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Information on EC 1.1.1.88 - hydroxymethylglutaryl-CoA reductase
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EC Tree
1.1.1.88 hydroxymethylglutaryl-CoA reductaseSpecify your search results
Word Map
- 1.1.1.88
- cholesterol
- statin
- lipoprotein
- simvastatin
- sterol
-
low-density
- coronary
- cardiovascular
- lovastatin
- hypercholesterolemia
- pravastatin
- atorvastatin
-
lipid-lowering
-
cholesterol-lowering
- 3-hydroxy-3-methylglutaryl-coa
- cerivastatin
- mevinolin
-
alpha-hydroxylase
-
statin-induced
- compactin
- mevalonolactone
- cholestyramine
- mevalonii
-
lipoprotein-deficient
- medicine
- 25-hydroxycholesterol
-
fibric
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Reaction Schemes
+
+
2
=
+
2
+
2
Synonyms
hydroxymethylglutaryl-coa reductase, hydroxymethylglutaryl coenzyme a reductase, 3-hydroxy-3-methylglutaryl-coenzyme-a reductase, 3-hydroxy-3-methylglutaryl coa reductase 1, mt hmgr1, nadh-dependent hmg-coa reductase, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-hydroxy-3-methylglutaryl coenzyme A reductase
beta-hydroxy-beta-methylglutaryl CoA-reductase
-
-
-
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beta-hydroxy-beta-methylglutaryl coenzyme A reductase
-
-
-
-
HMG-CoA reductase
HMGR
hydroxymethylglutaryl coenzyme A reductase
-
-
-
-
NADH-dependent HMG-CoA reductase
3-hydroxy-3-methylglutaryl coenzyme A reductase
-
-
-
-
HMG-CoA reductase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(R)-mevalonate + CoA + 2 NAD+ = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
reaction mechanism purposal
-
(R)-mevalonate + CoA + 2 NAD+ = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
There are two classes of enzyme, the third enzyme of the mevalonate pathway of isopentenyl diphosphate biosynthesis: the class I enzymes of eukaryotes and the class II enzymes of certain eubacteria
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(R)-mevalonate + CoA + 2 NAD+ = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
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-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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-
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oxidative acylation
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-
-
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redox reaction
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-
-
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reduction
-
-
-
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reductive deacylation
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
(R)-mevalonate:NAD+ oxidoreductase (CoA-acylating)
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CAS REGISTRY NUMBER
COMMENTARY
37250-24-1
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(R)-mevalonate + CoA + NADP+
3-hydroxy-3-methylglutaryl-CoA + NADPH + H+
-
-
-
-
r
3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
(R)-mevalonate + CoA + 2 NADP+
-
extremely low activity with NADPH
-
-
?
DL-mevaldate + CoA + NAD+
3-hydroxy-3-methylglutaryl-CoA NADH + H+
-
-
-
-
r
DL-mevaldate + CoA + NAD+
4-hydroxy-3-methylglutaryl-CoA NADH + H+
-
-
-
-
r
DL-mevaldate + CoA + NAD+
5-hydroxy-3-methylglutaryl-CoA NADH + H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
NAD(H) is the preferred cofactor
-
-
r
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
with mevalonate as sole source of carbon enzyme acts as a biodegradative enzyme
-
-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
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with mevalonate as sole source of carbon enzyme acts as a biodegradative enzyme
-
-
r
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
Burkholderia cenocepacia 32315
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
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mevalonate is required for cholesterol and isoprenoid synthesis
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-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
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-
-
-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
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mevalonate is first commited intermediate in polyisoprenoid synthesis
-
-
?
3-hydroxy-3-methyl-glutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
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-
-
-
?
3-hydroxy-3-methyl-glutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
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mevalonate pathway
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-
?
3-hydroxy-3-methyl-glutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
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-
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
(R)-mevalonate + CoA + 2 NAD+
-
-
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
(R)-mevalonate + CoA + 2 NAD+
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the enzyme is highly specific for NADH
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-
?
3-hydroxy-3-methylglutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
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-
-
-
?
