Information on EC 4.1.3.4 - hydroxymethylglutaryl-CoA lyase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
4.1.3.4
-
RECOMMENDED NAME
GeneOntology No.
hydroxymethylglutaryl-CoA lyase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(S)-3-Hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
elimination
-
-
of an oxo-acid, C-C bond cleavage
-
enolization
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Butanoate metabolism
-
-
Geraniol degradation
-
-
ketogenesis
-
-
L-leucine degradation I
-
-
leucine metabolism
-
-
Metabolic pathways
-
-
mevalonate degradation
-
-
Synthesis and degradation of ketone bodies
-
-
Valine, leucine and isoleucine degradation
-
-
SYSTEMATIC NAME
IUBMB Comments
(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetate-lyase (acetyl-CoA-forming)
-
CAS REGISTRY NUMBER
COMMENTARY hide
9030-83-5
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
duck
-
-
Manually annotated by BRENDA team
-
Uniprot
Manually annotated by BRENDA team
bovine
-
-
Manually annotated by BRENDA team
-
Uniprot
Manually annotated by BRENDA team
goat
-
-
Manually annotated by BRENDA team
pigeon
-
-
Manually annotated by BRENDA team
chicken
-
-
Manually annotated by BRENDA team
gene hcl1
-
-
Manually annotated by BRENDA team
sheep
-
-
Manually annotated by BRENDA team
strain PAO1SM
-
-
Manually annotated by BRENDA team
strain PAO1SM
-
-
Manually annotated by BRENDA team
radish
-
-
Manually annotated by BRENDA team
pig
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
-
the enzyme catalyzes the last step in the leucine catabolism pathway
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(S)-3-Hydroxy-3-methylglutaryl-CoA
?
show the reaction diagram
(S)-3-Hydroxy-3-methylglutaryl-CoA
Acetyl-CoA + acetoacetate
show the reaction diagram
3-hydroxy-3-methylglutaryl-CoA
acetoacetate + acetyl-CoA
show the reaction diagram
Acetyl-CoA
?
show the reaction diagram
-
enolization
-
-
-
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(S)-3-Hydroxy-3-methylglutaryl-CoA
?
show the reaction diagram
(S)-3-Hydroxy-3-methylglutaryl-CoA
Acetyl-CoA + acetoacetate
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Bivalent cations
Ca2+
-
22% activation at 0.1 mM
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(-)-epicatechin gallate
-
a mixed-type noncompetitive inhibitor
(-)-epigallocatechin
-
a mixed-type noncompetitive inhibitor
(-)-epigallocatechin gallate
-
a mixed-type noncompetitive inhibitor, contribution of the gallyl moiety, which forms a hexa-coordination complex with the Mg2+ ion, to enzymatic inhibition
(R)-3-hydroxy-3-methylglutaryl-CoA
-
-
1,10-phenanthroline
-
43% activity after 4 h at 4 mM
2-Butynoyl-CoA
3-Hydroxyglutaryl-CoA
4-Methylnitrobenzene sulfonate
-
sensitivity to inactivation depends on redox state of enzyme, Kinact: 0.178 min-1, reduced, 0.028 min 1, oxidized
acetoacetate
-
-
acetyldithio-CoA
-
-
gallic acid
-
a noncompetitive inhibitor
o-phenanthroline
-
not m-Phenanthroline, probably acts as metal chelator
pyrogallol
-
a mixed-type noncompetitive inhibitor
S-(4-carboxy-3hydroxyisoamyl)-CoA
-
Ki: 0.08 mM
Thiomalic acid
-
-
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
daidzein
-
slight activation
dithiothreitol
thiols
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02 - 62
(S)-3-hydroxy-3-methylglutaryl-CoA
0.0134 - 0.0265
3-hydroxy-3-methylglutaryl-CoA
0.008 - 0.053
hydroxymethylglutaryl-CoA
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0004 - 158
(S)-3-hydroxy-3-methylglutaryl-CoA
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0441
(-)-epicatechin gallate
-
pH 7.5, 37C
0.0299
(-)-epigallocatechin
-
pH 7.5, 37C
0.0028
(-)-epigallocatechin gallate
-
pH 7.5, 37C
0.05
3-Hydroxyglutaryl-CoA
-
-
0.021
acetoacetate
-
-
0.17
acetyldithio-CoA
-
-
0.018
gallic acid
-
pH 7.5, 37C
0.0074
pyrogallol
-
pH 7.5, 37C
0.08
S-(4-carboxy-3hydroxyisoamyl)-CoA
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.1612
