HMGCL_MOUSE
ID HMGCL_MOUSE Reviewed; 325 AA.
AC P38060; Q8QZS6;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Hydroxymethylglutaryl-CoA lyase, mitochondrial;
DE Short=HL {ECO:0000303|PubMed:8102917};
DE Short=HMG-CoA lyase;
DE EC=4.1.3.4 {ECO:0000250|UniProtKB:P35914};
DE AltName: Full=3-hydroxy-3-methylglutarate-CoA lyase;
DE Flags: Precursor;
GN Name=Hmgcl;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8102917; DOI=10.1007/bf00360589;
RA Wang S., Nadeau J.H., Duncan A., Robert M.-F., Fontaine G., Schappert K.,
RA Johnson K.R., Zietkiewicz E., Hruz P., Miziorko H.;
RT "3-hydroxy-3-methylglutaryl coenzyme A lyase (HL): cloning and
RT characterization of a mouse liver HL cDNA and subchromosomal mapping of the
RT human and mouse HL genes.";
RL Mamm. Genome 4:382-387(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129;
RX PubMed=8617516; DOI=10.1006/geno.1996.0164;
RA Wang S.P., Robert M.-F., Gibson K.M., Wanders R.J.A., Mitchell G.A.;
RT "3-hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL)
RT cloning and detection of large gene deletions in two unrelated HL-deficient
RT patients.";
RL Genomics 33:99-104(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Hippocampus, Mammary gland, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
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 STRAIN=FVB/N; TISSUE=Liver;
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 [7]
RP SUBCELLULAR LOCATION.
RX PubMed=7527399; DOI=10.1016/s0021-9258(18)31784-8;
RA Ashmarina L.I., Rusnak N., Miziorko H.M., Mitchell G.A.;
RT "3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver
RT peroxisomes.";
RL J. Biol. Chem. 269:31929-31932(1994).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-48, SUCCINYLATION [LARGE SCALE
RP ANALYSIS] AT LYS-48; LYS-137 AND LYS-179, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast, and Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-48; LYS-111; LYS-137; LYS-179 AND
RP LYS-324, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23576753; DOI=10.1073/pnas.1302961110;
RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B.,
RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.;
RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria
RT identifies substrates of SIRT3 in metabolic pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013).
CC -!- FUNCTION: Mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that
CC catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-
CC methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in
CC ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-
CC hydroxybutyrate, acetoacetate and acetone) are essential as an
CC alternative source of energy to glucose, as lipid precursors and as
CC regulators of metabolism. {ECO:0000250|UniProtKB:P35914}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3S)-hydroxy-3-methylglutaryl-CoA = acetoacetate + acetyl-CoA;
CC Xref=Rhea:RHEA:24404, ChEBI:CHEBI:13705, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57288; EC=4.1.3.4;
CC Evidence={ECO:0000250|UniProtKB:P35914};
CC -!- PATHWAY: Metabolic intermediate metabolism; (S)-3-hydroxy-3-
CC methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-
CC methylglutaryl-CoA: step 1/1.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Can also form homotetramers.
CC {ECO:0000250|UniProtKB:P35914}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:7527399}. Peroxisome {ECO:0000269|PubMed:7527399}.
CC Note=Unprocessed form is peroxisomal.
CC -!- SIMILARITY: Belongs to the HMG-CoA lyase family. {ECO:0000305}.
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DR EMBL; S65036; AAB27965.1; -; mRNA.
DR EMBL; U49878; AAB03107.1; -; Genomic_DNA.
DR EMBL; U49870; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49871; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49872; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49873; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49874; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49875; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49876; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; U49877; AAB03107.1; JOINED; Genomic_DNA.
DR EMBL; AK132035; BAE20956.1; -; mRNA.
DR EMBL; AK145251; BAE26328.1; -; mRNA.
DR EMBL; AK154033; BAE32329.1; -; mRNA.
DR EMBL; AL672076; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466552; EDL29963.1; -; Genomic_DNA.
DR EMBL; BC025440; AAH25440.1; -; mRNA.
DR CCDS; CCDS18795.1; -.
DR RefSeq; NP_032280.2; NM_008254.2.
DR AlphaFoldDB; P38060; -.
DR SMR; P38060; -.
DR BioGRID; 200337; 5.
DR IntAct; P38060; 1.
DR STRING; 10090.ENSMUSP00000030432; -.
DR iPTMnet; P38060; -.
DR PhosphoSitePlus; P38060; -.
DR SwissPalm; P38060; -.
DR EPD; P38060; -.
DR jPOST; P38060; -.
DR MaxQB; P38060; -.
DR PaxDb; P38060; -.
DR PeptideAtlas; P38060; -.
DR PRIDE; P38060; -.
DR ProteomicsDB; 273366; -.
DR Antibodypedia; 1373; 340 antibodies from 29 providers.
DR DNASU; 15356; -.
