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Information on EC 1.21.3.3 - reticuline oxidase
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EC Tree
1.21.3.3 reticuline oxidaseIUBMB Comments
Contains FAD. The enzyme from the plant Eschscholtzia californica binds the cofactor covalently . Acts on (S)-reticuline and related compounds, converting the N-methyl group into the methylene bridge ('berberine bridge') of (S)-tetrahydroprotoberberines. The product of the reaction, (S)-scoulerine, is a precursor of protopine, protoberberine and benzophenanthridine alkaloid biosynthesis in plants.
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Word Map
- 1.21.3.3
- poppy
- sanguinarine
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s-reticuline
-
s-scoulerine
- papaver
-
benzylisoquinoline
- somniferum
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opium
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benzophenanthridine
- codeinone
- cyp80b1
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eschscholtzia
- papaveraceae
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vanillyl
-
flavinylated
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3\'-hydroxylase
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s-norcoclaurine
- synthesis
- medicine
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
berberine bridge enzyme, berberine bridge enzyme-like, flavin-dependent oxidase, reticuline oxidase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
BBE
berberine bridge enzyme
berberine bridge enzyme-like
berberine-bridge-forming enzyme
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EC 1.5.3.9
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formerly
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tetrahydroprotoberberine synthase
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BBE
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berberine bridge enzyme
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(S)-reticuline + O2 = (S)-scoulerine + H2O2
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
oxidative cyclization
redox reaction
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reduction
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oxidation
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
(S)-reticuline:oxygen oxidoreductase (methylene-bridge-forming)
Contains FAD. The enzyme from the plant Eschscholtzia californica binds the cofactor covalently [3]. Acts on (S)-reticuline and related compounds, converting the N-methyl group into the methylene bridge ('berberine bridge') of (S)-tetrahydroprotoberberines. The product of the reaction, (S)-scoulerine, is a precursor of protopine, protoberberine and benzophenanthridine alkaloid biosynthesis in plants.
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CAS REGISTRY NUMBER
COMMENTARY
152232-28-5
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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
(S)-coreximine + O2
(13aS)-2,11-dihydroxy-3,10-dimethoxy-5,8,13,13a-tetrahydroisoquinolino[3,2-a]isoquinolin-7-ium + H2O2
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?
1-(2-fluoro-3-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol + O2
(13aS)-12-fluoro-3-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-2,11-diol + H2O
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49% conversion, more than 99% of product (13aS)-12-fluoro-3-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-2,11-diol
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?
1-(2-fluoro-3-hydroxybenzyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol + O2
(13aS)-12-fluoro-2-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-3,11-diol + H2O
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49% conversion, more than 99% of product (13aS)-12-fluoro-2-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-3,11-diol
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?
1-(3-hydroxy-4-methoxybenzyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol + O2
(13aS)-2,10-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-3,9-diol + isocoreximine + H2O2
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53% conversion, ratio (13aS)-2,10-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-3,9-diol to isocoreximine is 98:2
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?
1-(3-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol + O2
(13aS)-3-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-2,9-diol + (1R)-1-(3-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol + H2O2
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reaction leads to the (S)-enantiomer of the product and enantiomerically pure (R)-substrate. 22% yield of (13aS)-3-methoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-2,9-diol in more than 97% enantiomeric excess, 549% yield of + (1R)-1-(3-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-olin more than 97% enantiomeric excess
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?
1-[(4-chlorophenyl)methyl]-2-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline + O2
(1S)-1-[(4-chlorophenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline + (1R)-1-[(4-chlorophenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline + H2O2
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?
2-ethyl-6,7-dimethoxy-1-[(3-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + O2
(1S)-6,7-dimethoxy-1-[(3-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + (1R)-6,7-dimethoxy-1-[(3-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + H2O2
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?
2-ethyl-6,7-dimethoxy-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + O2
(1S)-6,7-dimethoxy-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + (1R)-2-ethyl-6,7-dimethoxy-1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline + H2O2
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?
3-[(2-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]phenol + O2
3-[[(1S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol + 3-[[(1R)-2-ethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol + H2O2
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?
3-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]phenol + O2
(13aS)-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-9-ol + 3-[[(1R)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol + H2O2
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reaction leads to the (S)-enantiomer of the product and enantiomerically pure (R)-substrate. 46% yield of (13aS)-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-9-ol in more than 97% enantiomeric excess, 49% yield of + 3-[[(1R)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol in more than 97% enantiomeric excess
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?
3-[(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]-2-fluorophenol + O2
(13aS)-12-fluoro-2,3-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-11-ol + H2O
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48% conversion, more than 99% of product (13aS)-12-fluoro-2,3-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-11-ol
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?
3-[(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]phenol + O2
(13aS)-2,3-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-9-ol + 3-[[(1R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol + H2O2
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reaction leads to the (S)-enantiomer of the product and enantiomerically pure (R)-substrate. 42% yield of (13aS)-2,3-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-9-ol in more than 97% enantiomeric excess, 50% yield of + 3-[[(1R)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]phenol in more than 97% enantiomeric excess
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?