(-)-epicatechin gallate
Homo sapiens
-
pH 7.5, 37C
0.0575
(-)-epigallocatechin
Homo sapiens
-
pH 7.5, 37C
0.0424
(-)-epigallocatechin gallate
Homo sapiens
-
pH 7.5, 37C
0.0444
gallic acid
Homo sapiens
-
pH 7.5, 37C
0.0615
pyrogallol
Homo sapiens
-
pH 7.5, 37C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0018 - 0.11
-
C237 mutants
0.0098
-
-
0.022
-
at optimal pH
0.03
-
recombinant deletion mutant Mut15, at 37C
0.123
-
C170S/C266S mutant protein, pH not specified in the publication, temperature not specified in the publication
0.22
-
recombinant deletion mutant Mut12, at 37C
0.224
-
C266S mutant protein, pH not specified in the publication, temperature not specified in the publication
1.06
-
C170S/C174S mutant protein, pH not specified in the publication, temperature not specified in the publication
1.13
-
recombinant deletion mutant Mut3, at 37C
1.2
-
recombinant deletion mutant Mut6, at 37C
1.27
-
recombinant deletion mutant Mut9, at 37C
1.29
-
recombinant wild type enzyme, at 37C
1.3
-
-
9.5
wild type enzyme, at 37C
18.5
-
C170S/C323S mutant protein, pH not specified in the publication, temperature not specified in the publication
21.2
-
C197S mutant protein, pH not specified in the publication, temperature not specified in the publication
42
-
C141S mutant protein, pH not specified in the publication, temperature not specified in the publication
42.1
-
C174S mutant protein, pH not specified in the publication, temperature not specified in the publication
53.1
-
C170S mutant protein, pH not specified in the publication, temperature not specified in the publication
80
-
wild-type
87.8
-
K48N mutant protein, pH not specified in the publication, 30C
100.3
-
K48Q mutant protein, pH not specified in the publication, 30C
107
-
C323S mutant
114
-
wild-type
117
-
HMGCLL1 mutant G2A, pH 8.2, 37C
123
-
wild type protein, pH not specified in the publication, temperature not specified in the publication
128
-
C234S mutant protein, pH not specified in the publication, temperature not specified in the publication
132
-
C307S mutant protein, pH not specified in the publication, temperature not specified in the publication; C323S mutant protein, pH not specified in the publication, temperature not specified in the publication
136
-
wild type protein, pH not specified in the publication, 30C
150
-
wild-type HMGCLL1, pH 8.2, 37C
220
-
peroxisomal enzyme
249
-
mitochondrial enzyme
351
-
-
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
-
assay at
8.4
-
enzyme assay at
8.9
-
-
9 - 9.5
-
both isoenzymes
9.25
-
-
10
-
-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4 - 10.5
-
-
8 - 9
-
-
8 - 11
-
low activity below pH 8, discussion of kinetic data measured at lower pH
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.2
-
mitochondrial enzyme, isoelectric focusing
7.6
-
peroxisomal enzyme, isoelectric focusing
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
-
Manually annotated by BRENDA team
-
HMGCLL1 is overexpressed in certain types of human brain cancer cells
Manually annotated by BRENDA team
-
HMGCL
Manually annotated by BRENDA team
-
HMGCL; HMGCLL1
Manually annotated by BRENDA team
-
low activity
Manually annotated by BRENDA team
-
low activity
Manually annotated by BRENDA team
-
HMGCL; HMGCLL1
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
13% of activity
Manually annotated by BRENDA team
-
endogenous HMGCLL1 localized to punctate vesicles
-
Manually annotated by BRENDA team
-
wild-type 3-hydroxy-3-methylglutaryl-CoA lyase-like protein, myristoylation dependent association with nonmitochondrial membrane compartments
-
Manually annotated by BRENDA team
additional information
-
HMGCL is a mitochondrial enzyme; HMGCLL1 is an extramitochondrial enzyme
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Brucella melitensis biotype 1 (strain 16M / ATCC 23456 / NCTC 10094)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
31000
-
