Hydroxymethylglutaryl-CoA lyase, mitochondrial

NameHydroxymethylglutaryl-CoA lyase, mitochondrial
Synonyms
  • 3-hydroxy-3-methylglutarate-CoA lyase
  • 4.1.3.4
  • HL
Gene NameHMGCL
OrganismHuman
Amino acid sequence
>lcl|BSEQ0006501|Hydroxymethylglutaryl-CoA lyase, mitochondrial
MAAMRKALPRRLVGLASLRAVSTSSMGTLPKRVKIVEVGPRDGLQNEKNIVSTPVKIKLI
DMLSEAGLSVIETTSFVSPKWVPQMGDHTEVLKGIQKFPGINYPVLTPNLKGFEAAVAAG
AKEVVIFGAASELFTKKNINCSIEESFQRFDAILKAAQSANISVRGYVSCALGCPYEGKI
SPAKVAEVTKKFYSMGCYEISLGDTIGVGTPGIMKDMLSAVMQEVPLAALAVHCHDTYGQ
ALANTLMALQMGVSVVDSSVAGLGGCPYAQGASGNLATEDLVYMLEGLGIHTGVNLQKLL
EAGNFICQALNRKTSSKVAQATCKL
Number of residues325
Molecular Weight34359.84
Theoretical pI8.71
GO Classification
Functions
  • receptor binding
  • fatty-acyl-CoA binding
  • metal ion binding
  • manganese ion binding
  • carboxylic acid binding
  • magnesium ion binding
  • hydroxymethylglutaryl-CoA lyase activity
  • protein homodimerization activity
Processes
  • response to nutrient
  • response to starvation
  • response to fatty acid
  • acyl-CoA metabolic process
  • small molecule metabolic process
  • protein tetramerization
  • leucine catabolic process
  • cellular lipid metabolic process
  • mitochondrion organization
  • cellular ketone body metabolic process
  • ketone body biosynthetic process
  • liver development
Components
  • mitochondrial matrix
  • peroxisome
  • mitochondrion
  • mitochondrial inner membrane
General FunctionReceptor binding
Specific FunctionKey enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein IDNot Available
UniProtKB IDP35914
UniProtKB Entry NameHMGCL_HUMAN
Cellular LocationMitochondrion matrix
Gene sequence
>lcl|BSEQ0019402|Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL)
ATGGCAGCAATGAGGAAGGCGCTTCCGCGGCGACTGGTGGGCTTGGCGTCCCTCCGGGCT
GTCAGCACCTCATCTATGGGCACTTTACCAAAGCGGGTGAAAATTGTGGAAGTTGGTCCC
CGAGATGGACTACAAAATGAAAAGAATATCGTATCTACTCCAGTGAAAATCAAGCTGATA
GACATGCTTTCTGAAGCAGGACTCTCTGTTATAGAAACCACCAGCTTTGTGTCTCCTAAG
TGGGTTCCCCAGATGGGTGACCACACTGAAGTCTTGAAGGGCATTCAGAAGTTTCCTGGC
ATCAACTACCCAGTCCTGACCCCAAATTTGAAAGGCTTCGAGGCAGCGGTTGCTGCTGGA
GCCAAGGAAGTAGTCATCTTTGGAGCTGCCTCAGAGCTCTTCACCAAGAAGAACATCAAT
TGTTCCATAGAGGAGAGTTTTCAGAGGTTTGACGCAATCCTGAAGGCAGCGCAGTCAGCC
AATATTTCTGTGCGGGGGTACGTCTCCTGTGCTCTTGGCTGCCCTTATGAAGGGAAGATC
TCCCCAGCTAAAGTAGCTGAGGTCACCAAGAAGTTCTACTCAATGGGCTGCTACGAGATC
TCCCTGGGGGACACCATTGGTGTGGGCACCCCAGGGATCATGAAAGACATGCTATCTGCT
GTCATGCAGGAAGTGCCTCTGGCTGCCCTGGCTGTCCACTGCCATGACACCTATGGTCAA
GCCCTGGCCAACACCTTGATGGCCCTGCAGATGGGAGTGAGTGTCGTGGACTCTTCTGTG
GCAGGACTTGGAGGCTGTCCCTACGCACAGGGGGCATCAGGAAACTTGGCCACAGAAGAC
CTGGTCTACATGCTAGAGGGCTTGGGCATTCACACGGGTGTGAATCTCCAGAAGCTTCTG
GAAGCTGGAAACTTTATCTGTCAAGCCCTGAACAGAAAAACTAGCTCCAAAGTGGCTCAG
GCTACCTGTAAACTCTGA
GenBank Gene IDL07033
GeneCard IDNot Available
GenAtlas IDHMGCL
HGNC IDHGNC:5005
Chromosome Location1
Locus1p36.1-p35
References
  1. 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. 8440722
  2. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  3. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, Scott CE, Howe KL, Woodfine K, Spencer CC, Jones MC, Gillson C, Searle S, Zhou Y, Kokocinski F, McDonald L, Evans R, Phillips K, Atkinson A, Cooper R, Jones C, Hall RE, Andrews TD, Lloyd C, Ainscough R, Almeida JP, Ambrose KD, Anderson F, Andrew RW, Ashwell RI, Aubin K, Babbage AK, Bagguley CL, Bailey J, Beasley H, Bethel G, Bird CP, Bray-Allen S, Brown JY, Brown AJ, Buckley D, Burton J, Bye J, Carder C, Chapman JC, Clark SY, Clarke G, Clee C, Cobley V, Collier RE, Corby N, Coville GJ, Davies J, Deadman R, Dunn M, Earthrowl M, Ellington AG, Errington H, Frankish A, Frankland J, French L, Garner P, Garnett J, Gay L, Ghori MR, Gibson R, Gilby LM, Gillett W, Glithero RJ, Grafham DV, Griffiths C, Griffiths-Jones S, Grocock R, Hammond S, Harrison ES, Hart E, Haugen E, Heath PD, Holmes S, Holt K, Howden PJ, Hunt AR, Hunt SE, Hunter G, Isherwood J, James R, Johnson C, Johnson D, Joy A, Kay M, Kershaw JK, Kibukawa M, Kimberley AM, King A, Knights AJ, Lad H, Laird G, Lawlor S, Leongamornlert DA, Lloyd DM, Loveland J, Lovell J, Lush MJ, Lyne R, Martin