ID   HMCS_CAEEL              Reviewed;         462 AA.
AC   P54871; Q22962;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   20-JUN-2002, sequence version 2.
DT   03-AUG-2022, entry version 149.
DE   RecName: Full=Hydroxymethylglutaryl-CoA synthase;
DE            Short=HMG-CoA synthase;
DE            EC=2.3.3.10;
DE   AltName: Full=3-hydroxy-3-methylglutaryl coenzyme A synthase;
GN   Name=hmgs-1 {ECO:0000312|WormBase:F25B4.6};
GN   ORFNames=F25B4.6 {ECO:0000312|WormBase:F25B4.6};
OS   Caenorhabditis elegans.
OC   Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC   Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC   Caenorhabditis.
OX   NCBI_TaxID=6239;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Bristol N2;
RX   PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG   The C. elegans sequencing consortium;
RT   "Genome sequence of the nematode C. elegans: a platform for investigating
RT   biology.";
RL   Science 282:2012-2018(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 5-462.
RX   PubMed=7851882; DOI=10.1006/geno.1994.1542;
RA   Boukaftane Y., Duncan A., Wang S., Labuda D., Robert M.-F., Sarrazin J.,
RA   Schappert K.T., Mitchell G.A.;
RT   "Human mitochondrial HMG CoA synthase: liver cDNA and partial genomic
RT   cloning, chromosome mapping to 1p12-p13, and possible role in vertebrate
RT   evolution.";
RL   Genomics 23:552-559(1994).
RN   [3]
RP   SUMOYLATION, UBIQUITINATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP   LYS-291; LYS-314; LYS-408 AND LYS-420.
RX   PubMed=25187565; DOI=10.1073/pnas.1414748111;
RA   Sapir A., Tsur A., Koorman T., Ching K., Mishra P., Bardenheier A.,
RA   Podolsky L., Bening-Abu-Shach U., Boxem M., Chou T.F., Broday L.,
RA   Sternberg P.W.;
RT   "Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates
RT   metabolism during aging.";
RL   Proc. Natl. Acad. Sci. U.S.A. 111:E3880-E3889(2014).
CC   -!- FUNCTION: This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form
CC       HMG-CoA, which is the substrate for HMG-CoA reductase.
CC       {ECO:0000250|UniProtKB:P54869}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-hydroxy-3-
CC         methylglutaryl-CoA + CoA + H(+); Xref=Rhea:RHEA:10188,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43074,
CC         ChEBI:CHEBI:57286, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288; EC=2.3.3.10;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10116};
CC   -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC       biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3.
CC   -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:25187565}.
CC   -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown results in sterility,
CC       slow development, reduced body size, severe paralysis and reduced
CC       pharyngeal pumping. {ECO:0000269|PubMed:25187565}.
CC   -!- SIMILARITY: Belongs to the thiolase-like superfamily. HMG-CoA synthase
CC       family. {ECO:0000305}.
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DR   EMBL; FO080538; CCD64508.1; -; Genomic_DNA.
DR   EMBL; U12787; AAA92672.1; -; mRNA.
DR   PIR; T25726; T25726.
DR   RefSeq; NP_504496.1; NM_072095.3.
DR   AlphaFoldDB; P54871; -.
DR   SMR; P54871; -.
DR   BioGRID; 44005; 9.
DR   IntAct; P54871; 1.
DR   STRING; 6239.F25B4.6; -.
DR   EPD; P54871; -.
DR   PaxDb; P54871; -.
DR   PeptideAtlas; P54871; -.
DR   EnsemblMetazoa; F25B4.6.1; F25B4.6.1; WBGene00017769.
DR   GeneID; 178956; -.
DR   KEGG; cel:CELE_F25B4.6; -.
DR   UCSC; F25B4.6; c. elegans.
DR   CTD; 178956; -.
DR   WormBase; F25B4.6; CE09624; WBGene00017769; hmgs-1.
DR   eggNOG; KOG1393; Eukaryota.
DR   GeneTree; ENSGT00390000006096; -.
DR   HOGENOM; CLU_008065_0_1_1; -.
DR   InParanoid; P54871; -.
DR   OMA; DDAYNWI; -.
DR   OrthoDB; 495111at2759; -.
DR   PhylomeDB; P54871; -.
DR   BRENDA; 2.3.3.10; 1045.