mitochondrial enzyme, SDS-PAGE
31500
-
SDS-PAGE, mitochondrial enzyme
31600
-
-
32000
-
SDS-PAGE
49000
-
gel filtration
64000
-
calculated from Stokes' radius
65000
-
mitochondrial enzyme, gel filtration
70000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hexamer
-
X-ray crystallography, the hexamer consists of three dimers which are supposed to be the physiological enzyme form in solution
homodimer
-
SDS-PAGE (reducing and non-reducing conditions)
monomer
-
1 * 34500, peroxisomal enzyme, SDS-PAGE
tetramer
-
analytical ultracentrifugation, enzyme exists as a mixture of dimers and tetramers
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
lipoprotein
-
the deduced 3-hydroxy-3-methylglutaryl-CoA lyase-like protein, HMGCLL1, sequence contains an N-terminal myristoylation motif. Myristoylation of HMGCLL1 affects its cellular localization
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hanging-drop vapour diffusion method; hanging drop vapour diffusion method with 22.5% (w/v) PEG 3350, 210 mM sodium iodide, 5 mM EDTA, 10 mM dithiothreitol
hanging-drop vapour diffusion method; hanging drop vapour diffusion method with 19% (w/v) PEG 3350, 200 mM CaCl2, 10 mM dithiothreitol
crystal structure at 2.1 A resolution of the recombinant mitochondrial HMG-CoA lyase containing a bound activator cation and 3-hydroxyglutarate. For crystallization experiments, the enzyme is diluted to 5 6 mg/ml. The competitive inhibitor hydroxyglutaryl-CoA is added to the diluted protein at about 1mM concentration. The inhibitor is necessary for generation of uniform diffraction quality crystals. Crystals sufficient for X-ray studies are obtained using an equilibration buffer of 0.1 M Hepes, pH 7.5, 60 mM MgCl2,and 15% polyethylene glycol 8K. The enzyme is mixed 1:1 with the equilibration buffer using sitting drop trays at 19C. Crystals belong to the monoclinic space group C2 with unit cell parameters a = 197.0 A, b = 117.1 A, c = 86.8 A, and beta = 112.5. Six monomers are found in the asymmetric unit; sitting drop vapour diffusion method with 0.1 M HEPES, pH 7.5, 60 mM MgCl2, and 15% polyethylene glycol 8K
-
vapor diffusion method
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
rapidly inactivated above
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
extremely unstable
-
extremely unstable, even in presence of glycerol
-
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme is sensitive to oxidation, showing higher activity in reducing conditions
-
681959
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20C, Tris-HCl buffer, pH7.4, 1 mM cysteine, several months
-
-20C,Tris-HCl buffer, pH 7.1, 30% glycerol, 1 mM dithiothreitol, 6 weeks
-
-80C, phosphate buffer, pH 7.2, 20% glycerol, several weeks
-
-80C, potassium phosphate buffer, pH 7.4, at least 6 months
-
-80C, retains full activity for several months in phosphate buffer containing 20% glycerol at pH 7.2
-
-80C, several weeks
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; nickel-nitrilotriacetic acid column chromatography and Superdex 75 gel filtration
glutathione Sepharose column chromatography
-
immobilized metal ion affinity chromatography (Ni2+)
-
mitochondrial and peroxisomal enzyme
-
overexpressed in Escherichia coli, immunoreaction with avian liver enzyme antibodies
-
partial
-
Q-Sepharose column chromatography, phenyl-agarose column chromatography, and Superose 12 column chromatography
-
recombinant active wild-type 3-hydroxy-3-methylglutaryl-CoA lyase-like protein and its mutant G2A from Pichia pastoris by nickel affinity chromatography and ultrafiltration
-
recombinant wild-type enzyme and C323S mutant