S, Mashreghi-Mohammadi M, Matthews L, Matthews NS, McLaren S, Milne S, Mistry S, Moore MJ, Nickerson T, O'Dell CN, Oliver K, Palmeiri A, Palmer SA, Parker A, Patel D, Pearce AV, Peck AI, Pelan S, Phelps K, Phillimore BJ, Plumb R, Rajan J, Raymond C, Rouse G, Saenphimmachak C, Sehra HK, Sheridan E, Shownkeen R, Sims S, Skuce CD, Smith M, Steward C, Subramanian S, Sycamore N, Tracey A, Tromans A, Van Helmond Z, Wall M, Wallis JM, White S, Whitehead SL, Wilkinson JE, Willey DL, Williams H, Wilming L, Wray PW, Wu Z, Coulson A, Vaudin M, Sulston JE, Durbin R, Hubbard T, Wooster R, Dunham I, Carter NP, McVean G, Ross MT, Harrow J, Olson MV, Beck S, Rogers J, Bentley DR, Banerjee R, Bryant SP, Burford DC, Burrill WD, Clegg SM, Dhami P, Dovey O, Faulkner LM, Gribble SM, Langford CF, Pandian RD, Porter KM, Prigmore E: The DNA sequence and biological annotation of human chromosome 1. Nature. 2006 May 18;441(7091):315-21. 16710414
  4. 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. 15489334
  5. 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. 8617516
  6. Puisac B, Ramos M, Arnedo M, Menao S, Gil-Rodriguez MC, Teresa-Rodrigo ME, Pie A, de Karam JC, Wesselink JJ, Gimenez I, Ramos FJ, Casals N, Gomez-Puertas P, Hegardt FG, Pie J: Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway. Mol Biol Rep. 2012 Apr;39(4):4777-85. doi: 10.1007/s11033-011-1270-8. Epub 2011 Sep 28. 21952825
  7. Ashmarina LI, Rusnak N, Miziorko HM, Mitchell GA: 3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes. J Biol Chem. 1994 Dec 16;269(50):31929-32. 7527399
  8. Holmes HC, Burns SP, Chalmers RA, Bain MS, Iles RA: Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Biochem Soc Trans. 1995 Aug;23(3):489S. 8566388
  9. Tuinstra RL, Burgner JW 2nd, Miziorko HM: Investigation of the oligomeric status of the peroxisomal isoform of human 3-hydroxy-3-methylglutaryl-CoA lyase. Arch Biochem Biophys. 2002 Dec 15;408(2):286-94. 12464283
  10. 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. 12874287
  11. 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. 15122894
  12. 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. 19608861
  13. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  14. Montgomery C, Pei Z, Watkins PA, Miziorko HM: Identification and characterization of an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase. J Biol Chem. 2012 Sep 28;287(40):33227-36. Epub 2012 Aug 3. 22865860
  15. Arnedo M, Menao S, Puisac B, Teresa-Rodrigo ME, Gil-Rodriguez MC, Lopez-Vinas E, Gomez-Puertas P, Casals N, Casale CH, Hegardt FG, Pie J: Characterization of a novel HMG-CoA lyase enzyme with a dual location in endoplasmic reticulum and cytosol. J Lipid Res. 2012 Oct;53(10):2046-56. doi: 10.1194/jlr.M025700. Epub 2012 Jul 30. 22847177
  16. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  17. Vaca Jacome AS, Rabilloud T, Schaeffer-Reiss C, Rompais M, Ayoub D, Lane L, Bairoch A, Van Dorsselaer A, Carapito C: N-terminome analysis of the human mitochondrial proteome. Proteomics. 2015 Jul;15(14):2519-24. doi: 10.1002/pmic.201400617. Epub 2015 Jun 8. 25944712
  18. 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. 16330550
  19. 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. 8798725
  20. 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. 9463337
  21. 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. 9784232
  22. 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. 11129331
  23. 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. 12746442
  24. Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF: Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet. 2006 Dec 16;7:86. 17173698
  25. 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. 16601870
  26. 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. 17459752
  27. Lin WD, Wang CH, Lai CC, Tsai Y, Wu JY, Chen CP, Tsai FJ: Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency. Clin Chim Acta. 2009 Mar;401(1-2):33-6. doi: 10.1016/j.cca.2008.11.004. Epub 2008 Nov 12. 19036343
  28. 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. 19177531