4-coumaryl alcohol + O2
4-coumaryl aldehyde + H2O2
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6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline + H2O2
? + O2
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?
6-ethyl-5-[(4-methoxyphenyl)methyl]-5,6,7,8-tetrahydro-2H-[1,3]dioxolo[4,5-g]isoquinoline + O2
(5S)-5-[(4-methoxyphenyl)methyl]-5,6,7,8-tetrahydro-2H-[1,3]dioxolo[4,5-g]isoquinoline + (5R)-5-[(4-methoxyphenyl)methyl]-5,6,7,8-tetrahydro-2H-[1,3]dioxolo[4,5-g]isoquinoline + H2O2
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?
reticuline + O2
(S)-scoulerine + (S)-coreximine + H2O2
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50% conversion, ratio (S)-scoulerine to (S)-coreximine is >99 to <1
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?
(R,S)-laudanosoline + O2
? + H2O2
Berberis beaniana
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specific for the (S)-enantiomer
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?
(R,S)-laudanosoline + O2
? + H2O2
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specific for the (S)-enantiomer
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
Berberis beaniana
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reticuline is the biogenic precursor of the protoberine skeleton
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
highest activity
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of benzophenanthridine alkaloid biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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the enzyme is involved in the biosynthetic pathway for benzophenanthridine alkaloids in California poppy, Eschscholzia californica, cells, related alkaloids, overview
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
(S)-scoulerine is further oxidized to dehydroscoulerine in a second oxidation step
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first committed step in sanguinarine biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of benzophenanthridine alkaloid biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
additional information
?
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C-H bond cleavage is rate-limiting during flavin reduction. Solvent isotope effects on kred indicate that solvent exchangeable protons are not in flight during or before flavin reduction, thus eliminating a fully concerted mechanism. Deprotonation is not occurring before or during C-H bond cleavage, and a hydroxyl group must be present at C3 for cyclization. This could be due to the methoxy group being less electron-donating than a hydroxyl substituent or to disruption of the interaction between the glutamate and the substrate, causing altered binding. A concerted attack of a methyl amine by the C2-atom and hydride transfer is less likely than attack on a methylene iminium ion intermediate by the C2-atom, indicating that a stepwise mechanism is the likely mechanism
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?
additional information
?
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enzyme employs an enantioselective oxidative C-C bond formation
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?
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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
(S)-reticuline + O2
(S)-scoulerine + H2O2
Berberis beaniana
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reticuline is the biogenic precursor of the protoberine skeleton
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of benzophenanthridine alkaloid biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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the enzyme is involved in the biosynthetic pathway for benzophenanthridine alkaloids in California poppy, Eschscholzia californica, cells, related alkaloids, overview
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first committed step in sanguinarine biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of benzophenanthridine alkaloid biosynthesis
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
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first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
(S)-reticuline + O2
(S)-scoulerine + H2O2
first step of isoquinoline and benzophenanthridine alkaloid biosynthesis, involved in sanguinarine pathway
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?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
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covalently attached to enzyme at 8alpha position to H104 and also at 6 position to thiol group of C166. anaerobic photoirradiation leads to cleavage of the linkage to C166 yielding 6-mercaptoflavin and a peptide with C replaced by A due to breakage of the C-S bond
FAD
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residues His104 and Cys166, which are involved in the bi-covalent attachment of FAD to berberine bridge enzyme
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
expression of protein is enhanced by treatment with Botrytis cinerea homogenate
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additional information
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expression of protein is enhanced by treatment with Botrytis cinerea homogenate
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Infections
A transcriptomic approach highlights induction of secondary metabolism in citrus fruit in response to Penicillium digitatum infection.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
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steady-state kinetic analysis, and redox potentials for both wild type and C166A mutant enzyme are +132 mV and +53 mV, respectively, rapid reaction stopped-flow experiments, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8.9
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
9 - 10
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
overview of occurence of BBE in Berberidaceae, Ranunculaceae, Menispermaceae, Papaveraceae and Fumariaceae
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brenda
three genes, only one is expressed, Botrytis elicitor induces mRNA expression
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brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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gene transcripts are restricted to the protoderm of leaf primordia. Cell-type specific localization of protoberberine alkaloid biosynthesis and accumulation are temporally and spatially separated in roots and rhizomes, resp.
brenda
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sieve elements of root and hypocotyl, abundance of enzyme increases rapidly between 1 and 3 days of germination
brenda
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gene transcripts are localized to immature epidermis, pericycle, and partially to adjacent cortical cells. Cell-type specific localization of protoberberine alkaloid biosynthesis and accumulation are temporally and spatially separated in roots and rhizomes, resp.
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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vacuolar pH is below the functional range of BBE, it is active only before the entry into the vacuole, enters vacuole via a sorting determinant
brenda