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P35914

- HMGCL_HUMAN

UniProt

P35914 - HMGCL_HUMAN

Protein

Hydroxymethylglutaryl-CoA lyase, mitochondrial

Gene

HMGCL

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 150 (01 Oct 2014)
      Sequence version 2 (25 Oct 2002)
      Previous versions | rss
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    Functioni

    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.3 Publications

    Catalytic activityi

    (S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.2 PublicationsPROSITE-ProRule annotation

    Cofactori

    Divalent metal cations.1 Publication

    Enzyme regulationi

    Stimulated by reducing agents such as dithiothreitol (DTT).1 Publication

    Kineticsi

    1. KM=200 µM for magnesium ion2 Publications
    2. KM=48 µM for HMG-CoA2 Publications

    Vmax=191 µmol/min/mg enzyme2 Publications

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei41 – 411Substrate
    Metal bindingi42 – 421Divalent metal cation
    Metal bindingi233 – 2331Divalent metal cation
    Metal bindingi235 – 2351Divalent metal cation
    Active sitei266 – 2661PROSITE-ProRule annotation
    Metal bindingi275 – 2751Divalent metal cation

    GO - Molecular functioni

    1. carboxylic acid binding Source: Ensembl
    2. fatty-acyl-CoA binding Source: Ensembl
    3. hydroxymethylglutaryl-CoA lyase activity Source: UniProtKB
    4. magnesium ion binding Source: UniProtKB
    5. manganese ion binding Source: UniProtKB
    6. metal ion binding Source: UniProtKB
    7. protein homodimerization activity Source: UniProtKB
    8. receptor binding Source: UniProtKB

    GO - Biological processi

    1. acyl-CoA metabolic process Source: Ensembl
    2. cellular ketone body metabolic process Source: Reactome
    3. cellular lipid metabolic process Source: Reactome
    4. embryo development Source: Ensembl
    5. ketone body biosynthetic process Source: UniProtKB
    6. leucine catabolic process Source: UniProtKB
    7. liver development Source: Ensembl
    8. mitochondrion organization Source: Ensembl
    9. protein tetramerization Source: UniProtKB
    10. response to fatty acid Source: Ensembl
    11. response to nutrient Source: Ensembl
    12. response to starvation Source: Ensembl
    13. small molecule metabolic process Source: Reactome

    Keywords - Molecular functioni

    Lyase

    Keywords - Ligandi

    Metal-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS04116-MONOMER.
    BRENDAi4.1.3.4. 2681.
    ReactomeiREACT_1464. Synthesis of Ketone Bodies.
    SABIO-RKP35914.
    UniPathwayiUPA00896; UER00863.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Hydroxymethylglutaryl-CoA lyase, mitochondrial (EC:4.1.3.4)
    Short name:
    HL
    Short name:
    HMG-CoA lyase
    Alternative name(s):
    3-hydroxy-3-methylglutarate-CoA lyase
    Gene namesi
    Name:HMGCL
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 1

    Organism-specific databases

    HGNCiHGNC:5005. HMGCL.

    Subcellular locationi

    Mitochondrion matrix. Peroxisome
    Note: Unprocessed form is peroxisomal.

    GO - Cellular componenti

    1. mitochondrial inner membrane Source: Ensembl
    2. mitochondrial matrix Source: UniProtKB
    3. mitochondrion Source: UniProtKB
    4. peroxisome Source: UniProtKB

    Keywords - Cellular componenti

    Mitochondrion, Peroxisome

    Pathology & Biotechi

    Involvement in diseasei

    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.10 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti37 – 371E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058440
    Natural varianti41 – 411R → Q in HMGCLD; loss of activity and of proton exchange. 2 Publications
    VAR_003744
    Natural varianti42 – 421D → E in HMGCLD; reduced activity. 1 Publication
    VAR_003745
    Natural varianti42 – 421D → G in HMGCLD; loss of activity. 2 Publications
    VAR_003746
    Natural varianti42 – 421D → H in HMGCLD; loss of activity. 1 Publication
    VAR_003747
    Natural varianti48 – 481K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication
    VAR_058441
    Natural varianti70 – 701V → L in HMGCLD.
    VAR_003748
    Natural varianti75 – 751S → R in HMGCLD. 1 Publication
    VAR_058442
    Natural varianti142 – 1421S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058443
    Natural varianti165 – 1651R → Q in HMGCLD. 1 Publication
    Corresponds to variant rs199587895 [ dbSNP | Ensembl ].
    VAR_065453
    Natural varianti174 – 1741C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058444
    Natural varianti192 – 1921F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058445
    Natural varianti200 – 2001I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058446
    Natural varianti201 – 2011S → Y in HMGCLD. 1 Publication
    VAR_058447
    Natural varianti203 – 2031G → E in HMGCLD; complete loss of activity. 1 Publication
    VAR_058448
    Natural varianti204 – 2041D → N in HMGCLD. 1 Publication
    VAR_058449
    Natural varianti233 – 2331H → R in HMGCLD; loss of activity. 3 Publications
    VAR_003749
    Natural varianti263 – 2631L → P in HMGCLD. 1 Publication
    VAR_058450
    Natural varianti279 – 2791E → K in HMGCLD. 1 Publication
    Corresponds to variant rs28934894 [ dbSNP | Ensembl ].
    VAR_014202

