HMGCL_HUMAN
ID HMGCL_HUMAN Reviewed; 325 AA.
AC P35914; B4DUP4; B7UCC6; D3Y5K7; Q6IBC0; Q96FP8;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2002, sequence version 2.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Hydroxymethylglutaryl-CoA lyase, mitochondrial;
DE Short=HL;
DE Short=HMG-CoA lyase;
DE EC=4.1.3.4 {ECO:0000269|PubMed:22847177, ECO:0000269|PubMed:22865860};
DE AltName: Full=3-hydroxy-3-methylglutarate-CoA lyase;
DE Flags: Precursor;
GN Name=HMGCL;
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).
RC TISSUE=Liver;
RX PubMed=8440722; DOI=10.1016/s0021-9258(18)53620-6;
RA Mitchell G.A., Robert M.-F., Hruz P.W., Wang S., Fontaine G., Behnke C.E.,
RA Mende-Mueller L.M., Schappert K., Lee C., Gibson K.M., Miziorko H.M.;
RT "3-hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and
RT chicken liver HL cDNAs and characterization of a mutation causing human HL
RT deficiency.";
RL J. Biol. Chem. 268:4376-4381(1993).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Skeletal muscle, and Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
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., 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 [GENOMIC DNA] OF 21-325 (ISOFORM 1).
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 60-277 (ISOFORMS 2 AND 3), ALTERNATIVE
RP SPLICING, AND TISSUE SPECIFICITY.
RC TISSUE=Skeletal muscle;
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 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 [11]
RP FUNCTION.
RX PubMed=8566388; DOI=10.1042/bst023489s;
RA Holmes H.C., Burns S.P., Chalmers R.A., Bain M.S., Iles R.A.;
RT "Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-
RT methylglutaryl CoA lyase deficiency.";
RL Biochem. Soc. Trans. 23:489S-489S(1995).
RN [12]
RP SUBUNIT, SUBCELLULAR LOCATION, DISULFIDE BOND, AND MUTAGENESIS OF CYS-323.
RX PubMed=12464283; DOI=10.1016/s0003-9861(02)00584-2;
RA Tuinstra R.L., Burgner J.W. II, Miziorko H.M.;
RT "Investigation of the oligomeric status of the peroxisomal isoform of human
RT 3-hydroxy-3-methylglutaryl-CoA lyase.";
RL Arch. Biochem. Biophys. 408:286-294(2002).
RN [13]
RP MUTAGENESIS OF GLU-37; ASP-42; GLU-72; ASP-204; HIS-233; GLU-279 AND
RP ASP-280, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION.
RX PubMed=12874287; DOI=10.1074/jbc.m304472200;
RA Tuinstra R.L., Miziorko H.M.;
RT "Investigation of conserved acidic residues in 3-hydroxy-3-methylglutaryl-
RT CoA lyase: implications for human disease and for functional roles in a
RT family of related proteins.";
RL J. Biol. Chem. 278:37092-37098(2003).
RN [14]
RP MUTAGENESIS OF ARG-41; ASP-42 AND HIS-233, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=15122894; DOI=10.1021/bi0499765;
RA Tuinstra R.L., Wang C.-Z., Mitchell G.A., Miziorko H.M.;
RT "Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a
RT catalytic residue: use of acetyldithio-coenzyme A to monitor product
RT enolization.";
RL Biochemistry 43:5287-5295(2004).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-48, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-323.
RX PubMed=22865860; DOI=10.1074/jbc.m112.393231;
RA Montgomery C., Pei Z., Watkins P.A., Miziorko H.M.;
RT "Identification and characterization of an extramitochondrial human 3-
RT Hydroxy-3-methylglutaryl-CoA lyase.";
RL J. Biol. Chem. 287:33227-33236(2012).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22847177; DOI=10.1194/jlr.m025700;
RA Arnedo M., Menao S., Puisac B., Teresa-Rodrigo M.E., Gil-Rodriguez M.C.,
RA Lopez-Vinas E., Gomez-Puertas P., Casals N., Casale C.H., Hegardt F.G.,
RA Pie J.;
RT "Characterization of a novel HMG-CoA Lyase enzyme with a dual location in
RT endoplasmic reticulum and cytosol.";
RL J. Lipid Res. 53:2046-2056(2012).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [20]
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 [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 28-325 IN COMPLEX WITH MAGNESIUM
RP AND SUBSTRATE ANALOG, AND HOMODIMERIZATION.
