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Protein

3-hydroxymethyl-3-methylglutaryl-CoA lyase, cytoplasmic

Gene

HMGCLL1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Non-mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis, the products of which support energy production in nonhepatic animal tissues.2 Publications

Catalytic activityi

(S)-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate.2 Publications

Cofactori

a divalent metal cation1 Publication

Kineticsi

  1. KM=40 µM for (S)-3-hydroxy-3-methylglutaryl-CoA (at pH 9)2 Publications
  2. KM=75 µM for (S)-3-hydroxy-3-methylglutaryl-CoA (at pH 8)2 Publications
  3. KM=28 µM for (S)-3-hydroxy-3-methylglutaryl-CoA2 Publications
  4. KM=49 µM for (S)-3-hydroxy-3-methylglutaryl-CoA (in presence of magnesium)2 Publications
  5. KM=0.18 µM for (S)-3-hydroxy-3-methylglutaryl-CoA (in presence of manganese)2 Publications
  1. Vmax=12 nmol/min/mg enzyme with (S)-3-hydroxy-3-methylglutaryl-CoA as substrate at pH 92 Publications
  2. Vmax=25 nmol/min/mg enzyme with (S)-3-hydroxy-3-methylglutaryl-CoA as substrate at pH 82 Publications

Pathwayi: (S)-3-hydroxy-3-methylglutaryl-CoA degradation

This protein is involved in step 1 of the subpathway that synthesizes acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA.
Proteins known to be involved in this subpathway in this organism are:
  1. Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL), 3-hydroxymethyl-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1)
This subpathway is part of the pathway (S)-3-hydroxy-3-methylglutaryl-CoA degradation, which is itself part of Metabolic intermediate metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA, the pathway (S)-3-hydroxy-3-methylglutaryl-CoA degradation and in Metabolic intermediate metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei86SubstrateBy similarity1
Metal bindingi87Divalent metal cationBy similarity1
Metal bindingi278Divalent metal cationBy similarity1
Metal bindingi280Divalent metal cationBy similarity1
Active sitei311By similarity1
Metal bindingi320Divalent metal cationBy similarity1

GO - Molecular functioni

  • hydroxymethylglutaryl-CoA lyase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB

GO - Biological processi

  • ketone body biosynthetic process Source: UniProtKB

Keywordsi

Molecular functionLyase
LigandMetal-binding

Enzyme and pathway databases

ReactomeiR-HSA-77111 Synthesis of Ketone Bodies
UniPathwayiUPA00896; UER00863

Chemistry databases

SwissLipidsiSLP:000001291 [Q8TB92-2]

Names & Taxonomyi

Protein namesi
Recommended name:
3-hydroxymethyl-3-methylglutaryl-CoA lyase, cytoplasmic (EC:4.1.3.4)
Alternative name(s):
3-hydroxymethyl-3-methylglutaryl-CoA lyase-like protein 1
Endoplasmic reticulum 3-hydroxymethyl-3-methylglutaryl-CoA lyase
Short name:
er-cHL
Gene namesi
Name:HMGCLL1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

EuPathDBiHostDB:ENSG00000146151.12
HGNCiHGNC:21359 HMGCLL1
neXtProtiNX_Q8TB92

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2G → A: Abolishes myristoylation and induces a subcellular location change. 1 Publication1
Mutagenesisi86R → Q: Abolishes catalytic activity. 1 Publication1
Mutagenesisi237L → S: Abolishes catalytic activity. 1 Publication1
Mutagenesisi278H → R: Abolishes catalytic activity. 1 Publication1

Organism-specific databases

DisGeNETi54511
OpenTargetsiENSG00000146151
PharmGKBiPA134989971

Polymorphism and mutation databases

BioMutaiHMGCLL1
DMDMi189028466

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved
ChainiPRO_00003346692 – 3703-hydroxymethyl-3-methylglutaryl-CoA lyase, cytoplasmicAdd BLAST369

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine1 Publication1

Keywords - PTMi

Lipoprotein, Myristate

Proteomic databases

MaxQBiQ8TB92
PaxDbiQ8TB92
PeptideAtlasiQ8TB92
PRIDEiQ8TB92

PTM databases

iPTMnetiQ8TB92
PhosphoSitePlusiQ8TB92

Expressioni

Gene expression databases

BgeeiENSG00000146151
CleanExiHS_HMGCLL1
ExpressionAtlasiQ8TB92 baseline and differential
GenevisibleiQ8TB92 HS

Interactioni

Protein-protein interaction databases

BioGridi120006, 2 interactors
STRINGi9606.ENSP00000381654

Structurei

3D structure databases

ProteinModelPortaliQ8TB92
SMRiQ8TB92
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini78 – 345Pyruvate carboxyltransferasePROSITE-ProRule annotationAdd BLAST268

Sequence similaritiesi

Belongs to the HMG-CoA lyase family.Curated

Phylogenomic databases

eggNOGiKOG2368 Eukaryota
COG0119 LUCA
GeneTreeiENSGT00390000017690
HOGENOMiHOG000219757
HOVERGENiHBG064656
InParanoidiQ8TB92
KOiK01640
OMAiIHQYPGV
OrthoDBiEOG091G0DA9
PhylomeDBiQ8TB92
TreeFamiTF105363

Family and domain databases

Gene3Di3.20.20.70, 1 hit
InterProiView protein in InterPro
IPR013785 Aldolase_TIM
IPR030021 er-cHL
IPR000891 PYR_CT
PANTHERiPTHR42738:SF5 PTHR42738:SF5, 1 hit
PfamiView protein in Pfam
PF00682 HMGL-like, 1 hit
PROSITEiView protein in PROSITE
PS50991 PYR_CT, 1 hit

Sequences (4)i

Sequence statusi: Complete.