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi37 – 371E → D: Normal activity. 1 Publication
    Mutagenesisi41 – 411R → M: Reduced activity, and loss of proton exchange. 1 Publication
    Mutagenesisi42 – 421D → A or N: Loss of activity, and reduced proton exchange rate. 2 Publications
    Mutagenesisi72 – 721E → A: Loss of activity, and reduced affinity for metal cofactor and substrate. 1 Publication
    Mutagenesisi204 – 2041D → A: Reduced activity, and reduced affinity for metal cofactor and substrate. 1 Publication
    Mutagenesisi233 – 2331H → A: Loss of activity, and reduced proton exchange rate. 2 Publications
    Mutagenesisi266 – 2661C → A: Loss of activity.
    Mutagenesisi279 – 2791E → A: Reduced thermal stability, but normal activity. 1 Publication
    Mutagenesisi280 – 2801D → A: Normal activity. 1 Publication
    Mutagenesisi323 – 3231C → S: Abolishes interchain homodimerization. Exhibits no DTT stimulated activity. 2 Publications

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi246450. phenotype.
    Orphaneti20. 3-hydroxy-3-methylglutaric aciduria.
    PharmGKBiPA29336.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transit peptidei1 – 2727MitochondrionAdd
    BLAST
    Chaini28 – 325298Hydroxymethylglutaryl-CoA lyase, mitochondrialPRO_0000013478Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei48 – 481N6-acetyllysine; alternate1 Publication
    Modified residuei48 – 481N6-succinyllysine; alternateBy similarity
    Modified residuei111 – 1111N6-acetyllysineBy similarity
    Modified residuei137 – 1371N6-acetyllysine; alternateBy similarity
    Modified residuei137 – 1371N6-succinyllysine; alternateBy similarity
    Modified residuei179 – 1791N6-acetyllysine; alternateBy similarity
    Modified residuei179 – 1791N6-succinyllysine; alternateBy similarity
    Disulfide bondi323 – 323Interchain1 Publication
    Modified residuei324 – 3241N6-acetyllysineBy similarity

    Keywords - PTMi

    Acetylation, Disulfide bond

    Proteomic databases

    MaxQBiP35914.
    PaxDbiP35914.
    PRIDEiP35914.

    PTM databases

    PhosphoSiteiP35914.

    Expressioni

    Tissue specificityi

    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%).1 Publication

    Gene expression databases

    ArrayExpressiP35914.
    BgeeiP35914.
    CleanExiHS_HMGCL.
    GenevestigatoriP35914.

    Organism-specific databases

    HPAiHPA004727.

    Interactioni

    Subunit structurei

    Homodimer; disulfide-linked. Can also form homotetramers.2 Publications

    Protein-protein interaction databases

    BioGridi109398. 8 interactions.
    IntActiP35914. 8 interactions.
    MINTiMINT-3014127.
    STRINGi9606.ENSP00000363614.

    Structurei

    Secondary structure

    1
    325
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi34 – 374
    Turni39 – 413
    Helixi42 – 454
    Helixi53 – 6513
    Beta strandi69 – 713
    Turni79 – 813
    Helixi83 – 853
    Helixi88 – 947
    Helixi110 – 1189
    Beta strandi122 – 1309
    Helixi132 – 1398
    Helixi143 – 15917
    Beta strandi163 – 1697
    Turni170 – 1723
    Turni175 – 1773
    Helixi182 – 19413
    Beta strandi198 – 2047
    Helixi211 – 22414
    Helixi227 – 2293
    Beta strandi230 – 2356
    Helixi241 – 25010
    Beta strandi255 – 2595
    Helixi278 – 28811
    Helixi296 – 30914
    Helixi317 – 3226

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    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[»]
    ProteinModelPortaliP35914.
    SMRiP35914. Positions 28-323.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP35914.