RX PubMed=16330550; DOI=10.1074/jbc.m506880200;
RA Fu Z., Runquist J.A., Forouhar F., Hussain M., Hunt J.F., Miziorko H.M.,
RA Kim J.J.;
RT "Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights
RT into catalysis and the molecular basis for hydroxymethylglutaric
RT aciduria.";
RL J. Biol. Chem. 281:7526-7532(2006).
RN [23]
RP VARIANT HMGCLD ARG-233.
RX PubMed=8798725; DOI=10.1074/jbc.271.40.24604;
RA Roberts J., Mitchell G.A., Miziorko H.M.;
RT "Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-
RT CoA lyase deficiency implicates histidine-233 as an active site residue.";
RL J. Biol. Chem. 271:24604-24609(1996).
RN [24]
RP VARIANTS HMGCLD GLN-41; GLU-42; GLY-42 AND HIS-42.
RX PubMed=9463337; DOI=10.1086/301730;
RA Mitchell G.A., Ozand P.T., Robert M.-F., Ashmarina L., Roberts J.,
RA Gibson K.M., Wanders R.J., Wang S., Chevalier I., Ploechl E., Miziorko H.;
RT "HMG CoA lyase deficiency: identification of five causal point mutations in
RT codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.";
RL Am. J. Hum. Genet. 62:295-300(1998).
RN [25]
RP VARIANTS HMGCLD ARG-233 AND PRO-263.
RX PubMed=9784232; DOI=10.1006/abbi.1998.0788;
RA Zapater N., Pie J., Lloberas J., Rolland M.O., Leroux B., Vidailhet M.,
RA Divry P., Hegardt F.G., Casals N.;
RT "Two missense point mutations in different alleles in the 3-hydroxy-3-
RT methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric
RT aciduria in a French patient.";
RL Arch. Biochem. Biophys. 358:197-203(1998).
RN [26]
RP VARIANT HMGCLD LYS-279.
RX PubMed=11129331; DOI=10.1007/s004390000363;
RA Muroi J., Yorifuji T., Uematsu A., Shigematsu Y., Onigata K., Maruyama H.,
RA Nobutoki T., Kitamura A., Nakahata T.;
RT "Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-
RT methylglutaryl CoA lyase (HL) deficiency.";
RL Hum. Genet. 107:320-326(2000).
RN [27]
RP VARIANTS HMGCLD ARG-75; TYR-201 AND ASN-204.
RX PubMed=12746442; DOI=10.1074/jbc.m304276200;
RA Casals N., Gomez-Puertas P., Pie J., Mir C., Roca R., Puisac B., Aledo R.,
RA Clotet J., Menao S., Serra D., Asins G., Till J., Elias-Jones A.C.,
RA Cresto J.C., Chamoles N.A., Abdenur J.E., Mayatepek E., Besley G.,
RA Valencia A., Hegardt F.G.;
RT "Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-
RT coenzyme A lyase.";
RL J. Biol. Chem. 278:29016-29023(2003).
RN [28]
RP VARIANT HMGCLD GLN-41.
RX PubMed=17173698; DOI=10.1186/1471-2350-7-86;
RA Al-Sayed M., Imtiaz F., Alsmadi O.A., Rashed M.S., Meyer B.F.;
RT "Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in
RT the Saudi population.";
RL BMC Med. Genet. 7:86-86(2006).
RN [29]
RP VARIANT HMGCLD GLU-203, AND CHARACTERIZATION OF VARIANT HMGCLD GLU-203.
