR PRIDE; O74198; -.
DR GeneID; 3636655; -.
DR KEGG; cal:CAALFM_C302150CA; -.
DR CGD; CAL0000189580; ERG6.
DR VEuPathDB; FungiDB:C3_02150C_A; -.
DR eggNOG; KOG1269; Eukaryota.
DR HOGENOM; CLU_039068_5_3_1; -.
DR InParanoid; O74198; -.
DR OMA; NTFDKVY; -.
DR OrthoDB; 661953at2759; -.
DR UniPathway; UPA00768; UER00760.
DR PRO; PR:O74198; -.
DR Proteomes; UP000000559; Chromosome 3.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:CGD.
DR GO; GO:0003838; F:sterol 24-C-methyltransferase activity; IDA:CGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IGI:CGD.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR Gene3D; 3.40.50.150; -; 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 Pfam; PF08241; Methyltransf_11; 1.
DR Pfam; PF08498; Sterol_MT_C; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51685; SAM_MT_ERG6_SMT; 1.
PE 1: Evidence at protein level;
KW Lipid biosynthesis; Lipid metabolism; Methyltransferase;
KW Reference proteome; S-adenosyl-L-methionine; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase.
FT CHAIN 1..376
FT /note="Sterol 24-C-methyltransferase"
FT /id="PRO_0000124789"
FT CONFLICT 222
FT /note="V -> I (in Ref. 1; AAC26626)"
SQ SEQUENCE 376 AA; 43072 MW; 25253F9336BF3FA0 CRC64;
MSPVQLAEKN YERDEQFTKA LHGESYKKTG LSALIAKSKD AASVAAEGYF KHWDGGISKD
DEEKRLNDYS QLTHHYYNLV TDFYEYGWGS SFHFSRYYKG EAFRQATARH EHFLAHKMNL
NENMKVLDVG CGVGGPGREI TRFTDCEIVG LNNNDYQIER ANHYAKKYHL DHKLSYVKGD
FMQMDFEPES FDAVYAIEAT VHAPVLEGVY SEIYKVLKPG GVFGVYEWVM TDKYDETNEE
HRKIAYGIEV GDGIPKMYSR KVAEQALKNV GFEIEYQKDL ADVDDEIPWY YPLSGDLKFC
QTFGDYLTVF RTSRIGRFIT TESVGLMEKI GLAPKGSKQV THALEDAAVN LVEGGRQKLF
TPMMLYVVRK PLEKKD