DR   Reactome; R-CEL-191273; Cholesterol biosynthesis.
DR   Reactome; R-CEL-77111; Synthesis of Ketone Bodies.
DR   UniPathway; UPA00058; UER00102.
DR   PRO; PR:P54871; -.
DR   Proteomes; UP000001940; Chromosome V.
DR   Bgee; WBGene00017769; Expressed in pharyngeal muscle cell (C elegans) and 4 other tissues.
DR   GO; GO:0004421; F:hydroxymethylglutaryl-CoA synthase activity; IBA:GO_Central.
DR   GO; GO:0006084; P:acetyl-CoA metabolic process; IBA:GO_Central.
DR   GO; GO:0010142; P:farnesyl diphosphate biosynthetic process, mevalonate pathway; IBA:GO_Central.
DR   GO; GO:0016126; P:sterol biosynthetic process; IEA:UniProtKB-KW.
DR   Gene3D; 3.40.47.10; -; 1.
DR   InterPro; IPR000590; HMG_CoA_synt_AS.
DR   InterPro; IPR013746; HMG_CoA_synt_C_dom.
DR   InterPro; IPR013528; HMG_CoA_synth_N.
DR   InterPro; IPR010122; HMG_CoA_synthase_euk.
DR   InterPro; IPR016039; Thiolase-like.
DR   Pfam; PF08540; HMG_CoA_synt_C; 1.
DR   Pfam; PF01154; HMG_CoA_synt_N; 1.
DR   SUPFAM; SSF53901; SSF53901; 2.
DR   TIGRFAMs; TIGR01833; HMG-CoA-S_euk; 1.
DR   PROSITE; PS01226; HMG_COA_SYNTHASE; 1.
PE   1: Evidence at protein level;
KW   Isopeptide bond; Lipid biosynthesis; Lipid metabolism; Reference proteome;
KW   Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW   Sterol metabolism; Transferase; Ubl conjugation.
FT   CHAIN           1..462
FT                   /note="Hydroxymethylglutaryl-CoA synthase"
FT                   /id="PRO_0000213754"
FT   ACT_SITE        92
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT   ACT_SITE        124
FT                   /note="Acyl-thioester intermediate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT   ACT_SITE        257
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT   CROSSLNK        408
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO)"
FT                   /evidence="ECO:0000269|PubMed:25187565"
FT   MUTAGEN         291
FT                   /note="K->R: Reduced sumoylation; when associated with R-
FT                   314, R-408 and R-420."
FT                   /evidence="ECO:0000269|PubMed:25187565"
FT   MUTAGEN         314
FT                   /note="K->R: Reduced sumoylation; when associated with R-
FT                   291, R-408 and R-420."
FT                   /evidence="ECO:0000269|PubMed:25187565"
FT   MUTAGEN         408
FT                   /note="K->R: Reduced sumoylation."
FT                   /evidence="ECO:0000269|PubMed:25187565"
FT   MUTAGEN         420
FT                   /note="K->R: Reduced sumoylation; when associated with R-
FT                   291, R-314 and R-408."
FT                   /evidence="ECO:0000269|PubMed:25187565"
SQ   SEQUENCE   462 AA;  51416 MW;  89BDE382588F6D9F CRC64;
     MSLGQLSYTP VTDVGIGAIE LYFPQNFVDQ NDLEKFNNVS SGKYTIGLGQ QQMGFCSDNE
     DIVSISLTVT RKLIETYKIS TDSIGCLVVG TETMIDKSKS VKTALMDLFP GNSDIEGVDI
     KNACFGGAQA LLHAIDWVTV NHPLDKKNAI VVVADIAIYE EGPARCTGGA GAIAFLICPD
     ASIPIDRQFS ACHMKNTWDF FKPITPIPSE YPVVDGSLSL SSYLEAVRMT YTYFISKVNR
     HTTGIDGLNS FDGVFLHSPF TKMVQKGLAV MNYTDSQLRH KQLNGNGVDH KLDENDRAGL
     AKMIELSAQV WKEKTDPYLV FNRRIGNMYT PSLFAQLLAY LAADDCVTGE KSILFFAYGS
     GLASAIFPGR VRQTSNLDKI RQVAIRAIKR LDDRIQFTPE EFTETLQKRE VFLRSKEIPK
     SPSETSLFPN TYFLDNMDKL YRRSYTLHEE PNGVQNGNGI HH