RX PubMed=16601870; DOI=10.1007/s10545-006-0138-x;
RA Mir C., Lopez-Vinas E., Aledo R., Puisac B., Rizzo C., Dionisi-Vici C.,
RA Deodato F., Pie J., Gomez-Puertas P., Hegardt F.G., Casals N.;
RT "A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric
RT aciduria by occluding the substrate channel in the 3D structural model of
RT HMG-CoA lyase.";
RL J. Inherit. Metab. Dis. 29:64-70(2006).
RN [30]
RP VARIANT HMGCLD ASN-48, AND CHARACTERIZATION OF VARIANT HMGCLD ASN-48.
RX PubMed=17459752; DOI=10.1016/j.ymgme.2007.03.007;
RA Carrasco P., Menao S., Lopez-Vinas E., Santpere G., Clotet J., Sierra A.Y.,
RA Gratacos E., Puisac B., Gomez-Puertas P., Hegardt F.G., Pie J., Casals N.;
RT "C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in
RT substrate binding and enzyme activity.";
RL Mol. Genet. Metab. 91:120-127(2007).
RN [31]
RP VARIANT HMGCLD GLN-165.
RX PubMed=19036343; DOI=10.1016/j.cca.2008.11.004;
RA Lin W.D., Wang C.H., Lai C.C., Tsai Y., Wu J.Y., Chen C.P., Tsai F.J.;
RT "Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl
RT CoA lyase deficiency.";
RL Clin. Chim. Acta 401:33-36(2009).
RN [32]
RP VARIANTS HMGCLD LYS-37; GLY-42; PHE-142; TYR-174; SER-192; PHE-200 AND
RP ARG-233, AND CHARACTERIZATION OF VARIANTS HMGCLD LYS-37; PHE-142; TYR-174;
RP SER-192 AND PHE-200.
RX PubMed=19177531; DOI=10.1002/humu.20966;
RA Menao S., Lopez-Vinas E., Mir C., Puisac B., Gratacos E., Arnedo M.,
RA Carrasco P., Moreno S., Ramos M., Gil M.C., Pie A., Ribes A.,
RA Perez-Cerda C., Ugarte M., Clayton P.T., Korman S.H., Serra D., Asins G.,
RA Ramos F.J., Gomez-Puertas P., Hegardt F.G., Casals N., Pie J.;
RT "Ten novel HMGCL mutations in 24 patients of different origin with 3-
RT hydroxy-3-methyl-glutaric aciduria.";
RL Hum. Mutat. 30:E520-E529(2009).
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:0000269|PubMed:22847177,
CC ECO:0000269|PubMed:22865860, ECO:0000269|PubMed:8566388}.
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; Evidence={ECO:0000269|PubMed:22847177,
CC ECO:0000269|PubMed:22865860};
CC -!- COFACTOR:
CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC Evidence={ECO:0000269|PubMed:12874287};
CC -!- ACTIVITY REGULATION: Stimulated by reducing agents such as
CC dithiothreitol (DTT). {ECO:0000269|PubMed:12874287}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=200 uM for magnesium ion {ECO:0000269|PubMed:12874287,
CC ECO:0000269|PubMed:15122894};
CC KM=48 uM for HMG-CoA {ECO:0000269|PubMed:12874287,
CC ECO:0000269|PubMed:15122894};
CC Vmax=191 umol/min/mg enzyme {ECO:0000269|PubMed:12874287,
CC ECO:0000269|PubMed:15122894};
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:0000269|PubMed:12464283, ECO:0000269|PubMed:16330550}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000250|UniProtKB:P38060}. Peroxisome
CC {ECO:0000250|UniProtKB:P38060}. Note=Unprocessed form is peroxisomal.
