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P35914 (HMGCL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 148. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Hydroxymethylglutaryl-CoA lyase, mitochondrial

Short name=HL
Short name=HMG-CoA lyase
EC=4.1.3.4
Alternative name(s):
3-hydroxy-3-methylglutarate-CoA lyase
Gene names
Name:HMGCL
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length325 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Key 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. Ref.11 Ref.17 Ref.18

Catalytic activity

(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate. Ref.17 Ref.18

Cofactor

Divalent metal cations. Ref.13

Enzyme regulation

Stimulated by reducing agents such as dithiothreitol (DTT). Ref.13

Pathway

Metabolic intermediate metabolism; (S)-3-hydroxy-3-methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA: step 1/1.

Subunit structure

Homodimer; disulfide-linked. Can also form homotetramers. Ref.12 Ref.19

Subcellular location

Mitochondrion matrix. Peroxisome. Note: Unprocessed form is peroxisomal. Ref.10 Ref.12

Tissue specificity

Highest expression in liver. Expressed in pancreas, kidey, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%). Ref.9

Involvement in disease

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM:246450]: An autosomal recessive disease affecting ketogenesis and L-leucine catabolism. The disease usually appears in the first year of life after a fasting period and its clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and lethargy. These symptoms sometimes progress to coma, with fatal outcome in some cases.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29

Sequence similarities

Belongs to the HMG-CoA lyase family.

Biophysicochemical properties

Kinetic parameters:

KM=200 µM for magnesium ion Ref.13 Ref.14

KM=48 µM for HMG-CoA

Vmax=191 µmol/min/mg enzyme

Ontologies

Keywords
   Cellular componentMitochondrion
Peroxisome
   Coding sequence diversityAlternative splicing
   DiseaseDisease mutation
   DomainTransit peptide
   LigandMetal-binding
   Molecular functionLyase
   PTMAcetylation
Disulfide bond
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processacyl-CoA metabolic process

Inferred from electronic annotation. Source: Ensembl

cellular ketone body metabolic process

Traceable author statement. Source: Reactome

cellular lipid metabolic process

Traceable author statement. Source: Reactome

embryo development

Inferred from electronic annotation. Source: Ensembl

ketone body biosynthetic process

Inferred from direct assay Ref.18Ref.17PubMed 9200711. Source: UniProtKB

leucine catabolic process

Non-traceable author statement PubMed 9200711. Source: UniProtKB

liver development

Inferred from electronic annotation. Source: Ensembl

mitochondrion organization

Inferred from electronic annotation. Source: Ensembl

protein tetramerization

Inferred from direct assay Ref.12. Source: UniProtKB

response to fatty acid

Inferred from electronic annotation. Source: Ensembl

response to nutrient

Inferred from electronic annotation. Source: Ensembl

response to starvation

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentmitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrial matrix

Non-traceable author statement PubMed 8102917. Source: UniProtKB

mitochondrion

Inferred from direct assay PubMed 9869651. Source: UniProtKB

peroxisome

Inferred from direct assay PubMed 9869651. Source: UniProtKB

   Molecular_functioncarboxylic acid binding

Inferred from electronic annotation. Source: Ensembl

fatty-acyl-CoA binding

Inferred from electronic annotation. Source: Ensembl

hydroxymethylglutaryl-CoA lyase activity

Inferred from direct assay Ref.18Ref.17PubMed 8670134PubMed 9200711PubMed 9869651. Source: UniProtKB

magnesium ion binding

Inferred from direct assay PubMed 9200711. Source: UniProtKB

manganese ion binding

Inferred from direct assay PubMed 9200711. Source: UniProtKB

metal ion binding

Inferred from direct assay Ref.19. Source: UniProtKB

protein homodimerization activity

Inferred from direct assay Ref.12PubMed 8670134. Source: UniProtKB

receptor binding

Inferred from physical interaction PubMed 20178365. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P35914-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P35914-2)

Also known as: HMGCS2delta5,6;

The sequence of this isoform differs from the canonical sequence as follows:
     117-187: Missing.
Note: The transcript is not translated, but would result in a catatically impaired product if it was.
Isoform 3 (identifier: P35914-3)

Also known as: HMGCS2delta5,6,7;

