HMCS2_HUMAN
ID HMCS2_HUMAN Reviewed; 508 AA.
AC P54868; B7Z8R3; D3Y5K6; Q5SZU2; Q6IBF4;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 195.
DE RecName: Full=Hydroxymethylglutaryl-CoA synthase, mitochondrial;
DE Short=HMG-CoA synthase;
DE EC=2.3.3.10 {ECO:0000269|PubMed:11228257, ECO:0000269|PubMed:23751782, ECO:0000269|PubMed:29597274};
DE AltName: Full=3-hydroxy-3-methylglutaryl coenzyme A synthase;
DE Flags: Precursor;
GN Name=HMGCS2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=7893153; DOI=10.1006/abbi.1995.1178;
RA Mascaro C., Buesa C., Ortiz J.A., Haro D., Hegardt F.G.;
RT "Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-
RT 3-methylglutaryl-CoA synthase.";
RL Arch. Biochem. Biophys. 317:385-390(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=9305755; DOI=10.1016/s0378-1119(97)00067-x;
RA Boukaftane Y., Mitchell G.A.;
RT "Cloning and characterization of the human mitochondrial 3-hydroxy-3-
RT methylglutaryl CoA synthase gene.";
RL Gene 195:121-126(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 36-508 (ISOFORM 1).
RC TISSUE=Liver;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 91-316 (ISOFORM 3), ALTERNATIVE SPLICING, AND
RP TISSUE SPECIFICITY.
RX PubMed=21952825; DOI=10.1007/s11033-011-1270-8;
RA Puisac B., Ramos M., Arnedo M., Menao S., Gil-Rodriguez M.C.,
RA Teresa-Rodrigo M.E., Pie A., de Karam J.C., Wesselink J.J., Gimenez I.,
RA Ramos F.J., Casals N., Gomez-Puertas P., Hegardt F.G., Pie J.;
RT "Characterization of splice variants of the genes encoding human
RT mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the
RT ketogenesis pathway.";
RL Mol. Biol. Rep. 39:4777-4785(2012).
RN [10]
RP TISSUE SPECIFICITY.
RX PubMed=16940161; DOI=10.1158/1541-7786.mcr-05-0267;
RA Camarero N., Mascaro C., Mayordomo C., Vilardell F., Haro D., Marrero P.F.;
RT "Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells
RT of human colonic epithelium and down-regulated in colon cancer.";
RL Mol. Cancer Res. 4:645-653(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-433 AND SER-440, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 51-508, SUBUNIT, ACTIVE SITE, AND
RP SUBSTRATE-BINDING SITES.
RX PubMed=20346956; DOI=10.1016/j.jmb.2010.03.034;
RA Shafqat N., Turnbull A., Zschocke J., Oppermann U., Yue W.W.;
RT "Crystal structures of human HMG-CoA synthase isoforms provide insights
RT into inherited ketogenesis disorders and inhibitor design.";
RL J. Mol. Biol. 398:497-506(2010).
RN [13]
RP VARIANTS HMGCS2D ARG-212 AND HIS-500.
RX PubMed=11479731; DOI=10.1007/s004390100554;
RA Aledo R., Zschocke J., Pie J., Mir C., Fiesel S., Mayatepek E.,
RA Hoffmann G.F., Casals N., Hegardt F.G.;
RT "Genetic basis of mitochondrial HMG-CoA synthase deficiency.";
RL Hum. Genet. 109:19-23(2001).
RN [14]
RP VARIANT HMGCS2D LEU-174, CHARACTERIZATION OF VARIANT HMGCS2D LEU-174,
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=11228257; DOI=10.1203/00006450-200103000-00005;
RA Bouchard L., Robert M.-F., Vinarov D., Stanley C.A., Thompson G.N.,
RA Morris A., Leonard J.V., Quant P., Hsu B.Y.L., Boneh A., Boukaftane Y.,
RA Ashmarina L., Wang S., Miziorko H., Mitchell G.A.;
RT "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical
RT course and description of causal mutations in two patients.";
RL Pediatr. Res. 49:326-331(2001).
RN [15]
RP VARIANTS HMGCS2D MET-54 AND CYS-167.
RX PubMed=12647205; DOI=10.1007/s00431-002-1110-x;
RA Wolf N.I., Rahman S., Clayton P.T., Zschocke J.;
RT "Mitochondrial HMG-CoA synthase deficiency: identification of two further
RT patients carrying two novel mutations.";
RL Eur. J. Pediatr. 162:279-280(2003).