CC {ECO:0000250|UniProtKB:P38060}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P35914-1; Sequence=Displayed;
CC Name=2; Synonyms=HMGCS2delta5,6;
CC IsoId=P35914-2; Sequence=VSP_047444;
CC Name=3; Synonyms=HMGCS2delta5,6,7;
CC IsoId=P35914-3; Sequence=VSP_047444, VSP_043788;
CC -!- TISSUE SPECIFICITY: Highest expression in liver. Expressed in pancreas,
CC kidney, intestine, testis, fibroblasts and lymphoblasts. Very low
CC expression in brain and skeletal muscle. The relative expression of
CC isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle
CC (22%), and brain (14%). {ECO:0000269|PubMed:21952825}.
CC -!- DISEASE: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD)
CC [MIM:246450]: An autosomal recessive disease affecting ketogenesis and
CC L-leucine catabolism. The disease usually appears in the first year of
CC life after a fasting period and its clinical acute symptoms include
CC vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and
CC lethargy. These symptoms sometimes progress to coma, with fatal outcome
CC in some cases. {ECO:0000269|PubMed:11129331,
CC ECO:0000269|PubMed:12746442, ECO:0000269|PubMed:16601870,
CC ECO:0000269|PubMed:17173698, ECO:0000269|PubMed:17459752,
CC ECO:0000269|PubMed:19036343, ECO:0000269|PubMed:19177531,
CC ECO:0000269|PubMed:8798725, ECO:0000269|PubMed:9463337,
CC ECO:0000269|PubMed:9784232}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: The transcript is not translated, but would
CC result in a catalytically impaired product if it was. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Very low expression. The transcript is not
CC translated, but would result in a catalytically inactive product if it
CC was. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the HMG-CoA lyase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; L07033; AAA92733.1; -; mRNA.
DR EMBL; AK300733; BAG62406.1; -; mRNA.
DR EMBL; AK313869; BAG36597.1; -; mRNA.
DR EMBL; BT009792; AAP88794.1; -; mRNA.
DR EMBL; CR456884; CAG33165.1; -; mRNA.
DR EMBL; AL031295; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL590728; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471134; EAW95094.1; -; Genomic_DNA.
DR EMBL; BC010570; AAH10570.1; -; mRNA.
DR EMBL; AH003700; AAB19099.1; -; Genomic_DNA.
DR EMBL; FJ472654; ACK58684.1; -; mRNA.
DR EMBL; GU433941; ADD21697.1; -; mRNA.
DR CCDS; CCDS243.1; -. [P35914-1]
DR CCDS; CCDS53279.1; -. [P35914-2]
DR PIR; A45470; A45470.
DR RefSeq; NP_000182.2; NM_000191.2. [P35914-1]
DR RefSeq; NP_001159531.1; NM_001166059.1. [P35914-2]
DR PDB; 2CW6; X-ray; 2.10 A; A/B/C/D/E/F=28-325.
DR PDB; 3MP3; X-ray; 2.40 A; A/B/C/D/E/F=28-325.
DR PDB; 3MP4; X-ray; 2.20 A; A/B/C/D/E/F=28-325.
DR PDB; 3MP5; X-ray; 2.25 A; A/B/C/D/E/F=28-325.
DR PDBsum; 2CW6; -.
DR PDBsum; 3MP3; -.
DR PDBsum; 3MP4; -.
DR PDBsum; 3MP5; -.
DR AlphaFoldDB; P35914; -.
DR SMR; P35914; -.
DR BioGRID; 109398; 50.
DR IntAct; P35914; 11.
DR MINT; P35914; -.
DR STRING; 9606.ENSP00000363614; -.
DR DrugBank; DB04594; 3-hydroxyglutaric acid.
DR SwissLipids; SLP:000001292; -. [P35914-1]
DR GlyGen; P35914; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P35914; -.
DR PhosphoSitePlus; P35914; -.
DR BioMuta; HMGCL; -.
DR DMDM; 24418852; -.
DR EPD; P35914; -.
DR jPOST; P35914; -.
DR MassIVE; P35914; -.
DR MaxQB; P35914; -.
DR PaxDb; P35914; -.