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

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TB92-1) [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

        10         20         30         40         50
MGNVPSAVKH CLSYQQLLRE HLWIGDSVAG ALDPAQTSLL TNLHCFQPDV
60 70 80 90 100
SGFSVSLAGT VACIHWETSQ LSGLPEFVKI VEVGPRDGLQ NEKVIVPTDI
110 120 130 140 150
KIEFINRLSQ TGLSVIEVTS FVSSRWVPQM ADHTEVMKGI HQYPGVRYPV
160 170 180 190 200
LTPNLQGFHH AVAAGATEIS VFGAASESFS KKNINCSIEE SMGKFEEVVK
210 220 230 240 250
SARHMNIPAR GYVSCALGCP YEGSITPQKV TEVSKRLYGM GCYEISLGDT
260 270 280 290 300
IGVGTPGSMK RMLESVMKEI PPGALAVHCH DTYGQALANI LTALQMGINV
310 320 330 340 350
VDSAVSGLGG CPYAKGASGN VATEDLIYML NGLGLNTGVN LYKVMEAGDF
360 370
ICKAVNKTTN SKVAQASFNA
Length:370
Mass (Da):39,514
Last modified:May 20, 2008 - v3
Checksum:i7DDEE81555E092A1
GO
Isoform 2 (identifier: Q8TB92-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     37-66: Missing.

Show »
Length:340
Mass (Da):36,328
Checksum:i6F175387821614CC
GO
Isoform 3 (identifier: Q8TB92-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     37-53: TSLLTNLHCFQPDVSGF → ELQSVMLMLHHGPLRKP
     54-370: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. No experimental confirmation available.
Show »
Length:53
Mass (Da):5,874
Checksum:i16F3265215AF8A2A
GO
Isoform 4 (identifier: Q8TB92-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     37-66: Missing.
     130-161: Missing.

Note: No experimental confirmation available.
Show »
Length:308
Mass (Da):32,701
Checksum:i49ED9FE7EC8038BB
GO

Sequence cautioni

The sequence BAC87045 differs from that shown. Reason: Frameshift at position 253.Curated
The sequence BAG51462 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti99D → G in BAH11613 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_03375237 – 66Missing in isoform 2 and isoform 4. 2 PublicationsAdd BLAST30
Alternative sequenceiVSP_03802137 – 53TSLLT…DVSGF → ELQSVMLMLHHGPLRKP in isoform 3. 1 PublicationAdd BLAST17
Alternative sequenceiVSP_03802254 – 370Missing in isoform 3. 1 PublicationAdd BLAST317
Alternative sequenceiVSP_044324130 – 161Missing in isoform 4. 1 PublicationAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK055075 mRNA Translation: BAG51462.1 Sequence problems.
AK127587 mRNA Translation: BAC87045.1 Frameshift.
AK293856 mRNA Translation: BAH11613.1
AL590290 Genomic DNA No translation available.
AL590406 Genomic DNA No translation available.
CH471081 Genomic DNA Translation: EAX04442.1
CH471081 Genomic DNA Translation: EAX04444.1
BC024194 mRNA Translation: AAH24194.2
CCDSiCCDS43474.1 [Q8TB92-2]
CCDS43475.1 [Q8TB92-1]
CCDS75473.1 [Q8TB92-5]
RefSeqiNP_001035865.1, NM_001042406.1 [Q8TB92-2]
NP_001274670.1, NM_001287741.1 [Q8TB92-5]
NP_001274675.1, NM_001287746.1
NP_061909.2, NM_019036.2 [Q8TB92-1]
UniGeneiHs.147054

Genome annotation databases

EnsembliENST00000274901; ENSP00000274901; ENSG00000146151 [Q8TB92-2]
ENST00000308161; ENSP00000309737; ENSG00000146151 [Q8TB92-5]
ENST00000370852; ENSP00000359889; ENSG00000146151 [Q8TB92-4]
ENST00000398661; ENSP00000381654; ENSG00000146151 [Q8TB92-1]
GeneIDi54511
KEGGihsa:54511
UCSCiuc003pcn.4 human [Q8TB92-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiHMGC2_HUMAN
AccessioniPrimary (citable) accession number: Q8TB92
Secondary accession number(s): B1AQ42
, B3KNV0, B7Z1S7, F8W793, Q6ZSA9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 20, 2008
Last sequence update: May 20, 2008
Last modified: March 28, 2018
This is version 129 of the entry and version 3 of the sequence. See 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

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health