RN [16]
RP VARIANTS HMGCS2D HIS-188 AND THR-307.
RX PubMed=16601895; DOI=10.1007/s10545-006-0214-2;
RA Aledo R., Mir C., Dalton R.N., Turner C., Pie J., Hegardt F.G., Casals N.,
RA Champion M.P.;
RT "Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency.";
RL J. Inherit. Metab. Dis. 29:207-211(2006).
RN [17]
RP CATALYTIC ACTIVITY, FUNCTION, VARIANTS HMGCS2D MET-54; CYS-167; LEU-174;
RP HIS-188; ARG-212; THR-307; ARG-388; 424-ARG--VAL-508 DEL AND HIS-500,
RP CHARACTERIZATION OF VARIANTS HMGCS2D MET-54; CYS-167; LEU-174; HIS-188;
RP ARG-212; THR-307; ARG-388 AND HIS-500, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=23751782; DOI=10.1016/j.ejmg.2013.05.008;
RA Ramos M., Menao S., Arnedo M., Puisac B., Gil-Rodriguez M.C.,
RA Teresa-Rodrigo M.E., Hernandez-Marcos M., Pierre G., Ramaswami U.,
RA Baquero-Montoya C., Bueno G., Casale C., Hegardt F.G., Gomez-Puertas P.,
RA Pie J.;
RT "New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis
RT of eight mutations.";
RL Eur. J. Med. Genet. 56:411-415(2013).
RN [18]
RP VARIANTS HMGCS2D SER-168; ASP-169; ARG-185; VAL-232; SER-266; PRO-360;
RP THR-470; CYS-503 AND GLN-505.
RX PubMed=25511235; DOI=10.1007/s10545-014-9801-9;
RA Pitt J.J., Peters H., Boneh A., Yaplito-Lee J., Wieser S., Hinderhofer K.,
RA Johnson D., Zschocke J.;
RT "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary
RT organic acid profiles and expanded spectrum of mutations.";
RL J. Inherit. Metab. Dis. 38:459-466(2015).
RN [19]
RP VARIANTS HMGCS2D TRP-112 AND LEU-144, CHARACTERIZATION OF VARIANTS HMGCS2D
RP TRP-112 AND LEU-144, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=29597274; DOI=10.3390/ijms19041010;
RA Puisac B., Marcos-Alcalde I., Hernandez-Marcos M., Tobajas Morlana P.,
RA Levtova A., Schwahn B.C., DeLaet C., Lace B., Gomez-Puertas P., Pie J.;
RT "Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme
RT Dimerization Surface and Characterization of Three New Patients.";
RL Int. J. Mol. Sci. 19:0-0(2018).
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:0000269|PubMed:11228257, ECO:0000269|PubMed:23751782,
CC ECO:0000269|PubMed:29597274}.
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:0000269|PubMed:11228257, ECO:0000269|PubMed:23751782,
CC ECO:0000269|PubMed:29597274};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10189;
CC Evidence={ECO:0000305|PubMed:11228257, ECO:0000305|PubMed:23751782,
CC ECO:0000305|PubMed:29597274};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=87.3 uM for acetyl-CoA {ECO:0000269|PubMed:23751782};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3. {ECO:0000305}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:20346956}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P22791}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P54868-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P54868-2; Sequence=VSP_042892;
CC Name=3; Synonyms=HMGCS2delta4 {ECO:0000303|PubMed:21952825};
CC IsoId=P54868-3; Sequence=VSP_047445;
CC -!- TISSUE SPECIFICITY: Expression in liver is 200-fold higher than in any
CC other tissue. Low expression in colon, kidney, testis, and pancreas.
CC Very low expression in heart and skeletal muscle (PubMed:7893153,
CC PubMed:21952825, PubMed:16940161). Not detected in brain
CC (PubMed:21952825). {ECO:0000269|PubMed:16940161,
CC ECO:0000269|PubMed:21952825, ECO:0000269|PubMed:7893153}.
CC -!- TISSUE SPECIFICITY: [Isoform 3]: Highest expression detected in heart
CC and skeletal muscle. {ECO:0000269|PubMed:21952825}.
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 -!- DISEASE: 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency (HMGCS2D)
CC [MIM:605911]: A metabolic disorder characterized by severe hypoketotic
CC hypoglycemia, encephalopathy, and hepatomegaly.