DR PeptideAtlas; P35914; -.
DR PRIDE; P35914; -.
DR ProteomicsDB; 55164; -. [P35914-1]
DR ProteomicsDB; 55165; -. [P35914-2]
DR Antibodypedia; 1373; 340 antibodies from 29 providers.
DR DNASU; 3155; -.
DR Ensembl; ENST00000374490.8; ENSP00000363614.3; ENSG00000117305.15. [P35914-1]
DR Ensembl; ENST00000436439.6; ENSP00000389281.2; ENSG00000117305.15. [P35914-2]
DR GeneID; 3155; -.
DR KEGG; hsa:3155; -.
DR MANE-Select; ENST00000374490.8; ENSP00000363614.3; NM_000191.3; NP_000182.2.
DR UCSC; uc001bib.4; human. [P35914-1]
DR CTD; 3155; -.
DR DisGeNET; 3155; -.
DR GeneCards; HMGCL; -.
DR HGNC; HGNC:5005; HMGCL.
DR HPA; ENSG00000117305; Tissue enhanced (liver).
DR MalaCards; HMGCL; -.
DR MIM; 246450; phenotype.
DR MIM; 613898; gene.
DR neXtProt; NX_P35914; -.
DR OpenTargets; ENSG00000117305; -.
DR Orphanet; 20; 3-hydroxy-3-methylglutaric aciduria.
DR PharmGKB; PA29336; -.
DR VEuPathDB; HostDB:ENSG00000117305; -.
DR eggNOG; KOG2368; Eukaryota.
DR GeneTree; ENSGT00940000158484; -.
DR HOGENOM; CLU_022138_3_1_1; -.
DR InParanoid; P35914; -.
DR OMA; FGGCPMA; -.
DR OrthoDB; 1029775at2759; -.
DR PhylomeDB; P35914; -.
DR TreeFam; TF105363; -.
DR BioCyc; MetaCyc:HS04116-MON; -.
DR BRENDA; 4.1.3.4; 2681.
DR PathwayCommons; P35914; -.
DR Reactome; R-HSA-77111; Synthesis of Ketone Bodies.
DR Reactome; R-HSA-9033241; Peroxisomal protein import.
DR SABIO-RK; P35914; -.
DR SignaLink; P35914; -.
DR UniPathway; UPA00896; UER00863.
DR BioGRID-ORCS; 3155; 6 hits in 1082 CRISPR screens.
DR ChiTaRS; HMGCL; human.
DR EvolutionaryTrace; P35914; -.
DR GenomeRNAi; 3155; -.
DR Pharos; P35914; Tbio.
DR PRO; PR:P35914; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P35914; protein.
DR Bgee; ENSG00000117305; Expressed in right lobe of liver and 200 other tissues.
DR ExpressionAtlas; P35914; baseline and differential.
DR Genevisible; P35914; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005782; C:peroxisomal matrix; TAS:Reactome.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0004419; F:hydroxymethylglutaryl-CoA lyase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IDA:UniProtKB.
DR GO; GO:0046951; P:ketone body biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006552; P:leucine catabolic process; IBA:GO_Central.
