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Identification
HMDB Protein ID HMDBP00009
Secondary Accession Numbers
  • 5238
Name Hydroxymethylglutaryl-CoA lyase, mitochondrial
Synonyms
  1. 3-hydroxy-3-methylglutarate-CoA lyase
  2. HL
  3. HMG-CoA lyase
Gene Name HMGCL
Protein Type Enzyme
Biological Properties
General Function Involved in catalytic activity
Specific Function Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism.
Pathways
  • (S)-3-hydroxy-3-methylglutaryl-CoA degradation
  • 2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
  • 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
  • 3-hydroxyisobutyric acid dehydrogenase deficiency
  • 3-hydroxyisobutyric aciduria
  • 3-Methylcrotonyl Coa Carboxylase Deficiency Type I
  • 3-Methylglutaconic Aciduria Type I
  • 3-Methylglutaconic Aciduria Type III
  • 3-Methylglutaconic Aciduria Type IV
  • Beta-Ketothiolase Deficiency
  • Butanoate metabolism
  • Butyrate Metabolism
  • Isobutyryl-coa dehydrogenase deficiency
  • Isovaleric acidemia
  • Isovaleric Aciduria
  • Ketone Body Metabolism
  • Maple Syrup Urine Disease
  • Methylmalonate Semialdehyde Dehydrogenase Deficiency
  • Methylmalonic Aciduria
  • Peroxisome
  • Propionic Acidemia
  • Succinyl CoA: 3-ketoacid CoA transferase deficiency
  • Synthesis and degradation of ketone bodies
  • Valine, Leucine and Isoleucine Degradation
  • Valine, leucine and isoleucine degradation
Reactions
3-Hydroxy-3-methylglutaryl-CoA → Acetyl-CoA + Acetoacetic acid details
3-Hydroxy-3-(4-methylpent-3-en-1-yl)glutaryl-CoA → 7-Methyl-3-oxo-6-octenoyl-CoA + Acetic acid details
GO Classification
Biological Process
acyl-CoA metabolic process
embryo development
ketone body biosynthetic process
liver development
response to nutrient
response to starvation
protein tetramerization
response to fatty acid
mitochondrion organization
cellular lipid metabolic process
leucine catabolic process
Cellular Component
mitochondrial matrix
peroxisome
mitochondrial inner membrane
Function
catalytic activity
lyase activity
carbon-carbon lyase activity
oxo-acid-lyase activity
hydroxymethylglutaryl-coa lyase activity
Molecular Function
manganese ion binding
magnesium ion binding
carboxylic acid binding
protein homodimerization activity
hydroxymethylglutaryl-CoA lyase activity
fatty-acyl-CoA binding
Process
metabolic process
Cellular Location
  1. Mitochondrion matrix
Gene Properties
Chromosome Location 1
Locus 1p36.1-p35
SNPs HMGCL
Gene Sequence
>978 bp
ATGGCAGCAATGAGGAAGGCGCTTCCGCGGCGACTGGTGGGCTTGGCGTCCCTCCGGGCT
GTCAGCACCTCATCTATGGGCACTTTACCAAAGCGGGTGAAAATTGTGGAAGTTGGTCCC
CGAGATGGACTACAAAATGAAAAGAATATCGTATCTACTCCAGTGAAAATCAAGCTGATA
GACATGCTTTCTGAAGCAGGACTCTCTGTTATAGAAACCACCAGCTTTGTGTCTCCTAAG
TGGGTTCCCCAGATGGGTGACCACACTGAAGTCTTGAAGGGCATTCAGAAGTTTCCTGGC
ATCAACTACCCAGTCCTGACCCCAAATTTGAAAGGCTTCGAGGCAGCGGTTGCTGCTGGA
GCCAAGGAAGTAGTCATCTTTGGAGCTGCCTCAGAGCTCTTCACCAAGAAGAACATCAAT
TGTTCCATAGAGGAGAGTTTTCAGAGGTTTGACGCAATCCTGAAGGCAGCGCAGTCAGCC
AATATTTCTGTGCGGGGGTACGTCTCCTGTGCTCTTGGCTGCCCTTATGAAGGGAAGATC
TCCCCAGCTAAAGTAGCTGAGGTCACCAAGAAGTTCTACTCAATGGGCTGCTACGAGATC
TCCCTGGGGGACACCATTGGTGTGGGCACCCCAGGGATCATGAAAGACATGCTGTCTGCT
GTCATGCAGGAAGTGCCTCTGGCTGCCCTGGCTGTCCACTGCCATGACACCTATGGTCAA
GCCCTGGCCAACACCTTGATGGCCCTGCAGATGGGAGTGAGTGTCGTGGACTCTTCTGTG
GCAGGACTTGGAGGCTGTCCCTACGCACAGGGGGCATCAGGAAACTTGGCCACAGAAGAC
CTGGTCTACATGCTAGAGGGCTTGGGCATTCACACGGGTGTGAATCTCCAGAAGCTTCTG
GAAGCTGGAAACTTTATCTGTCAAGCCCTGAACAGAAAAACTAGCTCCAAAGTGGCTCAG
GCTACCTGTAAACTCTGA
Protein Properties
Number of Residues 325
Molecular Weight 34359.84
Theoretical pI 8.545
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Hydroxymethylglutaryl-CoA lyase, mitochondrial
MAAMRKALPRRLVGLASLRAVSTSSMGTLPKRVKIVEVGPRDGLQNEKNIVSTPVKIKLI
