Information on EC 2.3.3.10 - hydroxymethylglutaryl-CoA synthase

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

EC NUMBER
COMMENTARY hide
2.3.3.10
-
RECOMMENDED NAME
GeneOntology No.
hydroxymethylglutaryl-CoA synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
acetyl-CoA + H2O + acetoacetyl-CoA = (S)-3-hydroxy-3-methylglutaryl-CoA + CoA
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
condensation
hydrolysis
-
-
-
-
transacetylation
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Biosynthesis of antibiotics
-
-
Biosynthesis of secondary metabolites
-
-
Butanoate metabolism
-
-
ferrichrome A biosynthesis
-
-
isoprene biosynthesis II (engineered)
-
-
ketogenesis
-
-
Metabolic pathways
-
-
mevalonate metabolism
-
-
mevalonate pathway I
-
-
mevalonate pathway II (archaea)
-
-
mevalonate pathway III (archaea)
-
-
Synthesis and degradation of ketone bodies
-
-
Terpenoid backbone biosynthesis
-
-
Valine, leucine and isoleucine degradation
-
-
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming)
-
CAS REGISTRY NUMBER
COMMENTARY hide
9027-44-5
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Borrelia burgdorferi
BjHMGS1
-
-
Manually annotated by BRENDA team
BjHMGS2
-
-
Manually annotated by BRENDA team
BjHMGS3
-
-
Manually annotated by BRENDA team
BjHMGS4
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
guinea pig
-
-
Manually annotated by BRENDA team
pigeon
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
turkey
-
-
Manually annotated by BRENDA team
syrian hamster, golden hamster
-
-
Manually annotated by BRENDA team
Methanothermobacter thermautotrophicum
-
-
-
Manually annotated by BRENDA team
hydroxymethylglutaryl-CoA synthase is transcriptionally regulated by isovalerate
-
-
Manually annotated by BRENDA team
no activity in Streptomyces albus
-
-
-
Manually annotated by BRENDA team
pine
SwissProt
Manually annotated by BRENDA team
radish
-
-
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
Sprague-Dawley
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
Vitis vinifera x Vitis riparia
-
-
-
Manually annotated by BRENDA team
Vitis vinifera x Vitis vinifera
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
-
3-hydroxy-3-methylglutaryl-CoA synthase is the second enzyme in the cytosolic mevalonate 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
3-oxobutyryl-CoA + acetoacetyl-CoA + H2O
3-hydroxy-3-methyl-5-oxoheptanedioyl-CoA + CoA
show the reaction diagram
-
-
-
-
?
acetyl-3'-dephospho-CoA + acetoacetyl-CoA + H2O
3-hydroxy-3-methylglutaryl-CoA + 3'-dephospho-CoA
show the reaction diagram
acetyl-CoA + 3'-dephospho-CoA + H2O
acetyldephospho-CoA + CoA
show the reaction diagram
acetyl-CoA + acetoacetyl-ACP + H2O
3-hydroxy-3-methylglutaryl-ACP
show the reaction diagram
-
-
-
-
?
acetyl-CoA + acetoacetyl-CoA + H2O
(S)-3-hydroxy-3-methylglutaryl-CoA + CoA
show the reaction diagram
acetyl-CoA + cysteamine + H2O
? + CoA
show the reaction diagram
-
-
-
-
?
acetyl-CoA + H2O
acetate + CoA
show the reaction diagram
acetyl-CoA + H2O + acetoacetyl-CoA
(S)-3-hydroxy-3-methylglutaryl-CoA + CoA
show the reaction diagram
acetyl-CoA + N-acetyl-S-acetoacetylcysteamine + H2O
? + CoA
show the reaction diagram
-
-
-
-
?
acetylglutathione + acetoacetyl-CoA + H2O
?
show the reaction diagram
-
-
-
-
?
acetylpantetheine + acetoacetyl-CoA + H2O
3-hydroxy-3-methylglutaryl-CoA + pantetheine
show the reaction diagram
-
-
-
-
?
