HMCS2_RAT
ID HMCS2_RAT Reviewed; 508 AA.
AC P22791; F1M9Q5; Q68G44;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 17-JUN-2020, sequence version 2.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Hydroxymethylglutaryl-CoA synthase, mitochondrial;
DE Short=HMG-CoA synthase;
DE EC=2.3.3.10 {ECO:0000250|UniProtKB:P54868};
DE AltName: Full=3-hydroxy-3-methylglutaryl coenzyme A synthase;
DE Flags: Precursor;
GN Name=Hmgcs2;
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], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RX PubMed=1971108; DOI=10.1073/pnas.87.10.3874;
RA Ayte J., Gil-Gomez G., Haro D., Marrero P.F., Hegardt F.G.;
RT "Rat mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl-CoA synthases
RT are encoded by two different genes.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:3874-3878(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-35.
RX PubMed=8097464; DOI=10.1111/j.1432-1033.1993.tb17819.x;
RA Gil-Gomez G., Ayte J., Hegardt F.G.;
RT "The rat mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A-synthase gene
RT contains elements that mediate its multihormonal regulation and tissue
RT specificity.";
RL Eur. J. Biochem. 213:773-779(1993).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-440 AND SER-477, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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).
CC -!- FUNCTION: Catalyzes the first irreversible step in ketogenesis,
CC condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is
CC converted by HMG-CoA reductase (HMGCR) into mevalonate.
CC {ECO:0000250|UniProtKB:P54868}.
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:0000250|UniProtKB:P54868};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10189;
CC Evidence={ECO:0000250|UniProtKB:P54868};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3. {ECO:0000305}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P54868}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000305|PubMed:1971108}.
CC -!- TISSUE SPECIFICITY: Liver and kidney. {ECO:0000269|PubMed:1971108}.
CC -!- PTM: Succinylated. Desuccinylated by SIRT5. Succinylation, at least at
CC Lys-83 and Lys-310, inhibits the enzymatic activity.
CC {ECO:0000250|UniProtKB:P54869}.
CC -!- SIMILARITY: Belongs to the thiolase-like superfamily. HMG-CoA synthase
CC family. {ECO:0000305}.
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DR EMBL; M33648; AAA41336.1; -; mRNA.
DR EMBL; M63800; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR07012623; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AABR07012624; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH474015; EDL85567.1; -; Genomic_DNA.
DR EMBL; CH474015; EDL85568.1; -; Genomic_DNA.
DR EMBL; BC078695; AAH78695.1; -; mRNA.
DR EMBL; BC083543; AAH83543.1; -; mRNA.
DR PIR; A35865; A35865.
DR RefSeq; NP_775117.2; NM_173094.2.
DR RefSeq; XP_006233064.1; XM_006233002.3.
DR AlphaFoldDB; P22791; -.
DR SMR; P22791; -.
DR STRING; 10116.ENSRNOP00000026122; -.
DR iPTMnet; P22791; -.
DR PhosphoSitePlus; P22791; -.
DR SwissPalm; P22791; -.
DR jPOST; P22791; -.
DR PaxDb; P22791; -.
DR PRIDE; P22791; -.
DR Ensembl; ENSRNOT00000026121; ENSRNOP00000026122; ENSRNOG00000019120.
DR GeneID; 24450; -.
DR KEGG; rno:24450; -.
DR UCSC; RGD:2804; rat.
DR CTD; 3158; -.
DR RGD; 2804; Hmgcs2.
DR eggNOG; KOG1393; Eukaryota.
DR GeneTree; ENSGT00390000006096; -.
DR HOGENOM; CLU_008065_0_1_1; -.
DR InParanoid; P22791; -.
DR OMA; YFAFHAP; -.
DR OrthoDB; 495111at2759; -.
DR PhylomeDB; P22791; -.
DR TreeFam; TF105361; -.
DR BRENDA; 2.3.3.10; 5301.
DR Reactome; R-RNO-77111; Synthesis of Ketone Bodies.
DR UniPathway; UPA00058; UER00102.
DR PRO; PR:P22791; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Proteomes; UP000234681; Chromosome 2.
DR Bgee; ENSRNOG00000019120; Expressed in liver and 19 other tissues.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR GO; GO:0004421; F:hydroxymethylglutaryl-CoA synthase activity; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; ISO:RGD.
DR GO; GO:0060612; P:adipose tissue development; IEP:RGD.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEP:RGD.