3-hydroxy-3-methylglutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
-
-
-
-
r
DL-mevalonate + CoA + NADP+
3-hydroxy-3-methylglutaryl-CoA + NADPH + H+
-
-
-
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r
DL-mevalonate + CoA + NADP+
3-hydroxy-3-methylglutaryl-CoA + NADPH + H+
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-
-
-
r
additional information
?
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the substrates of the reductive reaction, HMG-CoA and NADH, both demonstrate sigmoidal behavior typical of positive cooperativity
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-
?
additional information
?
-
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The enzyme can play a role in indole alkaloid biosynthesis and a possible cosuppression of both the endogenous and foreign enzyme genes in clone 236
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-
?
additional information
?
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oxidative acylation of mevalonate: the carboxy-, 3-methyl-, and 3-hydroxy groups are essential for substrate binding to the enzyme
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-
?
additional information
?
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oxidative acylation of mevalonate: the carboxy-, 3-methyl-, and 3-hydroxy groups are essential for substrate binding to the enzyme
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-
?
additional information
?
-
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oxidative acylation of mevalonate: the carboxy-, 3-methyl-, and 3-hydroxy groups are essential for substrate binding to the enzyme
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-
?
additional information
?
-
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oxidative acylation of mevalonate: the carboxy-, 3-methyl-, and 3-hydroxy groups are essential for substrate binding to the enzyme
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-
?
additional information
?
-
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The biosynthetic pathway leading to plant cytosolic isoprenoids begins with the 3-hydroxy-3-methyl-glutaryl CoA reductase-mediated production of mevalonate
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-hydroxy-3-methyl-glutaryl-CoA + NADH + H+
mevalonate + CoA + NAD+
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mevalonate pathway
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-
?
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
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-
-
r
(R)-mevalonate + CoA + 2 NAD+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
?
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
Burkholderia cenocepacia 32315
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-
-
?
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(R)-mevalonate + CoA + 2 NAD+
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
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mevalonate is required for cholesterol and isoprenoid synthesis
-
-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
-
-
-
-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADH + H+
(R)-mevalonate + NAD+ + CoA
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mevalonate is first commited intermediate in polyisoprenoid synthesis
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
(R)-mevalonate + CoA + 2 NAD+
-
-
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADH + 2 H+
(R)-mevalonate + CoA + 2 NAD+
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the enzyme is highly specific for NADH
-
-
?
additional information
?
-
-
The enzyme can play a role in indole alkaloid biosynthesis and a possible cosuppression of both the endogenous and foreign enzyme genes in clone 236
-
-
?
additional information
?
-
-
The biosynthetic pathway leading to plant cytosolic isoprenoids begins with the 3-hydroxy-3-methyl-glutaryl CoA reductase-mediated production of mevalonate
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADP+
-
NAD+ is 600000fold more efficient than NADP+ in wild-type enzyme
NAD+
-
-
287495, 287496, 287497, 287498, 287499, 287501, 287502, 287504, 287505, 287506, 287508, 657303, 723092
NADH
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reverse reaction
additional information
-
very detailed kinetic studies of mutants concerning NAD+/NADP+-affinities, the best specificity improvement is achieved by the D146A/L148R-mutant
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additional information
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sequence comparisons of several species with class II (NAD(H)) and class I (NADP(H)) HMG-CoA reductases for analysis of cofactor binding, overview
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additional information
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sequence comparisons of several species with class II (NAD(H)) and class I (NADP(H)) HMG-CoA reductases for analysis of cofactor binding, overview
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additional information
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sequence comparisons of several species with class II (NAD(H)) and class I (NADP(H)) HMG-CoA reductases for analysis of cofactor binding, specificity-determining residue of HMGR from Pseudomonas mevalonii is D646, overview
