ID HMCS2_BOVIN Reviewed; 508 AA. AC Q2KIE6; DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 07-MAR-2006, sequence version 1. DT 27-MAR-2024, entry version 113. 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 Bos taurus (Bovine). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; OC Bovinae; Bos. OX NCBI_TaxID=9913; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=Hereford; TISSUE=Testis; RG NIH - Mammalian Gene Collection (MGC) project; RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases. RN [2] RP SUCCINYLATION AT LYS-310. RX PubMed=22076378; DOI=10.1126/science.1207861; RA Du J., Zhou Y., Su X., Yu J.J., Khan S., Jiang H., Kim J., Woo J., RA Kim J.H., Choi B.H., He B., Chen W., Zhang S., Cerione R.A., Auwerx J., RA Hao Q., Lin H.; RT "Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase."; RL Science 334:806-809(2011). 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. CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P54868}. CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P22791}. CC -!- PTM: Succinylated. Desuccinylated by SIRT5. Succinylation, at least at CC 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}. 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; BC112666; AAI12667.1; -; mRNA. DR RefSeq; NP_001039348.1; NM_001045883.1. DR RefSeq; XP_010801406.1; XM_010803104.2. DR AlphaFoldDB; Q2KIE6; -. DR SMR; Q2KIE6; -. DR STRING; 9913.ENSBTAP00000005088; -. DR PaxDb; 9913-ENSBTAP00000005088; -. DR PeptideAtlas; Q2KIE6; -. DR Ensembl; ENSBTAT00000005088.6; ENSBTAP00000005088.5; ENSBTAG00000003898.6. DR GeneID; 503684; -. DR KEGG; bta:503684; -. DR CTD; 3158; -. DR VEuPathDB; HostDB:ENSBTAG00000003898; -. DR VGNC; VGNC:29881; HMGCS2. DR eggNOG; KOG1393; Eukaryota. DR GeneTree; ENSGT00390000006096; -. DR HOGENOM; CLU_008065_0_1_1; -. DR InParanoid; Q2KIE6; -. DR OMA; GRLKYND; -. DR OrthoDB; 1060at2759; -. DR TreeFam; TF105361; -. DR Reactome; R-BTA-77111; Synthesis of Ketone Bodies. DR UniPathway; UPA00058; UER00102. DR Proteomes; UP000009136; Chromosome 3. DR Bgee; ENSBTAG00000003898; Expressed in digestive system secreted substance and 49 other cell types or tissues. DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central. DR GO; GO:0004421; F:hydroxymethylglutaryl-CoA synthase activity; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0006084; P:acetyl-CoA metabolic process; IBA:GO_Central. 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; 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. 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_0000236276" 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 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:0000269|PubMed:22076378" 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: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:0000250|UniProtKB:P54868" 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" SQ SEQUENCE 508 AA; 56895 MW; 12F31AAFBAE986BF CRC64; MQRLLTPVRQ VLQVKRVMQE ASLLPARLLP AAHPSFSTVP AVPLAKTDTW PKDVGILAME VYFPAQYVDQ TELEKFNKVE AGRYTVGLGQ TQMGFCSVQE DVNSLCLTVV QQLMERTQLP WDSVGRLEVG TETIIDKSKA VKTVLMELFQ DSGNTDIEGI DTTNACYGGT ASLFNAANWM ESSSWDGRYA LVVCGDIAVY PSGNARPTGG AGAVAMLVGP EAPLVLERGL RGTHMENVYD FYKPDVTSEY PLVDGKLSIQ CYLRALDKCY AFYRQKIEKQ WKQAGIDRPF TLDDVQYMIF HTPFCKLVQK SLARLMFNDF LLASGDTQTG IYKGLEAFRG LKLEDTYTNK DVDKAFLKAS LNMFNKKTKN SLYLSTYNGN MYTSSLYGCL ASLLAHHSAQ DLAGSRIGAF SYGSGLAASF FSFRVSQDAS PGSPLEKLVS STSDLQKRLA SRKRVSPEEF TEIMNQREQY YHKMNFSPPG DKNSLFPGTW YLERVDELYR RKYARRPV //