The sequence of this isoform differs from the canonical sequence as follows:
     117-187: Missing.
     188-250: Missing.
Note: Very low expression. The transcript is not translated, but would result in a catatically inactive product if it was.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 2727Mitochondrion
Chain28 – 325298Hydroxymethylglutaryl-CoA lyase, mitochondrial
PRO_0000013478

Regions

Motif323 – 3253Microbody targeting signal Potential

Sites

Active site2661 By similarity
Metal binding421Divalent metal cation
Metal binding2331Divalent metal cation
Metal binding2351Divalent metal cation
Metal binding2751Divalent metal cation
Binding site411Substrate

Amino acid modifications

Modified residue481N6-acetyllysine; alternate Ref.15
Modified residue481N6-succinyllysine; alternate By similarity
Modified residue1111N6-acetyllysine By similarity
Modified residue1371N6-acetyllysine; alternate By similarity
Modified residue1371N6-succinyllysine; alternate By similarity
Modified residue1791N6-acetyllysine; alternate By similarity
Modified residue1791N6-succinyllysine; alternate By similarity
Modified residue3241N6-acetyllysine By similarity
Disulfide bond323Interchain Ref.12

Natural variations

Alternative sequence117 – 18771Missing in isoform 2 and isoform 3.
VSP_047444
Alternative sequence188 – 25063Missing in isoform 3.
VSP_043788
Natural variant371E → K in HMGCLD; activity lower than 5% respect to the wild-type. Ref.29
VAR_058440
Natural variant411R → Q in HMGCLD; loss of activity and of proton exchange. Ref.21 Ref.25
VAR_003744
Natural variant421D → E in HMGCLD; reduced activity. Ref.21
VAR_003745
Natural variant421D → G in HMGCLD; loss of activity. Ref.21 Ref.29
VAR_003746
Natural variant421D → H in HMGCLD; loss of activity. Ref.21
VAR_003747
Natural variant481K → N in HMGCLD; abolishes almost all enzymatic activity. Ref.27
VAR_058441
Natural variant701V → L in HMGCLD.
VAR_003748
Natural variant751S → R in HMGCLD. Ref.24
VAR_058442
Natural variant1421S → F in HMGCLD; activity lower than 5% respect to the wild-type. Ref.29
VAR_058443
Natural variant1651R → Q in HMGCLD. Ref.28
Corresponds to variant rs199587895 [ dbSNP | Ensembl ].
VAR_065453
Natural variant1741C → Y in HMGCLD; activity lower than 5% respect to the wild-type. Ref.29
VAR_058444
Natural variant1921F → S in HMGCLD; activity lower than 5% respect to the wild-type. Ref.29
VAR_058445
Natural variant2001I → F in HMGCLD; activity lower than 5% respect to the wild-type. Ref.29
VAR_058446
Natural variant2011S → Y in HMGCLD. Ref.24
VAR_058447
Natural variant2031G → E in HMGCLD; complete loss of activity. Ref.26
VAR_058448
Natural variant2041D → N in HMGCLD. Ref.24
VAR_058449
Natural variant2331H → R in HMGCLD; loss of activity. Ref.20 Ref.22 Ref.29
VAR_003749
Natural variant2631L → P in HMGCLD. Ref.22
VAR_058450
Natural variant2791E → K in HMGCLD. Ref.23
Corresponds to variant rs28934894 [ dbSNP | Ensembl ].
VAR_014202

Experimental info

Mutagenesis371E → D: Normal activity. Ref.13
Mutagenesis411R → M: Reduced activity, and loss of proton exchange. Ref.14
Mutagenesis421D → A or N: Loss of activity, and reduced proton exchange rate. Ref.13 Ref.14
Mutagenesis721E → A: Loss of activity, and reduced affinity for metal cofactor and substrate. Ref.13
Mutagenesis2041D → A: Reduced activity, and reduced affinity for metal cofactor and substrate. Ref.13
Mutagenesis2331H → A: Loss of activity, and reduced proton exchange rate. Ref.13 Ref.14
Mutagenesis2661C → A: Loss of activity.
Mutagenesis2791E → A: Reduced thermal stability, but normal activity. Ref.13
Mutagenesis2801D → A: Normal activity. Ref.13
Mutagenesis3231C → S: Abolishes interchain homodimerization. Exhibits no DTT stimulated activity. Ref.12 Ref.17
Sequence conflict2431A → T in AAA92733. Ref.1

