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P35914

- HMGCL_HUMAN

UniProt

P35914 - HMGCL_HUMAN

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Protein
Hydroxymethylglutaryl-CoA lyase, mitochondrial
Gene
HMGCL
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

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 Publications

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-CoA

Vmax=191 µmol/min/mg enzyme

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 – 2661 By similarity
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
Complete GO annotation...

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
Complete GO annotation...

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-RKiP35914.
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.2 Publications

GO - Cellular componenti

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

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.
Note: The disease is caused by mutations affecting the gene represented in this entry.10 Publications
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 – 2727Mitochondrion
Add
BLAST
Chaini28 – 325298Hydroxymethylglutaryl-CoA lyase, mitochondrial
PRO_0000013478Add
BLAST

Amino acid modifications

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

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.

Miscellaneous databases

EvolutionaryTraceiP35914.

Family & Domainsi

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi323 – 3253Microbody targeting signal Reviewed prediction

Sequence similaritiesi

Belongs to the HMG-CoA lyase family.

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

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.
VSP_047444Add
BLAST
Alternative sequencei188 – 25063Missing in isoform 3.
VSP_043788Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti243 – 2431A → T in AAA92733. 1 Publication

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...

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-RKi 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

« Hide 'large scale' publications
  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: September 3, 2014
This is version 149 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

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