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
acetyl-CoA + acetoacetyl-CoA + H2O
(S)-3-hydroxy-3-methylglutaryl-CoA + CoA
show the reaction diagram
acetyl-CoA + H2O + acetoacetyl-CoA
(S)-3-hydroxy-3-methylglutaryl-CoA + CoA
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
KCl
optimal concentration
Mn2+
-
increases acetoacetate synthesis activity
additional information
-
no stimulation by Mg2+, Mn2+, Zn2+ and Co2+
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(E,E)-11-(3-hydroxymethyl-4-oxo-2-oxytanyl)-3,5,7-trimethyl-2,4-undecadienoic acid
-
i.e. F-244
(E,E)-11-[3-(hydroxymethyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2,4-undecadienenoic acid
(S)-3-hydroxy-3-methylglutaryl-CoA
-
-
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
2-benzyl-9-(3,6-dioxocyclohexa-1,4-dienyl)-2,3,7,8-tetrahydro-6H-pyrido[1,2-a]pyrazine-1,4-dione
-
-
3,3'-dimethylglutaryl-CoA
-
-
-
3-carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxyl-CoA
-
-
3-carboxypropionyl-CoA
-
-
3-Chloropropionyl-CoA
3-hydroxy-3-methylglutaryl-CoA
-
-
3-oxohexanoyl-CoA
-
-
5,5'-dithiobis(2-nitrobenzoate)
acetoacetyl-CoA
acetyloxy(phenyl)mercury
-
phenyl mercuric acetate
arsenite
-
in presence of CoA, residual activity 25%
Bromoacetyl-CoA
-
-
CdSO4
-
residual activity 9%
decanoyl-CoA
-
-
diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate
-
disulfiram
DL-3-hydroxy-3-methylglutaryl-CoA
DL-3-methylglutaryl-CoA
-
-
F-244
-
IC50: 35 nM
glutaryl-CoA
-
-
heptanoyl-CoA
-
-
Hexanoyl-CoA
-
-
hymeglusin
iodoacetamide
L-659,699
Lifibrol
Mg2+
-
mitochondrial enzyme
N-ethylmaleimide
NaAsO2
-
residual activity 90%
nonanoyl-CoA
-
-
Octanoyl-CoA
-
-
p-chloromercuribenzoate
palmitoyl-CoA
-
mitochondrial synthase
phenyl arsenious oxide
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in presence of CoA, residual activity 41%; residual activity 75%
propionyl-CoA
-
-
succinyl-CoA
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dithioerythritol
-
5 mM, activates
potassium phosphate
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-
Sodium phosphate
-
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.019 - 0.116
3-oxobutyl-CoA
0.0001 - 0.115
acetoacetyl-CoA
0.0015 - 1.561
acetyl-CoA
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0017 - 4.6
acetyl-CoA
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
92
acetyl-CoA
Haloferax volcanii
D4GWR6
pH 8.0, 30C
29
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.009 - 0.0389
(S)-3-hydroxy-3-methylglutaryl-CoA
0.12
3,3'-dimethylglutaryl-CoA
-
pH 8.0
-
0.015
3-Chloropropionyl-CoA
-
-
0.0011 - 0.0031
3-hydroxy-3-methylglutaryl-CoA
0.0071 - 0.014
3-oxohexanoyl-CoA
0.00126 - 0.242
acetoacetyl-CoA
0.033
Butyryl-CoA
-
pH 8.0
0.038 - 0.08
CoA
0.0027
decanoyl-CoA
-
pH 8.0
0.03 - 0.07
desulfo-CoA
0.012 - 0.013
DL-3-hydroxy-3-methylglutaryl-CoA
0.1
DL-3-methylglutaryl-CoA
-
pH 8.0
0.11
glutaryl-CoA
-
pH 8.0
0.0123
heptanoyl-CoA
-
pH 8.0
0.022
Hexanoyl-CoA
-
pH 8.0
0.00057 - 0.7
hymeglusin
0.0000537
L-659,699
-
-
0.004
nonanoyl-CoA
-
pH 8.0
0.0081
Octanoyl-CoA
-
pH 8.0
0.0005
palmityl-CoA
-
-
0.005
propionyl-CoA
-
pH 8.0
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000035
F-244
Brassica juncea
-
IC50: 35 nM
0.00032
hymeglusin
Cricetinae
-
IC50: 0.00032 mM, inhibitor binds to the thiol residue of Cys
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.00083
-
mitochondrial pellet
0.00133
-
mitochondrial pellet, 0.25 M sucrose
0.00245
-
disrupted mitochondria, 0.25 M sucrose
0.00288
-
mitochondrial pellet, 0.50 M sucrose