Secondary structure

................................................ 325
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 25, 2002. Version 2.
Checksum: B82B2488A10D6980

FASTA32534,360
        10         20         30         40         50         60 
MAAMRKALPR RLVGLASLRA VSTSSMGTLP KRVKIVEVGP RDGLQNEKNI VSTPVKIKLI 

        70         80         90        100        110        120 
DMLSEAGLSV IETTSFVSPK WVPQMGDHTE VLKGIQKFPG INYPVLTPNL KGFEAAVAAG 

       130        140        150        160        170        180 
AKEVVIFGAA SELFTKKNIN CSIEESFQRF DAILKAAQSA NISVRGYVSC ALGCPYEGKI 

       190        200        210        220        230        240 
SPAKVAEVTK KFYSMGCYEI SLGDTIGVGT PGIMKDMLSA VMQEVPLAAL AVHCHDTYGQ 

       250        260        270        280        290        300 
ALANTLMALQ MGVSVVDSSV AGLGGCPYAQ GASGNLATED LVYMLEGLGI HTGVNLQKLL 

       310        320 
EAGNFICQAL NRKTSSKVAQ ATCKL 

« Hide

Isoform 2 (HMGCS2delta5,6) [UniParc].

Checksum: FAD9D90A1A62F3AD
Show »

FASTA25426,910
Isoform 3 (HMGCS2delta5,6,7) [UniParc].

Checksum: D5540BECDB75D854
Show »

