Information on EC 1.1.1.218 - morphine 6-dehydrogenase

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

EC NUMBER
COMMENTARY hide
1.1.1.218
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RECOMMENDED NAME
GeneOntology No.
morphine 6-dehydrogenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
morphine + NAD(P)+ = morphinone + NAD(P)H + H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dehydrogenation
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-
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oxidation
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redox reaction
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-
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reduction
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Isoquinoline alkaloid biosynthesis
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Biosynthesis of secondary metabolites
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morphine biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
morphine:NAD(P)+ 6-oxidoreductase
Also acts on some other alkaloids, including codeine, normorphine and ethylmorphine, but only very slowly on 7,8-saturated derivatives such as dihydromorphine and dihydrocodeine. In the reverse direction, also reduces naloxone to the 6alpha-hydroxy analogue. Activated by 2-mercaptoethanol.
CAS REGISTRY NUMBER
COMMENTARY hide
106640-77-1
deleted Reg.No.
97002-71-6
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain Hartley
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Manually annotated by BRENDA team
strain Hartley
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Wistar
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Manually annotated by BRENDA team
Wistar
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
physiological function
mammalian morphine 6-dehydrogenase converts morphine into a reactive electrophile, morphinone. M6DH is involved in the toxic action of morphine including the development of tolerance to this drug
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1-indanol + NADP+
1-indanone + NADPH
show the reaction diagram
-
-
-
-
?
3-hydroxyhexobarbital + NADP+
?
show the reaction diagram
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does not serve as a substrate for guinea pig enzyme
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-
?
benzenedihydrodiol + NADP+
?
show the reaction diagram
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-
-
-
?
codeine + NAD(P)+
codeinone + NAD(P)H
show the reaction diagram
codeine + NADP+
codeinone + NADPH
show the reaction diagram
cyclohexene-2-ol + NADP+
cyclohexene-2-one + NADPH
show the reaction diagram
-
-
-
-
?
dihydrocodeine + NADP+
dihydrocodeinone + NADPH
show the reaction diagram
ethylmorphine + NAD(P)+
?
show the reaction diagram
morphine + NAD(P)+
morphinone + NAD(P)H
show the reaction diagram
-
-
-
-
ir
morphine + NAD+
?
show the reaction diagram
-
-
-
?
morphine + NAD+
?+morphinone + NADH + H+
show the reaction diagram
-
-
-
?
morphine + NAD+
morphinone + NADH + H+s
show the reaction diagram
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-
-
?
morphine + NADP+
morphinone + NADPH
show the reaction diagram
morphine + NADP+
morphinone + NADPH + H+
show the reaction diagram
nalorphine + NAD(P)+
(5alpha)-3-hydroxy-17-(prop-2-en-1-yl)-7,8-didehydro-4,5-epoxymorphinan-6-one + NAD(P)H + H+
show the reaction diagram
naloxone + NAD(P)H
6alpha-naloxol + NADP+
show the reaction diagram
normorphine + NAD(P)+
?
show the reaction diagram
trans-1,4-decalindiol + NADP+
?
show the reaction diagram
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about 30% of the activity observed with morphine
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-
?
trans-naphthalene dihydrodiol + NAD+
?
show the reaction diagram
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-
-
?
trans-naphthalene dihydrodiol + NAD+
? + NADH + H+
show the reaction diagram
-
-
-
?
additional information
?
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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
codeine + NADP+
codeinone + NADPH
show the reaction diagram
morphine + NAD+
?
show the reaction diagram
A0A097ZMY7
-
-
-
?
morphine + NAD+
?+morphinone + NADH + H+
show the reaction diagram
J7M9D0
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-
-
?
morphine + NADP+
morphinone + NADPH
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NAD(P)+
NAD(P)H
NADP+
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the Pseudomonas enzyme acts only with NADP+
additional information
the rabbit enzyme shows high coenzyme preference for NAD+ over NADP+. Also in the reverse reaction, the enzymes reduces several alpha-dicarbonyl compounds including S-camphorquinone using NADH as the coenzyme, exhibiting low Km values of 0.004-0.006 mM. The reductase activity of the enzyme determined with NADPH as the coenzyme is less than 40% of their NADH-linked activity
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
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2,2'-dipyridyl
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5alpha-dihydrotestosterone
5beta-dihydrotestosterone
androsterone
Barbital
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1mM, 68% inhibition
CdCl2
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dithiol modifier, strong competitive inhibitor to cofactor
chenodeoxycholic acid
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0.1 mM, 24% inhibition
cholic acid
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0.1 mM, 10% inhibition
CuSO4
epiandrosterone
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0.1 mM, 77% inhibition
estradiol
Hexestrol
hinokitiol
ikarisoside A
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indomethacin
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1 mM, 84% inhibition
iodoacetate
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Ketamine
lithocholic acid
naloxone
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1mM, 61% inhibition
noranhydroicaritin
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p-chloromercuribenzoic acid
Phenolphthalein
Phenylarsine oxide
prostaglandin E1
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pyrazole
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1 mM, 20% inhibition
quercetin
quercitrin
testosterone
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-mercaptoethanol
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reversible
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.12
1-Indanol
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cosubstrate NAD+
0.92
3-hydroxyhexobarbital
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cosubstrate NAD+
0.002
5alpha-androstan-17beta-ol-3-one
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similar values of other 17beta-hydroxysteroids
1.75
benzenedihydrodiol
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cosubstrate NAD+
0.033 - 0.45
codeine
0.12
codeinone
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cosubstrate NADPH
0.54
cyclohexene-2-ol
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cosubstrate NAD+
0.39 - 2.91
Dihydrocodeine
0.4 - 1.54
ethylmorphine
0.12 - 5.5
morphine
0.02
NAD+