DMLSEAGLSVIETTSFVSPKWVPQMGDHTEVLKGIQKFPGINYPVLTPNLKGFEAAVAAG
AKEVVIFGAASELFTKKNINCSIEESFQRFDAILKAAQSANISVRGYVSCALGCPYEGKI
SPAKVAEVTKKFYSMGCYEISLGDTIGVGTPGIMKDMLSAVMQEVPLAALAVHCHDTYGQ
ALANTLMALQMGVSVVDSSVAGLGGCPYAQGASGNLATEDLVYMLEGLGIHTGVNLQKLL
EAGNFICQALNRKTSSKVAQATCKL
GenBank ID Protein 14714839
UniProtKB/Swiss-Prot ID P35914
UniProtKB/Swiss-Prot Entry Name HMGCL_HUMAN
PDB IDs
GenBank Gene ID BC010570
GeneCard ID HMGCL
GenAtlas ID HMGCL
HGNC ID HGNC:5005
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. [PubMed:19608861 ]
  3. Mitchell GA, Robert MF, Hruz PW, Wang S, Fontaine G, Behnke CE, Mende-Mueller LM, Schappert K, Lee C, Gibson KM, Miziorko HM, et al.: 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem. 1993 Feb 25;268(6):4376-81. [PubMed:8440722 ]
  4. Wang SP, Robert MF, Gibson KM, Wanders RJ, Mitchell GA: 3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients. Genomics. 1996 Apr 1;33(1):99-104. [PubMed:8617516 ]
  5. Tuinstra RL, Miziorko HM: Investigation of conserved acidic residues in 3-hydroxy-3-methylglutaryl-CoA lyase: implications for human disease and for functional roles in a family of related proteins. J Biol Chem. 2003 Sep 26;278(39):37092-8. Epub 2003 Jul 21. [PubMed:12874287 ]
  6. Tuinstra RL, Wang CZ, Mitchell GA, Miziorko HM: Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization. Biochemistry. 2004 May 11;43(18):5287-95. [PubMed:15122894 ]
  7. Fu Z, Runquist JA, Forouhar F, Hussain M, Hunt JF, Miziorko HM, Kim JJ: Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria. J Biol Chem. 2006 Mar 17;281(11):7526-32. Epub 2005 Dec 5. [PubMed:16330550 ]
  8. Roberts JR, Mitchell GA, Miziorko HM: Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine 233 as an active site residue. J Biol Chem. 1996 Oct 4;271(40):24604-9. [PubMed:8798725 ]
  9. Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plochl E, Miziorko H: HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet. 1998 Feb;62(2):295-300. [PubMed:9463337 ]
  10. Zapater N, Pie J, Lloberas J, Rolland MO, Leroux B, Vidailhet M, Divry P, Hegardt FG, Casals N: Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric aciduria in a French patient. Arch Biochem Biophys. 1998 Oct 15;358(2):197-203. [PubMed:9784232 ]
  11. Muroi J, Yorifuji T, Uematsu A, Shigematsu Y, Onigata K, Maruyama H, Nobutoki T, Kitamura A, Nakahata T: Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. Hum Genet. 2000 Oct;107(4):320-6. [PubMed:11129331 ]
  12. Casals N, Gomez-Puertas P, Pie J, Mir C, Roca R, Puisac B, Aledo R, Clotet J, Menao S, Serra D, Asins G, Till J, Elias-Jones AC, Cresto JC, Chamoles NA, Abdenur JE, Mayatepek E, Besley G, Valencia A, Hegardt FG: Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. J Biol Chem. 2003 Aug 1;278(31):29016-23. Epub 2003 May 13. [PubMed:12746442 ]
  13. Mir C, Lopez-Vinas E, Aledo R, Puisac B, Rizzo C, Dionisi-Vici C, Deodato F, Pie J, Gomez-Puertas P, Hegardt FG, Casals N: A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG-CoA lyase. J Inherit Metab Dis. 2006 Feb;29(1):64-70. [PubMed:16601870 ]
  14. Carrasco P, Menao S, Lopez-Vinas E, Santpere G, Clotet J, Sierra AY, Gratacos E, Puisac B, Gomez-Puertas P, Hegardt FG, Pie J, Casals N: C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity. Mol Genet Metab. 2007 Jun;91(2):120-7. Epub 2007 Apr 24. [PubMed:17459752 ]
  15. Menao S, Lopez-Vinas E, Mir C, Puisac B, Gratacos E, Arnedo M, Carrasco P, Moreno S, Ramos M, Gil MC, Pie A, Ribes A, Perez-Cerda C, Ugarte M, Clayton PT, Korman SH, Serra D, Asins G, Ramos FJ, Gomez-Puertas P, Hegardt FG, Casals N, Pie J: Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. Hum Mutat. 2009 Mar;30(3):E520-9. doi: 10.1002/humu.20966. [PubMed:19177531 ]