0.00325
-
mitochondrial pellet, 0.88 M sucrose
0.00485
-
homogenate
0.00567
-
disrupted mitochondria, 0.50 M sucrose
0.00792
-
disrupted mitochondria, 0.88 M sucrose
0.00922
-
mitochondrial supernatant
0.00958
-
mitochondrial supernatant, 0.88 M sucrose
0.0101
-
-
0.01053
-
mitochondrial supernatant, 0.50 M sucrose
0.0111
-
mitochondrial supernatant, 0.25 M sucrose
0.035
activity in response to acetaminophen, APAP, treatment
0.057
control, no acetaminophen, APAP, treatment
0.5 - 1
-
liver enzyme
0.65
-
cytoplasmic enzyme, isozyme III and IV
0.76
-
-
0.8 - 1
-
recombinant enzyme
0.88
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.2
activity assay
9.2
-
synthase II
9.3
-
synthase I
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 9.5
-
pH 7.5: about 60% of maximal activity, pH 9.5: about 30% of maximal activity
7.75 - 9.5
-
-
8 - 9.6
-
-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
24
-
activity assay, A412 nm assay
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30 - 45
-
about 70% of maximal activity at 30C and at 45C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
enzyme is a direct target of c-Myc, which represses hydroxymethylglutaryl-CoA synthase transcriptional activity
Manually annotated by BRENDA team
-
developmental regulation
Manually annotated by BRENDA team
-
of adults
Manually annotated by BRENDA team
-
HMGS2 is well expressed
Manually annotated by BRENDA team
-
HMGS2 is poorly expressed
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
anterior midgut, topically applied juvenile hormone III induced enzyme mRNA levels up to 6.5fold
Manually annotated by BRENDA team
-
HMGS2 is well expressed
Manually annotated by BRENDA team
-
developmental regulation
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Myxococcus xanthus (strain DK 1622)
Myxococcus xanthus (strain DK 1622)
Myxococcus xanthus (strain DK 1622)
Myxococcus xanthus (strain DK 1622)
Staphylococcus aureus (strain MW2)
Staphylococcus aureus (strain MW2)
Staphylococcus aureus (strain MW2)
Streptococcus mutans serotype c (strain ATCC 700610 / UA159)
Streptococcus mutans serotype c (strain ATCC 700610 / UA159)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
51040
-
predicted from cDNA sequence
53000
-
SDS-PAGE
55500
-
SDS-PAGE
56000
-
recombinant enzyme, epressed in Escherichia coli
56800
determined by MALDI-TOF mass spectrometry
57250
-
deduced amino acid sequence
57290
-
deduced amino acid sequence
57370
-
deduced amino acid sequence
57490
-
deduced amino acid sequence
57600
-
SDS-PAGE
83900
-
analytical ultracentrifugation
84300
-
calculated from amino acid sequence
88000
-
gel filtration
90000
-
gel filtration, synthase I
94000 - 100000
-
gel filtration, synthase II
94600
-
sedimentation equilibrium
96000 - 105000
-
gel filtration, mitochondrial synthase
96000
-
gel filtration
100000
105000
-
sedimentation equlibrium
111000
-
gel filtration
116000
-
gel filtration
119300
-
sedimentation velocity and light-scattering
120000
-
gel filtration
130000
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
bound covalently via Cys 117 to inhibitor (E,E)-11-(3-hydroxymethyl-4-oxo-2-oxytanyl)-3,5,7-trimethyl-2,4-undecadienoic acid, and in complex with acetyl-CoA and hydroxymethylglutaryl-CoA
-
in complex with hymeglusin, hanging drop vapor diffusion method, using 0.1 M Bis-Tris (pH 6.3-6.5), 0.2 M NaCl, and 23% (w/v) polyethylene glycol 3350
