Information on EC 1.1.1.34 - hydroxymethylglutaryl-CoA reductase (NADPH) and Organism(s) Homo sapiens

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Homo sapiens


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


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
1.1.1.34
-
RECOMMENDED NAME
GeneOntology No.
hydroxymethylglutaryl-CoA reductase (NADPH)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(R)-mevalonate + CoA + 2 NADP+ = (S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
isoprene biosynthesis II (engineered)
-
-
mevalonate pathway I
-
-
mevalonate pathway II (archaea)
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-
mevalonate pathway III (archaea)
-
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mevalonate metabolism
-
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Terpenoid backbone biosynthesis
-
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Metabolic pathways
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Biosynthesis of secondary metabolites
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Biosynthesis of antibiotics
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SYSTEMATIC NAME
IUBMB Comments
(R)-mevalonate:NADP+ oxidoreductase (CoA-acylating)
The enzyme is inactivated by EC 2.7.11.31 {[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase} and reactivated by EC 3.1.3.47 {[hydroxymethylglutaryl-CoA reductase (NADPH)]-phosphatase}.
CAS REGISTRY NUMBER
COMMENTARY hide
9028-35-7
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(R)-mevalonate + CoA + 2 NADP+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
show the reaction diagram
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
(R)-mevalonate + CoA + 2 NADP+
show the reaction diagram
-
-
-
-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADPH
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + NADPH
mevaldyl-CoA + NADP+
show the reaction diagram
-
first step reaction
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
mevalonate + CoA + 2 NADP+
show the reaction diagram
-
-
-
-
r
3-hydroxy-3-methylglutaryl-CoA + NADPH
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
-
-
-
?
3-hydroxy-3-methylglutaryl-CoA + NADPH
mevalonate + CoA + NADP+
show the reaction diagram
-
-
-
?
mevaldehyde + NADPH + H+
(R)-mevalonate + NADP+
show the reaction diagram
-
-
-
-
?
mevaldyl-CoA + NADPH + H+ + H2O
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
second step reaction
-
-
?
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
(R)-mevalonate + CoA + 2 NADP+
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
show the reaction diagram
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
(R)-mevalonate + CoA + 2 NADP+
show the reaction diagram
-
-
-
-
?
(S)-3-hydroxy-3-methylglutaryl-CoA + NADPH
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
-
-
-
r
(S)-3-hydroxy-3-methylglutaryl-CoA + NADPH
mevaldyl-CoA + NADP+
show the reaction diagram
-
first step reaction
-
-
?
3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H+
mevalonate + CoA + 2 NADP+
show the reaction diagram
-
-
-
-
r
3-hydroxy-3-methylglutaryl-CoA + NADPH
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
-
-
-
?
mevaldyl-CoA + NADPH + H+ + H2O
(R)-mevalonate + CoA + NADP+
show the reaction diagram
-
second step reaction
-
-
?
additional information
?
-
-
the reaction is a highly regulated process within the cholesterol biosynthetic pathway
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-
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(S)-4-carboxy-3-hydroxy-3-methylbutyryl-CoA
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competitive inhibitor
(S)-4-carboxy-3-hydroxybutyryl-CoA
-
competitive inhibitor
3,3-dimethylglutaryl-CoA
-
competitive inhibitor
3-Hydroxyglutaryl-CoA
-
competitive inhibitor
3-methylglutaryl-CoA
-
competitive inhibitor
AFGYVAE
-
-
atorvastatin
brutieridin
-
i.e. hesperetin 7-(2''-alpha-rhamnosyl-6''-(3''''-hydroxy-3''''-methylglutaryl)-beta-D-glucoside), a flavonoid conjugate from bergamot fruit extract, structural analogue of statins, computational study, overview
ceramide
-
treatment with exogenous ceramides, or increasing the endogenous ceramide levels inhibits HMGCR by 6080%
cerivastatin
-
-
cycloheximide
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downregulation of protein synthesis, synergistic with eicosapentanoic acid and myristic acid
DFGYVAE
-
-
EFGYVAE
-
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eicosapentaenoic acid
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inhibits translation of the enzyme about 50% at 0.15 mM, downregulation, slightly increases downregulation of protein synthesis by cycloheximide
FFGYVAE
-
-
FFYVAE
-
-
FG-(4-fluoro)FVAE
-
-
FGYVAE
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-
fluvastatin
FPYVAE
-
-
GFGYVAE
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-
IAVPTGVA
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-
IFGYVAE
-
-
Ile-Ala-Val-Glu
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-
Ile-Ala-Val-Pro-Gly-Glu-Val-Ala
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Ile-Val-Ala-Glu
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-
Leu-Pro-Tyr-Pro
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-
LFGYVAE
-
-
lovastatin
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-
melitidin
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i.e. naringenin 7-(2''-alpha-rhamnosyl-6''-(3''''-hydroxy-3''''-methylglutaryl)-beta-D-glucoside), a flavonoid conjugate from bergamot fruit extract, structural analogue of statins, computational study, overview
mevastatin
-
-
PFGYVAE
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pravastatin
rosuvastatin
SFGYVAE peptide
-
most active inhibitory peptide; shows high ability to inhibit HMGR by competitive inhibition with respect to (S)-3-hydroxy-3-methylglutaryl-CoA
simvastatin
SMase C
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treatment of fibroblasts with SMase C results in a 90% inhibition of HMGCR