DR GO; GO:0006629; P:lipid metabolic process; IDA:BHF-UCL.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
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 3D-structure; Acetylation; Alternative splicing; Disease variant;
KW Disulfide bond; Lipid metabolism; Lyase; Metal-binding; Mitochondrion;
KW Peroxisome; Reference proteome; Transit peptide.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT CHAIN 28..325
FT /note="Hydroxymethylglutaryl-CoA lyase, mitochondrial"
FT /id="PRO_0000013478"
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 BINDING 42
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT BINDING 233
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT BINDING 235
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT BINDING 275
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT MOD_RES 48
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 48
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 111
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 137
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 137
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 179
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 179
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT MOD_RES 324
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P38060"
FT DISULFID 323
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:12464283"
FT VAR_SEQ 117..187
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:21952825"
FT /id="VSP_047444"
FT VAR_SEQ 188..250
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:21952825"
FT /id="VSP_043788"
FT VARIANT 37
FT /note="E -> K (in HMGCLD; activity lower than 5% respect to
FT the wild-type)"
FT /evidence="ECO:0000269|PubMed:19177531"
FT /id="VAR_058440"
FT VARIANT 41
FT /note="R -> Q (in HMGCLD; loss of activity and of proton
FT exchange; dbSNP:rs121964997)"
FT /evidence="ECO:0000269|PubMed:17173698,
FT ECO:0000269|PubMed:9463337"
FT /id="VAR_003744"
FT VARIANT 42
FT /note="D -> E (in HMGCLD; reduced activity)"
FT /evidence="ECO:0000269|PubMed:9463337"
FT /id="VAR_003745"
FT VARIANT 42
FT /note="D -> G (in HMGCLD; loss of activity;
FT dbSNP:rs1467902610)"
FT /evidence="ECO:0000269|PubMed:19177531,
FT ECO:0000269|PubMed:9463337"
FT /id="VAR_003746"
FT VARIANT 42
FT /note="D -> H (in HMGCLD; loss of activity)"
FT /evidence="ECO:0000269|PubMed:9463337"
FT /id="VAR_003747"
FT VARIANT 48
FT /note="K -> N (in HMGCLD; abolishes almost all enzymatic
FT activity)"
FT /evidence="ECO:0000269|PubMed:17459752"
FT /id="VAR_058441"
FT VARIANT 70
FT /note="V -> L (in HMGCLD; dbSNP:rs121964996)"
FT /id="VAR_003748"
FT VARIANT 75
FT /note="S -> R (in HMGCLD; dbSNP:rs1357942068)"
FT /evidence="ECO:0000269|PubMed:12746442"
FT /id="VAR_058442"
FT VARIANT 142
FT /note="S -> F (in HMGCLD; activity lower than 5% respect to
FT the wild-type)"
FT /evidence="ECO:0000269|PubMed:19177531"
FT /id="VAR_058443"
FT VARIANT 165
FT /note="R -> Q (in HMGCLD; dbSNP:rs199587895)"
FT /evidence="ECO:0000269|PubMed:19036343"
FT /id="VAR_065453"
FT VARIANT 174
FT /note="C -> Y (in HMGCLD; activity lower than 5% respect to
FT the wild-type; dbSNP:rs765475941)"
FT /evidence="ECO:0000269|PubMed:19177531"
FT /id="VAR_058444"
FT VARIANT 192
FT /note="F -> S (in HMGCLD; activity lower than 5% respect to
FT the wild-type)"
FT /evidence="ECO:0000269|PubMed:19177531"
FT /id="VAR_058445"
FT VARIANT 200
FT /note="I -> F (in HMGCLD; activity lower than 5% respect to
FT the wild-type)"
FT /evidence="ECO:0000269|PubMed:19177531"
FT /id="VAR_058446"
FT VARIANT 201
FT /note="S -> Y (in HMGCLD; dbSNP:rs760106433)"
FT /evidence="ECO:0000269|PubMed:12746442"
FT /id="VAR_058447"
FT VARIANT 203
FT /note="G -> E (in HMGCLD; complete loss of activity;
FT dbSNP:rs1553131940)"
FT /evidence="ECO:0000269|PubMed:16601870"
FT /id="VAR_058448"
FT VARIANT 204
FT /note="D -> N (in HMGCLD)"
FT /evidence="ECO:0000269|PubMed:12746442"
FT /id="VAR_058449"
FT VARIANT 233
FT /note="H -> R (in HMGCLD; loss of activity;
FT dbSNP:rs727503963)"
FT /evidence="ECO:0000269|PubMed:19177531,
FT ECO:0000269|PubMed:8798725, ECO:0000269|PubMed:9784232"
FT /id="VAR_003749"
FT VARIANT 263
FT /note="L -> P (in HMGCLD)"
FT /evidence="ECO:0000269|PubMed:9784232"
FT /id="VAR_058450"
FT VARIANT 279
FT /note="E -> K (in HMGCLD; dbSNP:rs121964998)"
FT /evidence="ECO:0000269|PubMed:11129331"
FT /id="VAR_014202"
FT MUTAGEN 37
FT /note="E->D: Normal activity."