mutant A110G. Amide nitrogen of mutants S308 shifts 0.4 A toward the catalytic site cysteine residue stabilizing the intermediate negative charge. The hydroxyl group of S308 rotates to a position where it is able to stabilize the carbanion intermediate of the acetyl-S-enzyme during its condensation with acetoacetyl-CoA
-
unliganded and in complex with its second substrate/inhibitor acetoacetyl-CoA. The acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and acetoacetate covalently bound to the active site cysteine through a thioester bond
-
in complex with Co-A, sitting drop vapor diffusion method, using 0.1 M Bis-Tris (pH 6.5), 25% (w/v) polyethylene glycol (PEG) 3350, 0.2 M ammonium sulfate, at 4C; in complex with (S)-3-hydroxy-3-methylglutaryl-CoA, sitting drop vapor diffusion method, using 0.2 M ammonium sulfate, 0.1 M Bis-Tris (pH 6.5), 25% (w/v) PEG 3350, at 20C
sitting-drop vapour-diffusion method, crystal strcuture of full-length enzyme expressed in Escherichia coli is determined at 2.0 A resolution, crystal structure of HMG-CoA synthase with acetoacetyl-CoA is determined at 2.5 A resolution
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45
in the presence of an excess of acetyl-CoA, the half-life of the active enzyme is 27 h
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
can be rapidly frozen in solid CO2/acetone and freeze-dried for long-term storage, not stable to freezing and thawing in absence of glycerol
-
enzyme is labile to freezing and thawing, stabilized by glycerol
-
enzyme is vulnerable to proteolysis, expression in Escherichia coli leads to an quite stable enzyme
-
relatively stable dialyzed against 10 mM potassium phosphate in 0.1 mM dithiothreitol and EDTA for 4-10 days
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20, stored in presence of dithiothreitol and 30-50% glycerol purified enzyme retains complete activity for up to 3 months
-
-20C, may be stored in 30% glycerin solution for 2-3 months with no loss of activity
-
-20C, purified synthase may be stored for 2-3 months with little loss of activity by adding 30% glyerol
-
-20C, stored in presence of 30% glycerol and 5 mM dithiothreitol, remains active for several months
-
-80C, recombinant enzyme, negligible loss of activity after 1 year
-
-85C, in presence of 30% glycerol stable for over 1 year
-
-90C, purified synthases II-IV in 20 mM potassium phosphate, pH 7.0, 5 mM dithiothreitol, can be stored as pellets following precipitation by 60% saturated ammonium sulfate up to 3 months without loss of activity
-
0C, purified synthase I stored frozen in 40% glycerol containing 20 mM potassium phosphate, pH 7.0, 5 mM dithiothreitol, stable for 3-4 months
-
4C, enzyme loses activity in absence of glycerol
-
4C, in presence of 30% glycerol stable for several days
-
4C, purified synthase I stored in 40% glycerol containing 20 mM potassium phosphate, pH 7.0, 5 mM dithiothreitol is unstable
-
4C, purified synthases II-IV in 20 mM potassium phosphate, pH 7.0, 5 mM dithiothreitol, stable for several weeks
-
4C, recombinant enzyme, loses 50% activity after 1 year
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cytosolic synthase
-
mitochondria are prepared
mitochondrial form
-
Ni-Sepharose resin column chromatography and Superdex 200 gel filtration; Ni-Sepharose resin column chromatography and Superdex 200 gel filtration
Ni2+-NTA Sepharose column chromatography and Resource Q anion-exchange column chromatography
partially
recombinant
recombinant enzyme
recombinant enzyme, expressed in Escherichia coli
-
several mutants partially purified
-
synthase species I-IV
-