FASTA19120,222

References

« Hide 'large scale' references
[1]"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."
Mitchell G.A., Robert M.-F., Hruz P.W., Wang S., Fontaine G., Behnke C.E., Mende-Mueller L.M., Schappert K., Lee C., Gibson K.M., Miziorko H.M.
J. Biol. Chem. 268:4376-4381(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Liver.
[2]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
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. expand/collapse author list , 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 T.-O., 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.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Tissue: Skeletal muscle and Testis.
[4]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[8]"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."
Wang S.P., Robert M.-F., Gibson K.M., Wanders R.J.A., Mitchell G.A.
Genomics 33:99-104(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 21-325 (ISOFORM 1).
[9]"Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway."
Puisac B., Ramos M., Arnedo M., Menao S., Gil-Rodriguez M.C., Teresa-Rodrigo M.E., Pie A., de Karam J.C., Wesselink J.J., Gimenez I., Ramos F.J., Casals N., Gomez-Puertas P., Hegardt F.G., Pie J.
Mol. Biol. Rep. 39:4777-4785(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 60-277 (ISOFORMS 2 AND 3), ALTERNATIVE SPLICING, TISSUE SPECIFICITY.
Tissue: Skeletal muscle.
[10]"3-Hydroxy-3-methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes."
Ashmarina L.I., Rusnak N., Miziorko H.M., Mitchell G.A.
J. Biol. Chem. 269:31929-31932(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[11]"Ketogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiency."
Holmes H.C., Burns S.P., Chalmers R.A., Bain M.S., Iles R.A.
Biochem. Soc. Trans. 23:489S-489S(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"Investigation of the oligomeric status of the peroxisomal isoform of human 3-hydroxy-3-methylglutaryl-CoA lyase."
Tuinstra R.L., Burgner J.W. II, Miziorko H.M.
Arch. Biochem. Biophys. 408:286-294(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, SUBCELLULAR LOCATION, DISULFIDE BOND, MUTAGENESIS OF CYS-323.
[13]"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."
Tuinstra R.L., Miziorko H.M.
J. Biol. Chem. 278:37092-37098(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF GLU-37; ASP-42; GLU-72; ASP-204; HIS-233; GLU-279 AND ASP-280, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
[14]"Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization."
Tuinstra R.L., Wang C.-Z., Mitchell G.A., Miziorko H.M.
Biochemistry 43:5287-5295(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ARG-41; ASP-42 AND HIS-233, BIOPHYSICOCHEMICAL PROPERTIES.
[15]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-48, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"Identification and characterization of an extramitochondrial human 3-Hydroxy-3-methylglutaryl-CoA lyase."
Montgomery C., Pei Z., Watkins P.A., Miziorko H.M.
J. Biol. Chem. 287:33227-33236(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF CYS-323.
[18]"Characterization of a novel HMG-CoA Lyase enzyme with a dual location in endoplasmic reticulum and cytosol."
Arnedo M., Menao S., Puisac B., Teresa-Rodrigo M.E., Gil-Rodriguez M.C., Lopez-Vinas E., Gomez-Puertas P., Casals N., Casale C.H., Hegardt F.G., Pie J.
J. Lipid Res. 53:2046-2056(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY.
[19]"Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase: insights into catalysis and the molecular basis for hydroxymethylglutaric aciduria."
Fu Z., Runquist J.A., Forouhar F., Hussain M., Hunt J.F., Miziorko H.M., Kim J.J.
J. Biol. Chem. 281:7526-7532(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 28-325 IN COMPLEX WITH MAGNESIUM AND SUBSTRATE ANALOG, HOMODIMERIZATION.
[20]"Modeling of a mutation responsible for human 3-hydroxy-3-methylglutaryl-CoA lyase deficiency implicates histidine-233 as an active site residue."
Roberts J., Mitchell G.A., Miziorko H.M.
J. Biol. Chem. 271:24604-24609(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD ARG-233.
[21]"HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q."
Mitchell G.A., Ozand P.T., Robert M.-F., Ashmarina L., Roberts J., Gibson K.M., Wanders R.J., Wang S., Chevalier I., Ploechl E., Miziorko H.
Am. J. Hum. Genet. 62:295-300(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HMGCLD GLN-41; GLU-42; GLY-42 AND HIS-42.
[22]"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."
Zapater N., Pie J., Lloberas J., Rolland M.O., Leroux B., Vidailhet M., Divry P., Hegardt F.G., Casals N.
Arch. Biochem. Biophys. 358:197-203(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HMGCLD ARG-233 AND PRO-263.
[23]"Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency."
Muroi J., Yorifuji T., Uematsu A., Shigematsu Y., Onigata K., Maruyama H., Nobutoki T., Kitamura A., Nakahata T.
Hum. Genet. 107:320-326(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD LYS-279.
[24]"Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase."
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 A.C., Cresto J.C., Chamoles N.A., Abdenur J.E., Mayatepek E., Besley G., Valencia A., Hegardt F.G.
J. Biol. Chem. 278:29016-29023(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HMGCLD ARG-75; TYR-201 AND ASN-204.
[25]"Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population."
Al-Sayed M., Imtiaz F., Alsmadi O.A., Rashed M.S., Meyer B.F.
BMC Med. Genet. 7:86-86(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD GLN-41.
[26]"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."
Mir C., Lopez-Vinas E., Aledo R., Puisac B., Rizzo C., Dionisi-Vici C., Deodato F., Pie J., Gomez-Puertas P., Hegardt F.G., Casals N.
J. Inherit. Metab. Dis. 29:64-70(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD GLU-203, CHARACTERIZATION OF VARIANT HMGCLD GLU-203.
[27]"C-terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity."
Carrasco P., Menao S., Lopez-Vinas E., Santpere G., Clotet J., Sierra A.Y., Gratacos E., Puisac B., Gomez-Puertas P., Hegardt F.G., Pie J., Casals N.
Mol. Genet. Metab. 91:120-127(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD ASN-48, CHARACTERIZATION OF VARIANT HMGCLD ASN-48.
[28]"Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency."
Lin W.D., Wang C.H., Lai C.C., Tsai Y., Wu J.Y., Chen C.P., Tsai F.J.
Clin. Chim. Acta 401:33-36(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT HMGCLD GLN-165.
[29]"Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria."
Menao S., Lopez-Vinas E., Mir C., Puisac B., Gratacos E., Arnedo M., Carrasco P., Moreno S., Ramos M., Gil M.C., Pie A., Ribes A., Perez-Cerda C., Ugarte M., Clayton P.T., Korman S.H., Serra D., Asins G. expand/collapse author list , Ramos F.J., Gomez-Puertas P., Hegardt F.G., Casals N., Pie J.
Hum. Mutat. 30:E520-E529(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HMGCLD LYS-37; GLY-42; PHE-142; TYR-174; SER-192; PHE-200 AND ARG-233, CHARACTERIZATION OF VARIANTS HMGCLD LYS-37; PHE-142; TYR-174; SER-192 AND PHE-200.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L07033 mRNA. Translation: AAA92733.1.
AK300733 mRNA. Translation: BAG62406.1.
AK313869 mRNA. Translation: BAG36597.1.
BT009792 mRNA. Translation: AAP88794.1.
CR456884 mRNA. Translation: CAG33165.1.
AL031295 Genomic DNA. No translation available.
AL590728 Genomic DNA. No translation available.
CH471134 Genomic DNA. Translation: EAW95094.1.
BC010570 mRNA. Translation: AAH10570.1.
AH003700 Genomic DNA. Translation: AAB19099.1.
FJ472654 mRNA. Translation: ACK58684.1.
GU433941 mRNA. Translation: ADD21697.1.
CCDSCCDS243.1. [P35914-1]
CCDS53279.1. [P35914-2]
PIRA45470.
RefSeqNP_000182.2. NM_000191.2. [P35914-1]
NP_001159531.1. NM_001166059.1. [P35914-2]
UniGeneHs.533444.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2CW6X-ray2.10A/B/C/D/E/F28-325[»]
3MP3X-ray2.40A/B/C/D/E/F28-325[»]
3MP4X-ray2.20A/B/C/D/E/F28-325[»]
3MP5X-ray2.25A/B/C/D/E/F28-325[»]
ProteinModelPortalP35914.
SMRP35914. Positions 28-323.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109398. 8 interactions.
IntActP35914. 8 interactions.
MINTMINT-3014127.
STRING9606.ENSP00000363614.