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SMase D
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treatment of fibroblasts with SMase D inhibits by 29%
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TFGYVAE
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-
Tyr-Ala-Val-Glu
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Tyr-Val-Ala-Glu
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VFGYVAE
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-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
myristic acid
-
stimulates translation of the enzyme about 1.8fold at 0.15 mM, upregulation
additional information
-
phosphorylation of HMGCR is stimulated by SMase C or exogenous ceramide
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.07 - 0.6
3-hydroxy-3-methylglutaryl-CoA
0.021
NADPH
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000008 - 0.000014
atorvastatin
0.0000057 - 0.00001
cerivastatin
0.000028 - 0.000256
fluvastatin
0.000044 - 0.000103
pravastatin
0.0000023 - 0.0000035
rosuvastatin
0.000012
SFGYVAE peptide
-
pH and temperature not specified in the publication
0.000011
simvastatin
-
-
additional information
additional information
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00049
AFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.00016
DFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.00024
EFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.00032
FFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.0025
FFYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.0085
FG-(4-fluoro)FVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.0004
FGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.0014
FPYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.00027
GFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.152
IAVPTGVA
Homo sapiens;
-
pH and temperature not specified in the publication
0.00035
IFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.075
Ile-Ala-Val-Glu
Homo sapiens;
-
pH and temperature not specified in the publication
0.201
Ile-Ala-Val-Pro-Gly-Glu-Val-Ala
Homo sapiens;
-
pH and temperature not specified in the publication
0.052
Ile-Val-Ala-Glu
Homo sapiens;
-
pH and temperature not specified in the publication
0.484
Leu-Pro-Tyr-Pro
Homo sapiens;
-
pH and temperature not specified in the publication
0.00037
LFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.00043
PFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.000033
SFGYVAE peptide
Homo sapiens;
-
pH and temperature not specified in the publication
0.00026
TFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
0.044
Tyr-Ala-Val-Glu
Homo sapiens;
-
pH and temperature not specified in the publication
0.041
Tyr-Val-Ala-Glu
Homo sapiens;
-
pH and temperature not specified in the publication
0.00045
VFGYVAE
Homo sapiens;
-
pH and temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8
-
assay at
7.5
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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samples of patients with cardiovascular disorders
Manually annotated by BRENDA team
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recombinant enzyme
Manually annotated by BRENDA team
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colon cancer cell line
Manually annotated by BRENDA team
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NCTC 2544 cells. HMG-CoA reductase and peroxisome proliferator-activated receptor alpha are involved in clofibrate-induced apoptosis in human keratinocytes
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
transmembrane protein
Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
52000 - 56000
-
proteolytically cleaved soluble enzyme fragment
96000
-
intact membrane protein
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
the catalytic portion of human HMG-CoA, after cleavage of the probable dimeric form found in the endoplasmic reticulum, 18 crystallized as a dimer of dimers. However, the dimer-dimer interface is distant from the active site and only the dimer of the molecule seems crucial for catalysis
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
-
phosphoprotein
-
activity is regulated by phosphorylation and dephosphorylation
proteolytic modification
-
proteolysis releases a soluble, active fragment of 52-56 kDa
additional information
-
genistein, eicosapentaenoic acid and docosahexaenoic acid down-regulate reductase activity, primarily through posttranscriptional effects
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
analysis of the enzyme crystal structure (PDV ID 1DQA) at 2.0 A resolution
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cDNA encoding the wild-type and mutant forms of human HMG-CoA reductase expressed under control of the yeast MET25 promoter in a Saccharomyces cerevisiae strain with deletions of both HMG1 and HMG2
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Q766H
-
restores viability of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes, thus is catalytically active in yeast cells. Q766H mutation, which affects the structure of the catalytic domain, increases the sensitivity of the enzyme towards statin treatment
R393Q
-
restores viability of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes, thus is catalytically active in yeast cells. R393Q mutation does not change the properties of the enzyme towards statin treatment
additional information
-
expression of human HMG-CoA reductase in yeast complements the lethal phenotype of Saccharomyces cerevisiae strains lacking the HMG1 and HMG2 genes
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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a yeast expression system can serve to study the influence of selected mutations in human HMG-CoA reductase on the sensitivity of the enzyme to commonly prescribed statins, thus this model system is suitable for the development and selection of lipid-lowering drugs as well as for the examination of DNA sequence variations in the context of statin therapy
medicine