pH 7.4, 25C
0.0022 - 0.033
NADH
0.35
NADP+
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-
0.0065
NADPH
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-
0.015 - 0.048
nalorphine
0.27 - 0.44
naloxone
0.044 - 0.64
normorphine
0.009
testosterone
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cosubstrate NAD+
0.027
trans-naphthalene dihydrodiol
pH 7.4, 25C
additional information
additional information
Michaelis-Menten kinetics
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.49
morphine
pH 7.4, 25C
0.004
NAD+
pH 7.4, 25C
0.067
trans-naphthalene dihydrodiol
pH 7.4, 25C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0013 - 0.073
Hexestrol
0.0032 - 0.037
hinokitiol
0.05
icarisid II
Oryctolagus cuniculus
J7M9D0
above, pH 7.4, 25C, recombinant enzyme
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0.013
ikarisoside A
Oryctolagus cuniculus
J7M9D0
pH 7.4, 25C, recombinant enzyme
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0.02
kaempferol
Oryctolagus cuniculus
J7M9D0
above, pH 7.4, 25C, recombinant enzyme
0.0064
noranhydroicaritin
Oryctolagus cuniculus
J7M9D0
pH 7.4, 25C, recombinant enzyme
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0.00065 - 0.007
Phenolphthalein
0.026
quercetin
Oryctolagus cuniculus
J7M9D0
pH 7.4, 25C, recombinant enzyme
0.04
quercitrin
Oryctolagus cuniculus
J7M9D0
pH 7.4, 25C, recombinant enzyme
0.05
zearalenone
Oryctolagus cuniculus
J7M9D0
above, pH 7.4, 25C, recombinant enzyme
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.08
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morphine, NADP+
0.21
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morphine, NAD+
0.43
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morphine, NAD+
0.53
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morphine, NAD+
0.86
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morphine, NADP+
0.9
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naloxone, NADPH
2.67
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morphine, NADP+
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.2
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with NADH als cofactor, 67 mM sodium phosphate buffer
6.5
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in presence of NADPH reduction of codeinone to codeine, in MOPS buffer
6.8
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with NADPH as cofactor, 67 mM sodium phosphate buffer
8.6
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with NADP+ as cofactor, in glycine-NaCl-NaOH buffer
9.1
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with NADP+ as cofactor, in tricine-NaOH buffer
9.4
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with NAD+ as cofactor, in glycine-NaCl-NaOH buffer
9.5
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with NADP+ as cofactor, in glycine-NaOH buffer, oxidizing the C-6 hydroxy group of morphine and codeine
9.7
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with NAD+ as cofactor, in glycine-NaCl-NaOH buffer
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
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enzyme assay
37
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enzyme assay, reduction of naloxone
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
in male hamsters
Manually annotated by BRENDA team
in female hamsters
Manually annotated by BRENDA team
high expression level of AKR1C26
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
29000
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gel filtration
31990
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based on sequence data
36000
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denatured enzyme, SDS-PAGE
310000
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1 * 310000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
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in 50 mM sodium phosphate buffer + 100 mM 2-mercaptoethanol + NAD+ at least for a week stable at 2-4C
286281
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
2-mercaptoethanol stabilizes
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2-mercaptoethanol stabilizes during purification and storage, removal inactivates, reversible
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dithiothreitol stabilizes
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enzyme stable without 2-mercaptoethanol
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80C, 10% loss of activity over 2 months
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-80C, 20% glycerol, v/v, stable at least four months
2-4C, 50 mM sodium phosphate buffer + 100 mM 2-mercaptoethanol, pH 6., 90% of the activity retained with both NAD+ and NADP+ for a week
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4C, 80% of the activity after a week in 50 mM sodium phosphate buffer, pH 6.0, 100 mM 2-mercaptoethanol, more stable at pH 6.0 than at pH 8.0
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
gel filtration, various chromatographic techniques
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3)pLysS by nickel affinity chromatography, ultrafiltration, and dialysis
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
gene AKR1C26, DNA and amino acid sequence determination and analysis, sequence comparisons, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21(DE3)pLysS
gene AKR1C34, cloned from liver, DNA and amino acid sequence determination and analysis, sequence comparisons, recombinant expression of His-tagged enzyme in Escherichia coli strain BL21(DE3)pLysS
gene encoding morphine dehydrogenase on natural plasmid, expressed in Escherichia coli
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plasmid containing the gene for morphine dehydrogenase: pMDH1.7
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C80S
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change of cysteine to serine: significantly improved stability
D47N
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residue modified by site-directed mutagenesis, resulting in substantial loss of activity
K76M
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residue modified by site-directed mutagenesis, resulting in substantial loss of activity
C80S
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change of cysteine to serine: significantly improved stability
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D47N
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residue modified by site-directed mutagenesis, resulting in substantial loss of activity
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K76M
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residue modified by site-directed mutagenesis, resulting in substantial loss of activity
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Y52F
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F is incapable of acting as proton donor /aim: NAD+-dependent morphine dehydrogenase for biotransformation morphine-morphinone-hydromorphine, codeine-hydrocodone respectively (medically useful semisynthetic opiates); residue modified by site-directed mutagenesis, resulting in substantial loss of activity
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