    Family & Domainsi

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi323 – 3253Microbody targeting signalSequence Analysis

    Sequence similaritiesi

    Belongs to the HMG-CoA lyase family.Curated

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiCOG0119.
    HOGENOMiHOG000219757.
    HOVERGENiHBG064656.
    InParanoidiP35914.
    KOiK01640.
    OMAiNITACLD.
    OrthoDBiEOG73Z2TR.
    PhylomeDBiP35914.
    TreeFamiTF105363.

    Family and domain databases

    Gene3Di3.20.20.70. 1 hit.
    InterProiIPR013785. Aldolase_TIM.
    IPR000138. HMG_CoA_lyase_AS.
    IPR000891. PYR_CT.
    [Graphical view]
    PfamiPF00682. HMGL-like. 1 hit.
    [Graphical view]
    PROSITEiPS01062. HMG_COA_LYASE. 1 hit.
    PS50991. PYR_CT. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P35914-1) [UniParc]FASTAAdd to Basket

    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.

    « Hide

    MAAMRKALPR RLVGLASLRA VSTSSMGTLP KRVKIVEVGP RDGLQNEKNI    50
    VSTPVKIKLI DMLSEAGLSV IETTSFVSPK WVPQMGDHTE VLKGIQKFPG 100
    INYPVLTPNL KGFEAAVAAG AKEVVIFGAA SELFTKKNIN CSIEESFQRF 150
    DAILKAAQSA NISVRGYVSC ALGCPYEGKI SPAKVAEVTK KFYSMGCYEI 200
    SLGDTIGVGT PGIMKDMLSA VMQEVPLAAL AVHCHDTYGQ ALANTLMALQ 250
    MGVSVVDSSV AGLGGCPYAQ GASGNLATED LVYMLEGLGI HTGVNLQKLL 300
    EAGNFICQAL NRKTSSKVAQ ATCKL 325
    Length:325
    Mass (Da):34,360
    Last modified:October 25, 2002 - v2
    Checksum:iB82B2488A10D6980
    GO
    Isoform 2 (identifier: P35914-2) [UniParc]FASTAAdd to Basket

    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.

    Show »
    Length:254
    Mass (Da):26,910
    Checksum:iFAD9D90A1A62F3AD
    GO
    Isoform 3 (identifier: P35914-3) [UniParc]FASTAAdd to Basket

    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.

    Show »
    Length:191
    Mass (Da):20,222
    Checksum:iD5540BECDB75D854
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti243 – 2431A → T in AAA92733. (PubMed:8440722)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti37 – 371E → K in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058440
    Natural varianti41 – 411R → Q in HMGCLD; loss of activity and of proton exchange. 2 Publications
    VAR_003744
    Natural varianti42 – 421D → E in HMGCLD; reduced activity. 1 Publication
    VAR_003745
    Natural varianti42 – 421D → G in HMGCLD; loss of activity. 2 Publications
    VAR_003746
    Natural varianti42 – 421D → H in HMGCLD; loss of activity. 1 Publication
    VAR_003747
    Natural varianti48 – 481K → N in HMGCLD; abolishes almost all enzymatic activity. 1 Publication
    VAR_058441
    Natural varianti70 – 701V → L in HMGCLD.
    VAR_003748
    Natural varianti75 – 751S → R in HMGCLD. 1 Publication
    VAR_058442
    Natural varianti142 – 1421S → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058443
    Natural varianti165 – 1651R → Q in HMGCLD. 1 Publication
    Corresponds to variant rs199587895 [ dbSNP | Ensembl ].
    VAR_065453
    Natural varianti174 – 1741C → Y in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058444
    Natural varianti192 – 1921F → S in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058445
    Natural varianti200 – 2001I → F in HMGCLD; activity lower than 5% respect to the wild-type. 1 Publication
    VAR_058446
    Natural varianti201 – 2011S → Y in HMGCLD. 1 Publication
    VAR_058447
    Natural varianti203 – 2031G → E in HMGCLD; complete loss of activity. 1 Publication
    VAR_058448
    Natural varianti204 – 2041D → N in HMGCLD. 1 Publication
    VAR_058449
    Natural varianti233 – 2331H → R in HMGCLD; loss of activity. 3 Publications
    VAR_003749
    Natural varianti263 – 2631L → P in HMGCLD. 1 Publication
    VAR_058450
    Natural varianti279 – 2791E → K in HMGCLD. 1 Publication
    Corresponds to variant rs28934894 [ dbSNP | Ensembl ].
    VAR_014202

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei117 – 18771Missing in isoform 2 and isoform 3. 2 PublicationsVSP_047444Add
    BLAST
    Alternative sequencei188 – 25063Missing in isoform 3. 1 PublicationVSP_043788Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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.
    CCDSiCCDS243.1. [P35914-1]
    CCDS53279.1. [P35914-2]
    PIRiA45470.
    RefSeqiNP_000182.2. NM_000191.2. [P35914-1]
    NP_001159531.1. NM_001166059.1. [P35914-2]
    UniGeneiHs.533444.