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cloning of 3-hydroxy-3-methylglutaryl-CoA lyase-like protein, sequence comparison of HMGCLL1 and HMGCL, expression of 3-hydroxy-3-methylglutaryl-CoA lyase-like protein mutant G2A in COS-1 cell cytosol, recombinant expression of wild-type 3-hydroxy-3-methylglutaryl-CoA lyase-like protein in Escherichia coli and Pichia pastoris, in insoluble form; sequence comparison of HMGCLL1 and HMGCL, expression of 3-hydroxy-3-methylglutaryl-CoA lyase wild-type in COS-1 cell cytosol, recombinant expression of wild-type 3-hydroxy-3-methylglutaryl-CoA lyase in Escherichia coli and Pichia pastoris, in active form
-
expressed as His-tagged recombinant protein in Escherichia coli pTrcAtuE cells
-
expressed in Escherichia coli
expressed in Escherichia coli BL21 cells
-
expressed in Escherichia coli JM105 cells
expressed in Escherichia coli; mitochondrial and peroxisomal enzyme
-
expressed in Escherichia coli; overexpression of wild-type enzyme and synthetic C323 mutant
-
expression in Escherichia coli
His-tagged version
-
His-tagged version expressed in Escherichia coli BL21(DE3)
-
nucleotide sequence
-
nucleotide sequence, identification of a 2-base pair deletion in S69 codon of enzyme-deficient patients
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C240A
increased Km relative to the wild type enzyme
C240S
decreased Km relative to the wild type enzyme
D16E
decreased Km relative to the wild type enzyme
D16N
decreased Km relative to the wild type enzyme
D178A
increased Km relative to the wild type enzyme
D254A
decreased Km relative to the wild type enzyme
E11D
decreased Km relative to the wild type enzyme
E253A
decreased Km relative to the wild type enzyme
E46A
increased Km relative to the wild type enzyme
H207A
increased Km relative to the wild type enzyme
H207D
increased Km relative to the wild type enzyme
H207R
decreased Km relative to the wild type enzyme
K297S
increased Km relative to the wild type enzyme
R15Q
increased Km relative to the wild type enzyme
A252A
decreased Km relative to the wild type enzyme
C238A
increased Km relative to the wild type enzyme
C238S
decreased Km relative to the wild type enzyme
D14E
decreased Km relative to the wild type enzyme
D176A
increased Km relative to the wild type enzyme
E44A
increased Km relative to the wild type enzyme
E9D
decreased Km relative to the wild type enzyme
H205A
increased Km relative to the wild type enzyme
H205D
increased Km relative to the wild type enzyme
H205R
decreased Km relative to the wild type enzyme
R13Q
increased Km relative to the wild type enzyme
V251A
decreased Km relative to the wild type enzyme
C141S
-
strong inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
C170S
-
inter-subunit dimer formation not observed (SDS-PAGE, non-reducing conditions)
C170S/C174S
-
moderate inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
C170S/C266S
-
inter-subunit dimer formation not observed (SDS-PAGE, non-reducing conditions)
C170S/C323S
-
inter-subunit dimer formation not observed (SDS-PAGE, non-reducing conditions)
C174S
-
moderate inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
C197S
-
weak inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
C234S
-
weak inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
C266S
-
inter-subunit dimer formation not observed (SDS-PAGE, non-reducing conditions)
C307S
-
moderate inter-subunit dimer formation (SDS-PAGE, non-reducing conditions)
E37X
-
E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency
G109T
-
Spanish patients with the Mediterranean nonsense mutation G109T. The mutation can produce aberrant splicing with three mRNA variants: one of the expected size, the second with deletion of exon 2, and the third with deletion of exons 2 and 3
G2A
-
site-directed mutagenesis of HMGCLL1, eliminatin of N-terminal myristoylation motif by construction of a 3-hydroxy-3-methylglutaryl-CoA lyase-like protein HMGCLL1 G2A mutant, the mutant shows reduced activity compared to wild-type HMGCLL1
K48Q
-
mimics Lys acetylation
L263P
-
lack of enzymatic activity
V70L
-
lack of enzymatic activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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