DR Ensembl; ENSMUST00000030432; ENSMUSP00000030432; ENSMUSG00000028672.
DR GeneID; 15356; -.
DR KEGG; mmu:15356; -.
DR UCSC; uc012dnc.1; mouse.
DR CTD; 3155; -.
DR MGI; MGI:96158; Hmgcl.
DR VEuPathDB; HostDB:ENSMUSG00000028672; -.
DR eggNOG; KOG2368; Eukaryota.
DR GeneTree; ENSGT00940000158484; -.
DR HOGENOM; CLU_022138_3_1_1; -.
DR InParanoid; P38060; -.
DR OMA; FGGCPMA; -.
DR OrthoDB; 1029775at2759; -.
DR PhylomeDB; P38060; -.
DR TreeFam; TF105363; -.
DR Reactome; R-MMU-77111; Synthesis of Ketone Bodies.
DR Reactome; R-MMU-9033241; Peroxisomal protein import.
DR UniPathway; UPA00896; UER00863.
DR BioGRID-ORCS; 15356; 0 hits in 76 CRISPR screens.
DR ChiTaRS; Hmgcl; mouse.
DR PRO; PR:P38060; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; P38060; protein.
DR Bgee; ENSMUSG00000028672; Expressed in ileal epithelium and 252 other tissues.
DR Genevisible; P38060; MM.
DR GO; GO:0005743; C:mitochondrial inner membrane; HDA:MGI.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0005777; C:peroxisome; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0031406; F:carboxylic acid binding; ISO:MGI.
DR GO; GO:0000062; F:fatty-acyl-CoA binding; ISO:MGI.
DR GO; GO:0004419; F:hydroxymethylglutaryl-CoA lyase activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISO:MGI.
DR GO; GO:0030145; F:manganese ion binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; ISS:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; ISO:MGI.
DR GO; GO:0006637; P:acyl-CoA metabolic process; ISO:MGI.
DR GO; GO:0046951; P:ketone body biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006552; P:leucine catabolic process; IBA:GO_Central.
DR GO; GO:0006629; P:lipid metabolic process; ISO:MGI.
DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR000138; HMG_CoA_lyase_AS.
DR InterPro; IPR043594; HMGL.
DR InterPro; IPR000891; PYR_CT.
DR PANTHER; PTHR42738; PTHR42738; 1.
DR Pfam; PF00682; HMGL-like; 1.
DR PROSITE; PS01062; HMG_COA_LYASE; 1.
DR PROSITE; PS50991; PYR_CT; 1.
PE 1: Evidence at protein level;
KW Acetylation; Disulfide bond; Lipid metabolism; Lyase; Metal-binding;
KW Mitochondrion; Peroxisome; Reference proteome; Transit peptide.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 28..325
FT /note="Hydroxymethylglutaryl-CoA lyase, mitochondrial"
FT /id="PRO_0000013480"
FT DOMAIN 33..300
FT /note="Pyruvate carboxyltransferase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01151"
FT MOTIF 323..325
FT /note="Microbody targeting signal"
FT /evidence="ECO:0000255"
FT ACT_SITE 266
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10115"
FT BINDING 41
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 42
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT BINDING 233
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT BINDING 235
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT BINDING 275
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /evidence="ECO:0000250"
FT MOD_RES 48
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753,
FT ECO:0007744|PubMed:23806337"
FT MOD_RES 48
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 111
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 137
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 137
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 179
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 179
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 324
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23576753"
FT DISULFID 323
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT CONFLICT 62..63
FT /note="ML -> IV (in Ref. 2; AAB03107)"
FT /evidence="ECO:0000305"
FT CONFLICT 80
FT /note="K -> N (in Ref. 1; AAB27965)"
FT /evidence="ECO:0000305"
FT CONFLICT 231
FT /note="A -> G (in Ref. 1; AAB27965)"
FT /evidence="ECO:0000305"
FT CONFLICT 238
FT /note="Y -> I (in Ref. 1; AAB27965)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 325 AA; 34239 MW; E6A85659EBA1D87F CRC64;
MASVRKAFPR RLVGLTSLRA VSTSSMGTLP KQVKIVEVGP RDGLQNEKSI VPTPVKIRLI
DMLSEAGLPV IEATSFVSPK WVPQMADHSD VLKGIQKFPG INYPVLTPNM KGFEEAVAAG
AKEVSVFGAV SELFTRKNAN CSIEESFQRF AGVMQAAQAA SISVRGYVSC ALGCPYEGKV
SPAKVAEVAK KLYSMGCYEI SLGDTIGVGT PGLMKDMLTA VMHEVPVTAL AVHCHDTYGQ
ALANTLVALQ MGVSVVDSSV AGLGGCPYAK GASGNLATED LVYMLNGLGI HTGVNLQKLL
EAGDFICQAL NRKTSSKVAQ ATCKL