DR GO; GO:0071398; P:cellular response to fatty acid; IEP:RGD.
DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEP:RGD.
DR GO; GO:0032870; P:cellular response to hormone stimulus; IEP:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEP:RGD.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEP:RGD.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0010142; P:farnesyl diphosphate biosynthetic process, mevalonate pathway; IBA:GO_Central.
DR GO; GO:0046951; P:ketone body biosynthetic process; IEP:RGD.
DR GO; GO:0001822; P:kidney development; IEP:RGD.
DR GO; GO:0001889; P:liver development; IEP:RGD.
DR GO; GO:0030324; P:lung development; IEP:RGD.
DR GO; GO:0007494; P:midgut development; IEP:RGD.
DR GO; GO:0033555; P:multicellular organismal response to stress; IEP:RGD.
DR GO; GO:0009617; P:response to bacterium; IEP:RGD.
DR GO; GO:0051591; P:response to cAMP; IEP:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:0033762; P:response to glucagon; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0060416; P:response to growth hormone; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:RGD.
DR GO; GO:0070543; P:response to linoleic acid; IEP:RGD.
DR GO; GO:0010038; P:response to metal ion; IEP:RGD.
DR GO; GO:0034284; P:response to monosaccharide; IEP:RGD.
DR GO; GO:0007584; P:response to nutrient; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR GO; GO:0034696; P:response to prostaglandin F; IEP:RGD.
DR GO; GO:0042594; P:response to starvation; IEP:RGD.
DR GO; GO:0009266; P:response to temperature stimulus; IEP:RGD.
DR GO; GO:0033574; P:response to testosterone; IEP:RGD.
DR GO; GO:0034014; P:response to triglyceride; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
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 Acetylation; Cholesterol biosynthesis; Cholesterol metabolism;
KW Lipid biosynthesis; Lipid metabolism; Mitochondrion; Phosphoprotein;
KW Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transferase; Transit peptide.
FT TRANSIT 1..37
FT /note="Mitochondrion"
FT /evidence="ECO:0000305"
FT CHAIN 38..508
FT /note="Hydroxymethylglutaryl-CoA synthase, mitochondrial"
FT /id="PRO_0000013486"
FT ACT_SITE 132
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT ACT_SITE 166
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT ACT_SITE 301
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10116"
FT BINDING 80
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P54868"
FT BINDING 204
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P54868"
FT BINDING 258
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P54868"
FT BINDING 380
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P54868"
FT MOD_RES 52
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 83
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 83
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 118
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 118
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 221
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 243
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 256
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 256
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 306
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 310
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 310
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q2KIE6"
FT MOD_RES 327
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 327
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 333
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 342
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 342
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 350
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 350
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 354
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 354
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 358
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 358
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 427
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 433
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P54868"
FT MOD_RES 437
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 440
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 447
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 447
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 473
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 473
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P54869"
FT MOD_RES 477
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT CONFLICT 205
FT /note="A -> P (in Ref. 1; AAA41336)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 508 AA; 56886 MW; 9DEAD8EC5F2C6E1A CRC64;
MQRLLAPARR VLQVKRVMQE SSLSPAHLLP AAQQRFSTIP PAPLAKTDTW PKDVGILALE
VYFPAQYVDQ TDLEKFNNVE AGKYTVGLGQ TRMGFCSVQE DINSLCLTVV QRLMERTKLP
WDAVGRLEVG TETIIDKSKA VKTVLMELFQ DSGNTDIEGI DTTNACYGGT ASLFNAANWM
ESSYWDGRYA LVVCGDIAVY PSGNARPTGG AGAVAMLIGP KAPLVLEQGL RGTHMENAYD
FYKPNLASEY PLVDGKLSIQ CYLRALDRCY AAYRRKIQNQ WKQAGNNQPF TLDDVQYMIF
HTPFCKMVQK SLARLMFNDF LSSSSDKQNN LYKGLEAFKG LKLEETYTNK DVDKALLKAS
LDMFNKKTKA SLYLSTNNGN MYTSSLYGCL ASLLSHHSAQ ELAGSRIGAF SYGSGLAASF
FSFRVSKDAS PGSPLEKLVS SVSDLPKRLD SRRRMSPEEF TEIMNQREQF YHKVNFSPPG
DTSNLFPGTW YLERVDEMHR RKYARRPV