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additional information
the enzyme prefers NAD(H) over NADP(H) as a cofactor, suggesting an oxidative physiological role for the enzyme
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-(3-methylbutanoyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-[[(E)-2-phenylethenyl]sulfonyl]-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
(3S,6Z)-3-benzyl-4-(3,3-dimethylbutanoyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
(3S,6Z)-4-(biphenyl-4-ylsulfonyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3-methyl-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
citrate
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competitive inhibition with respect to 3-hydroxy-3-methylglutaryl-CoA
lovastatin
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pharmacological inhibition of HMGR activities decreases nodule number and delays nodulation
simvastatin
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treatment prevents endotoxemic liver injury by inhibiting leukocyte infiltration and hepatocellular apoptosis. The protective effects are dependent on the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-(3-methylbutanoyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
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purified enzyme, 52.6% residual activity at 0.01 mM
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-(3-methylbutanoyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
antiproliferative activity in L-1210 cell, IC50 0.00148 mM
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-[[(E)-2-phenylethenyl]sulfonyl]-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
purified enzyme, 32.3% residual activity at 0.01 mM
(3S,6Z)-3-benzyl-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-4-[[(E)-2-phenylethenyl]sulfonyl]-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
antiproliferative activity in L-1210 cell, IC50 0.0023 mM
(3S,6Z)-3-benzyl-4-(3,3-dimethylbutanoyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
purified enzyme, 43.4% residual activity at 0.01 mM
(3S,6Z)-3-benzyl-4-(3,3-dimethylbutanoyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
antiproliferative activity in L-1210 cell, IC50 0.00143 mM
(3S,6Z)-4-(biphenyl-4-ylsulfonyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3-methyl-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
purified enzyme, 54.4% residual activity at 0.01 mM
(3S,6Z)-4-(biphenyl-4-ylsulfonyl)-1-(4-fluorobenzyl)-8-(4-methoxyphenyl)-3-methyl-3,4,5,8-tetrahydro-1,4-diazocin-2(1H)-one
-
antiproliferative activity in L-1210 cell, IC50 0.00119 mM
acetoacetate
-
competivive inhibitor vs. mevalonate, non inhibitory vs. NAD+
mevalonate
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the addition of reaction product results in a dramatic loss of immunoreactive enzyme
additional information
-
peptic and tryptic soybean hydrolysates (2.5 mg/ml) inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase activity in Hep-G2 cells by 16% and 76.9%, respectively
-
additional information
-
no inhibition citrate, succinate, glutarate, 3,3-dimethylacrylate, 2,2-dimethylpropionate, acetoacetate
-
additional information
-
no inhibition citrate, succinate, glutarate, 3,3-dimethylacrylate, 2,2-dimethylpropionate, acetoacetate
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
docosahexaenoic acid ethyl ester
-
in 18-month-old aged mice but not in 8-month-old mice, HMG-CoA reductase activity is enhanced with dietary intake of docosahexaenoic acid ethyl ester (DHA-EE)
mevastatin
-
The increased accumulation of the enzyme-FLAG using the open-ring form and the closed-ring form of mevastatin is observed. The mevastatin-induced enzyme increases are possibly explained by the inhibition of a feedback-regulated down-regulation due to lowered pools of mevalonate or its product
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.078
(S)-3-hydroxy-3-methylglutaryl-CoA
pH and temperature not specified in the publication
0.00734
3-hydroxy-3-methylglutaryl-CoA
-
at pH 7.4, temperature not specified in the publication
additional information
additional information
kinetic analysis, overview. The enzyme exhibits positive cooperativity toward the substrates of the reductive reaction, but the oxidative reaction exhibits unusual double-saturation kinetics, distinctive among characterized HMG-CoA reductases. The unusual kinetics may arise from the presence of multiple active oligomeric states, each with different Vmax values
-
0.27
(R,S)-mevalonate
-
H381A mutant, oxidative acylation of mevalonate
0.45
(R,S)-mevalonate
-
wild-type enzyme, oxidative acylation of mevalonate
0.71
(R,S)-mevalonate
-
H381Q mutant, oxidative acylation of mevalonate
0.75
(R,S)-mevalonate
-
H381K mutant, oxidative acylation of mevalonate
0.05
DL-3-hydroxy-3-methylglutaryl-CoA
-
reductive deacylation to mevalonate
0.3
DL-3-hydroxy-3-methylglutaryl-CoA
-
reductive deacylation to mevalonate
0.072
NADH
pH and temperature not specified in the publication
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
22.3
3-hydroxy-3-methylglutaryl-CoA
-
at pH 7.4, temperature not specified in the publication
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3040
3-hydroxy-3-methylglutaryl-CoA
-
at pH 7.4, temperature not specified in the publication