PTM databases

PhosphoSiteP35914.

Polymorphism databases

DMDM24418852.

Proteomic databases

MaxQBP35914.
PaxDbP35914.
PRIDEP35914.

Protocols and materials databases

DNASU3155.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000374490; ENSP00000363614; ENSG00000117305. [P35914-1]
ENST00000436439; ENSP00000389281; ENSG00000117305. [P35914-2]
GeneID3155.
KEGGhsa:3155.
UCSCuc001bib.3. human. [P35914-1]
uc010oec.2. human. [P35914-2]

Organism-specific databases

CTD3155.
GeneCardsGC01M024128.
HGNCHGNC:5005. HMGCL.
HPAHPA004727.
MIM246450. phenotype.
613898. gene.
neXtProtNX_P35914.
Orphanet20. 3-hydroxy-3-methylglutaric aciduria.
PharmGKBPA29336.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0119.
HOGENOMHOG000219757.
HOVERGENHBG064656.
InParanoidP35914.
KOK01640.
OMANITACLD.
OrthoDBEOG73Z2TR.
PhylomeDBP35914.
TreeFamTF105363.

Enzyme and pathway databases

BioCycMetaCyc:HS04116-MONOMER.
BRENDA4.1.3.4. 2681.
ReactomeREACT_111217. Metabolism.
SABIO-RKP35914.
UniPathwayUPA00896; UER00863.

Gene expression databases

ArrayExpressP35914.
BgeeP35914.
CleanExHS_HMGCL.
GenevestigatorP35914.

Family and domain databases

Gene3D3.20.20.70. 1 hit.
InterProIPR013785. Aldolase_TIM.
IPR000138. HMG_CoA_lyase_AS.
IPR000891. PYR_CT.
[Graphical view]
PfamPF00682. HMGL-like. 1 hit.
[Graphical view]
PROSITEPS01062. HMG_COA_LYASE. 1 hit.
PS50991. PYR_CT. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSHMGCL. human.
EvolutionaryTraceP35914.
GenomeRNAi3155.
NextBio12496.
PROP35914.
SOURCESearch...

Entry information

Entry nameHMGCL_HUMAN
AccessionPrimary (citable) accession number: P35914
Secondary accession number(s): B4DUP4 expand/collapse secondary AC list , B7UCC6, D3Y5K7, Q6IBC0, Q96FP8
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: October 25, 2002
Last modified: July 9, 2014
This is version 148 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM