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 27-MAR-2024, entry version 204. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. 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; 9606-ENSP00000358414; -. DR PeptideAtlas; P54868; -. DR ProteomicsDB; 56743; -. [P54868-1] DR ProteomicsDB; 56744; -. [P54868-2] DR Antibodypedia; 33918; 226 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 AGR; HGNC:5008; -. 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; GRLKYND; -. DR OrthoDB; 1060at2759; -. DR PhylomeDB; P54868; -. DR TreeFam; TF105361; -. DR BioCyc; MetaCyc:HS05836-MONOMER; -. 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; 14 hits in 1148 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 139 other cell types or tissues. DR ExpressionAtlas; P54868; baseline and differential. 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: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 CDD; cd00827; init_cond_enzymes; 1. 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 NCBIfam; TIGR01833; HMG-CoA-S_euk; 1. DR PANTHER; PTHR43323; 3-HYDROXY-3-METHYLGLUTARYL COENZYME A SYNTHASE; 1. DR PANTHER; PTHR43323:SF1; HYDROXYMETHYLGLUTARYL-COA SYNTHASE, MITOCHONDRIAL; 1. DR Pfam; PF08540; HMG_CoA_synt_C; 1. DR Pfam; PF01154; HMG_CoA_synt_N; 1. DR SUPFAM; SSF53901; Thiolase-like; 2. DR PROSITE; PS01226; HMG_COA_SYNTHASE; 1. DR Genevisible; P54868; HS. 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 //