FT /evidence="ECO:0000269|PubMed:12874287"
FT MUTAGEN 41
FT /note="R->M: Reduced activity, and loss of proton
FT exchange."
FT /evidence="ECO:0000269|PubMed:15122894"
FT MUTAGEN 42
FT /note="D->A,N: Loss of activity, and reduced proton
FT exchange rate."
FT /evidence="ECO:0000269|PubMed:12874287,
FT ECO:0000269|PubMed:15122894"
FT MUTAGEN 72
FT /note="E->A: Loss of activity, and reduced affinity for
FT metal cofactor and substrate."
FT /evidence="ECO:0000269|PubMed:12874287"
FT MUTAGEN 204
FT /note="D->A: Reduced activity, and reduced affinity for
FT metal cofactor and substrate."
FT /evidence="ECO:0000269|PubMed:12874287"
FT MUTAGEN 233
FT /note="H->A: Loss of activity, and reduced proton exchange
FT rate."
FT /evidence="ECO:0000269|PubMed:12874287,
FT ECO:0000269|PubMed:15122894"
FT MUTAGEN 266
FT /note="C->A: Loss of activity."
FT MUTAGEN 279
FT /note="E->A: Reduced thermal stability, but normal
FT activity."
FT /evidence="ECO:0000269|PubMed:12874287"
FT MUTAGEN 280
FT /note="D->A: Normal activity."
FT /evidence="ECO:0000269|PubMed:12874287"
FT MUTAGEN 323
FT /note="C->S: Abolishes interchain homodimerization.
FT Exhibits no DTT stimulated activity."
FT /evidence="ECO:0000269|PubMed:12464283,
FT ECO:0000269|PubMed:22865860"
FT CONFLICT 243
FT /note="A -> T (in Ref. 1; AAA92733)"
FT /evidence="ECO:0000305"
FT STRAND 34..37
FT /evidence="ECO:0007829|PDB:2CW6"
FT TURN 39..41
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 42..45
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 53..65
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:2CW6"
FT TURN 79..81
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 88..94
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 110..118
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 122..130
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 132..139
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 143..159
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 163..169
FT /evidence="ECO:0007829|PDB:2CW6"
FT TURN 170..172
FT /evidence="ECO:0007829|PDB:2CW6"
FT TURN 175..177
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 182..194
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 198..204
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 211..224
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 227..229
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 230..235
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 241..250
FT /evidence="ECO:0007829|PDB:2CW6"
FT STRAND 255..259
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 278..288
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 296..309
FT /evidence="ECO:0007829|PDB:2CW6"
FT HELIX 317..322
FT /evidence="ECO:0007829|PDB:2CW6"
SQ SEQUENCE 325 AA; 34360 MW; B82B2488A10D6980 CRC64;
MAAMRKALPR RLVGLASLRA VSTSSMGTLP KRVKIVEVGP RDGLQNEKNI VSTPVKIKLI
DMLSEAGLSV IETTSFVSPK WVPQMGDHTE VLKGIQKFPG INYPVLTPNL KGFEAAVAAG
AKEVVIFGAA SELFTKKNIN CSIEESFQRF DAILKAAQSA NISVRGYVSC ALGCPYEGKI
SPAKVAEVTK KFYSMGCYEI SLGDTIGVGT PGIMKDMLSA VMQEVPLAAL AVHCHDTYGQ
ALANTLMALQ MGVSVVDSSV AGLGGCPYAQ GASGNLATED LVYMLEGLGI HTGVNLQKLL
EAGNFICQAL NRKTSSKVAQ ATCKL