CC {ECO:0000269|PubMed:11228257, ECO:0000269|PubMed:11479731,
CC ECO:0000269|PubMed:12647205, ECO:0000269|PubMed:16601895,
CC ECO:0000269|PubMed:23751782, ECO:0000269|PubMed:25511235,
CC ECO:0000269|PubMed:29597274}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the thiolase-like superfamily. HMG-CoA synthase
CC family. {ECO:0000305}.
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DR EMBL; X83618; CAA58593.1; -; mRNA.
DR EMBL; U81859; AAB72036.1; -; Genomic_DNA.
DR EMBL; U81851; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81852; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81853; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81854; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81855; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81856; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81857; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; U81858; AAB72036.1; JOINED; Genomic_DNA.
DR EMBL; CR456850; CAG33131.1; -; mRNA.
DR EMBL; AK303777; BAH14049.1; -; mRNA.
DR EMBL; AL589734; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471122; EAW56709.1; -; Genomic_DNA.
DR EMBL; BC044217; AAH44217.1; -; mRNA.
DR EMBL; U12788; AAA92673.1; -; mRNA.
DR EMBL; U12789; AAA92674.1; -; mRNA.
DR EMBL; GU433940; ADD21696.1; -; mRNA.
DR CCDS; CCDS53353.1; -. [P54868-2]
DR CCDS; CCDS905.1; -. [P54868-1]
DR PIR; S71623; S71623.
DR RefSeq; NP_001159579.1; NM_001166107.1. [P54868-2]
DR RefSeq; NP_005509.1; NM_005518.3. [P54868-1]
DR RefSeq; XP_011539615.1; XM_011541313.1. [P54868-3]
DR PDB; 2WYA; X-ray; 1.70 A; A/B/C/D=51-508.
DR PDBsum; 2WYA; -.
DR AlphaFoldDB; P54868; -.
DR SMR; P54868; -.
DR BioGRID; 109401; 22.
DR IntAct; P54868; 6.
DR MINT; P54868; -.
DR STRING; 9606.ENSP00000358414; -.
DR SwissLipids; SLP:000001249; -. [P54868-1]
DR GlyGen; P54868; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P54868; -.
DR PhosphoSitePlus; P54868; -.
DR SwissPalm; P54868; -.
DR BioMuta; HMGCS2; -.
DR DMDM; 1708234; -.
DR REPRODUCTION-2DPAGE; IPI00008934; -.
DR jPOST; P54868; -.
DR MassIVE; P54868; -.
DR MaxQB; P54868; -.
DR PaxDb; P54868; -.
DR PeptideAtlas; P54868; -.
DR PRIDE; P54868; -.
DR ProteomicsDB; 56743; -. [P54868-1]
DR ProteomicsDB; 56744; -. [P54868-2]
DR Antibodypedia; 33918; 204 antibodies from 26 providers.
DR DNASU; 3158; -.
DR Ensembl; ENST00000369406.8; ENSP00000358414.3; ENSG00000134240.12. [P54868-1]
DR Ensembl; ENST00000544913.2; ENSP00000439495.2; ENSG00000134240.12. [P54868-2]
DR GeneID; 3158; -.
DR KEGG; hsa:3158; -.
DR MANE-Select; ENST00000369406.8; ENSP00000358414.3; NM_005518.4; NP_005509.1.
DR UCSC; uc001eid.4; human. [P54868-1]
DR CTD; 3158; -.
DR DisGeNET; 3158; -.
DR GeneCards; HMGCS2; -.
DR HGNC; HGNC:5008; HMGCS2.
DR HPA; ENSG00000134240; Tissue enriched (liver).
DR MalaCards; HMGCS2; -.
DR MIM; 600234; gene.
DR MIM; 605911; phenotype.
DR neXtProt; NX_P54868; -.
DR OpenTargets; ENSG00000134240; -.
DR Orphanet; 35701; 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.
DR PharmGKB; PA29338; -.
DR VEuPathDB; HostDB:ENSG00000134240; -.
DR eggNOG; KOG1393; Eukaryota.
DR GeneTree; ENSGT00390000006096; -.
DR HOGENOM; CLU_008065_0_1_1; -.
DR InParanoid; P54868; -.
DR OMA; YFAFHAP; -.
DR PhylomeDB; P54868; -.
DR TreeFam; TF105361; -.
DR BioCyc; MetaCyc:HS05836-MON; -.
DR BRENDA; 2.3.3.10; 2681.
DR PathwayCommons; P54868; -.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-77111; Synthesis of Ketone Bodies.
DR SignaLink; P54868; -.
DR SIGNOR; P54868; -.
DR UniPathway; UPA00058; UER00102.
DR BioGRID-ORCS; 3158; 13 hits in 1069 CRISPR screens.
DR ChiTaRS; HMGCS2; human.
DR EvolutionaryTrace; P54868; -.
DR GenomeRNAi; 3158; -.
DR Pharos; P54868; Tbio.
DR PRO; PR:P54868; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P54868; protein.
DR Bgee; ENSG00000134240; Expressed in right lobe of liver and 137 other tissues.
DR ExpressionAtlas; P54868; baseline and differential.
DR Genevisible; P54868; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0004421; F:hydroxymethylglutaryl-CoA synthase activity; IMP:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; IMP:UniProtKB.
DR GO; GO:0060612; P:adipose tissue development; IEA:Ensembl.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071398; P:cellular response to fatty acid; IEA:Ensembl.
DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
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; IMP:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0007494; P:midgut development; IEA:Ensembl.
DR GO; GO:0033555; P:multicellular organismal response to stress; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon; IEA:Ensembl.
DR GO; GO:0060416; P:response to growth hormone; IEA:Ensembl.
DR GO; GO:0070543; P:response to linoleic acid; IEA:Ensembl.
DR GO; GO:0010038; P:response to metal ion; IEA:Ensembl.
DR GO; GO:0034284; P:response to monosaccharide; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0034696; P:response to prostaglandin F; IEA:Ensembl.
DR GO; GO:0042594; P:response to starvation; IEA:Ensembl.
DR GO; GO:0009266; P:response to temperature stimulus; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl.
DR GO; GO:0034014; P:response to triglyceride; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
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 3D-structure; Acetylation; Alternative splicing; Cholesterol biosynthesis;
KW Cholesterol metabolism; Disease variant; Lipid biosynthesis;
KW Lipid metabolism; Mitochondrion; Phosphoprotein; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW 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_0000013483"
FT ACT_SITE 132
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000305|PubMed:20346956"
FT ACT_SITE 166
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10116,
FT ECO:0000269|PubMed:20346956"
FT ACT_SITE 301
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000305|PubMed:20346956"
FT BINDING 80
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20346956"
FT BINDING 204
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20346956"
FT BINDING 258
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20346956"
FT BINDING 380
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:20346956"
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 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 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 433
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
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:24275569"
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:0000250|UniProtKB:P22791"
FT VAR_SEQ 187..228
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042892"
FT VAR_SEQ 229..283
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:21952825"
FT /id="VSP_047445"
FT VARIANT 54
FT /note="V -> M (in HMGCS2D; abolished protein expression;
FT dbSNP:rs28937320)"
FT /evidence="ECO:0000269|PubMed:12647205,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_032757"
FT VARIANT 112
FT /note="R -> W (in HMGCS2D; decreased protein abundance;
FT abolished enzymatic activity; dbSNP:rs768707273)"
FT /evidence="ECO:0000269|PubMed:29597274"
FT /id="VAR_083500"
FT VARIANT 144
FT /note="V -> L (in HMGCS2D; decreased protein abundance;
FT stong reduction of enzymatic activity; dbSNP:rs775528207)"
FT /evidence="ECO:0000269|PubMed:29597274"
FT /id="VAR_083501"
FT VARIANT 167
FT /note="Y -> C (in HMGCS2D; abolished enzymatic activity;
FT dbSNP:rs137852640)"
FT /evidence="ECO:0000269|PubMed:12647205,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_032758"
FT VARIANT 168
FT /note="G -> S (in HMGCS2D; dbSNP:rs746217014)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083502"
FT VARIANT 169
FT /note="G -> D (in HMGCS2D; decreased protein abundance;
FT abolished enzymatic activity; dbSNP:rs1237226874)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083503"
FT VARIANT 174
FT /note="F -> L (in HMGCS2D; reduced peptide level; strong
FT reduction of enzymatic activity; dbSNP:rs137852636)"
FT /evidence="ECO:0000269|PubMed:11228257,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_032711"
FT VARIANT 185
FT /note="W -> R (in HMGCS2D; strong decreased of protein
FT expression; abolished enzymatic activity)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083504"
FT VARIANT 188
FT /note="R -> H (in HMGCS2D; abolished protein expression;
FT dbSNP:rs761373362)"
FT /evidence="ECO:0000269|PubMed:16601895,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_083505"
FT VARIANT 212
FT /note="G -> R (in HMGCS2D; abolished protein expression;
FT dbSNP:rs137852638)"
FT /evidence="ECO:0000269|PubMed:11479731,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_032759"
FT VARIANT 232
FT /note="G -> V (in HMGCS2D; decreased protein abundance;
FT abolished enzymatic activity; dbSNP:rs1002548815)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083506"
FT VARIANT 266
FT /note="L -> S (in HMGCS2D; decreased protein abundance;
FT abolished enzymatic activity; dbSNP:rs918691885)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083507"
FT VARIANT 307
FT /note="M -> T (in HMGCS2D; abolished enzymatic activity)"
FT /evidence="ECO:0000269|PubMed:16601895,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_083508"
FT VARIANT 360
FT /note="S -> P (in HMGCS2D)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083509"
FT VARIANT 388
FT /note="G -> R (in HMGCS2D; abolished protein expression;
FT dbSNP:rs752626288)"
FT /evidence="ECO:0000269|PubMed:23751782"
FT /id="VAR_083510"
FT VARIANT 424..508
FT /note="Missing (in HMGCS2D)"
FT /evidence="ECO:0000269|PubMed:23751782"
FT /id="VAR_083511"
FT VARIANT 470
FT /note="F -> T (in HMGCS2D; decreased protein abundance;
FT abolished enzymatic activity; requires 2 nucleotide
FT substitutions)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083512"
FT VARIANT 500
FT /note="R -> H (in HMGCS2D; abolished enzymatic activity;
FT dbSNP:rs137852639)"
FT /evidence="ECO:0000269|PubMed:11479731,
FT ECO:0000269|PubMed:23751782"
FT /id="VAR_032760"
FT VARIANT 503
FT /note="Y -> C (in HMGCS2D; decreased protein abundance;
FT stong reduction of enzymatic activity)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083513"
FT VARIANT 505
FT /note="R -> Q (in HMGCS2D; decreased protein abundance;
FT stong reduction of enzymatic activity; dbSNP:rs758519315)"
FT /evidence="ECO:0000269|PubMed:25511235"
FT /id="VAR_083514"
FT CONFLICT 234
FT /note="H -> Y (in Ref. 3; CAG33131)"
FT /evidence="ECO:0000305"
FT CONFLICT 385
FT /note="S -> T (in Ref. 3; CAG33131)"
FT /evidence="ECO:0000305"
FT STRAND 55..62
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 65..69
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 70..76
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 83..88
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 92..94
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 102..117
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 124..130
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 137..139
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 141..145
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 146..148
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 161..164
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 165..167
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 168..180
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 189..198
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 206..208
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 210..221
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 223..226
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 232..235
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 240..242
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 255..283
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 292..294
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 296..300
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 305..322
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 325..331
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 333..338
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 343..347
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 350..367
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 369..372
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 373..378
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 382..384
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 385..396
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 399..402
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 406..413
FT /evidence="ECO:0007829|PDB:2WYA"
FT TURN 414..416
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 417..425
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 434..440
FT /evidence="ECO:0007829|PDB:2WYA"
FT TURN 441..444
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 445..450
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 452..455
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 457..470
FT /evidence="ECO:0007829|PDB:2WYA"
FT HELIX 482..484
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 490..495
FT /evidence="ECO:0007829|PDB:2WYA"
FT STRAND 501..505
FT /evidence="ECO:0007829|PDB:2WYA"
SQ SEQUENCE 508 AA; 56635 MW; BD362D631F7C3C80 CRC64;
MQRLLTPVKR ILQLTRAVQE TSLTPARLLP VAHQRFSTAS AVPLAKTDTW PKDVGILALE
VYFPAQYVDQ TDLEKYNNVE AGKYTVGLGQ TRMGFCSVQE DINSLCLTVV QRLMERIQLP
WDSVGRLEVG TETIIDKSKA VKTVLMELFQ DSGNTDIEGI DTTNACYGGT ASLFNAANWM
ESSSWDGRYA MVVCGDIAVY PSGNARPTGG AGAVAMLIGP KAPLALERGL RGTHMENVYD
FYKPNLASEY PIVDGKLSIQ CYLRALDRCY TSYRKKIQNQ WKQAGSDRPF TLDDLQYMIF
HTPFCKMVQK SLARLMFNDF LSASSDTQTS LYKGLEAFGG LKLEDTYTNK DLDKALLKAS
QDMFDKKTKA SLYLSTHNGN MYTSSLYGCL ASLLSHHSAQ ELAGSRIGAF SYGSGLAASF
FSFRVSQDAA PGSPLDKLVS STSDLPKRLA SRKCVSPEEF TEIMNQREQF YHKVNFSPPG
DTNSLFPGTW YLERVDEQHR RKYARRPV