    Genome annotation databases

    EnsembliENST00000374490; ENSP00000363614; ENSG00000117305. [P35914-1]
    ENST00000436439; ENSP00000389281; ENSG00000117305. [P35914-2]
    GeneIDi3155.
    KEGGihsa:3155.
    UCSCiuc001bib.3. human. [P35914-1]
    uc010oec.2. human. [P35914-2]

    Polymorphism databases

    DMDMi24418852.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    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 .
    CCDSi CCDS243.1. [P35914-1 ]
    CCDS53279.1. [P35914-2 ]
    PIRi A45470.
    RefSeqi NP_000182.2. NM_000191.2. [P35914-1 ]
    NP_001159531.1. NM_001166059.1. [P35914-2 ]
    UniGenei Hs.533444.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2CW6 X-ray 2.10 A/B/C/D/E/F 28-325 [» ]
    3MP3 X-ray 2.40 A/B/C/D/E/F 28-325 [» ]
    3MP4 X-ray 2.20 A/B/C/D/E/F 28-325 [» ]
    3MP5 X-ray 2.25 A/B/C/D/E/F 28-325 [» ]
    ProteinModelPortali P35914.
    SMRi P35914. Positions 28-323.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109398. 8 interactions.
    IntActi P35914. 8 interactions.
    MINTi MINT-3014127.
    STRINGi 9606.ENSP00000363614.

    PTM databases

    PhosphoSitei P35914.

    Polymorphism databases

    DMDMi 24418852.

    Proteomic databases

    MaxQBi P35914.
    PaxDbi P35914.
    PRIDEi P35914.

    Protocols and materials databases

    DNASUi 3155.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000374490 ; ENSP00000363614 ; ENSG00000117305 . [P35914-1 ]
    ENST00000436439 ; ENSP00000389281 ; ENSG00000117305 . [P35914-2 ]
    GeneIDi 3155.
    KEGGi hsa:3155.
    UCSCi uc001bib.3. human. [P35914-1 ]
    uc010oec.2. human. [P35914-2 ]

    Organism-specific databases

    CTDi 3155.
    GeneCardsi GC01M024128.
    HGNCi HGNC:5005. HMGCL.
    HPAi HPA004727.
    MIMi 246450. phenotype.
    613898. gene.
    neXtProti NX_P35914.
    Orphaneti 20. 3-hydroxy-3-methylglutaric aciduria.
    PharmGKBi PA29336.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0119.
    HOGENOMi HOG000219757.
    HOVERGENi HBG064656.
    InParanoidi P35914.
    KOi K01640.
    OMAi NITACLD.
    OrthoDBi EOG73Z2TR.
    PhylomeDBi P35914.
    TreeFami TF105363.

    Enzyme and pathway databases

    UniPathwayi UPA00896 ; UER00863 .
    BioCyci MetaCyc:HS04116-MONOMER.
    BRENDAi 4.1.3.4. 2681.
    Reactomei REACT_1464. Synthesis of Ketone Bodies.
    SABIO-RK P35914.

    Miscellaneous databases

    ChiTaRSi HMGCL. human.
    EvolutionaryTracei P35914.
    GenomeRNAii 3155.
    NextBioi 12496.
    PROi P35914.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P35914.
    Bgeei P35914.
    CleanExi HS_HMGCL.
    Genevestigatori P35914.

    Family and domain databases

    Gene3Di 3.20.20.70. 1 hit.
    InterProi IPR013785. Aldolase_TIM.
    IPR000138. HMG_CoA_lyase_AS.
    IPR000891. PYR_CT.
    [Graphical view ]
    Pfami PF00682. HMGL-like. 1 hit.
    [Graphical view ]
    PROSITEi PS01062. HMG_COA_LYASE. 1 hit.
    PS50991. PYR_CT. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.
      , 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.
      , 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. 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. 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. 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. 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.

    Entry informationi

    Entry nameiHMGCL_HUMAN
    AccessioniPrimary (citable) accession number: P35914
    Secondary accession number(s): B4DUP4
    , B7UCC6, D3Y5K7, Q6IBC0, Q96FP8
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 1, 1994
    Last sequence update: October 25, 2002
    Last modified: October 1, 2014
    This is version 150 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 1
      Human chromosome 1: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3