BRENDA - Enzyme Database

Complete biosynthesis of noscapine and halogenated alkaloids in yeast

Li, Y.; Li, S.; Thodey, K.; Trenchard, I.; Cravens, A.; Smolke, C.; Proc. Natl. Acad. Sci. USA 115, E3922-E3931 (2018) View publication on PubMedView publication on EuropePMC

Data extracted from this reference:

Application
EC Number
Application
Commentary
Organism
1.1.1.415
synthesis
complete biosynthesis of noscapine and halogenated alkaloids in yeast and optimizing noscapine production toward scalable manufacturing. Engineered strain contains 25 heterologous plant, bacteria, and mammalian genes and 6 mutant or overexpressed yeast genes. The noscapine biosynthetic pathway incorporates seven endomembrane-localized plant enzymes, highlighting the ability of the yeast to functionally express and properly localize large numbers of heterologous enzymes into the endoplasm reticulum. Noscapine titers were improved by 18000fold (to low mg/l levels) via a combination of enzyme engineering, pathway and strain engineering, and fermentation optimization. Microbial fermentation can be used to produce halogenated alkaloid derivatives, which can ultimately serve as potential drug leads, through feeding amino acid derivatives to strains
Papaver somniferum
1.14.14.163
synthesis
de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself, including 7 plant endoplasmic reticulum (ER)-localized enzymes. Optimization directed to tuning expression of pathway enzymes, host endogenous metabolic pathways, and fermentation conditions led to an over 18,000-fold improvement from initial noscapine titers to 2.2 mg/l
Papaver somniferum
2.3.1.285
synthesis
de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself. Optimization of conditions leads to an over 18,000fold improvement from initial noscapine titers to about2.2 mg/l. By feeding modified tyrosine derivatives to the optimized noscapine-producing strain, microbial production of halogenated benzylisoquinoline alkaloids is possible
Papaver somniferum
Cloned(Commentary)
EC Number
Cloned (Commentary)
Organism
1.1.1.415
Saccharomyces cerevisiae CSY1060 and CSY1061 strains are used as the base strain for construction of the de novo noscapine biosynthetic strains
Papaver somniferum
1.14.14.166
expression in Saccharomyces cerevisiae
Papaver somniferum
Natural Substrates/ Products (Substrates)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
ID
1.1.1.415
narcotine hemiacetal + NAD+
Papaver somniferum
-
noscapine + NADH + H+
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine is a 10-gene cluster
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
Organism
EC Number
Organism
UniProt
Commentary
Textmining
1.1.1.415
Papaver somniferum
I3PLR3
-
-
1.14.14.163
Papaver somniferum
I3PLR0
-
-
1.14.14.166
Papaver somniferum
I3PLR1
-
-
1.14.14.167
Papaver somniferum
I3V6B7
-
-
2.3.1.285
Papaver somniferum
I3PLR4
-
-
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
Substrate Product ID
1.1.1.415
narcotine hemiacetal + NAD+
-
749191
Papaver somniferum
noscapine + NADH + H+
-
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
749191
Papaver somniferum
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine is a 10-gene cluster
749191
Papaver somniferum
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
2.3.1.285
acetyl-CoA + (13S,14R)-1,13-dihydroxy-N-methylcanadine
-
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + CoA
-
-
-
?
Synonyms
EC Number
Synonyms
Commentary
Organism
1.1.1.415
SDR1
-
Papaver somniferum
1.1.1.415
short-chain dehydrogenase/reductase
-
Papaver somniferum
1.14.14.163
1-hydroxy-N-methylcanadine 13-hydroxylase
-
Papaver somniferum
1.14.14.163
CYP82X2
-
Papaver somniferum
1.14.14.166
1-hydroxy-N-methylcanadine synthase
-
Papaver somniferum
1.14.14.166
CYP82Y1
-
Papaver somniferum
1.14.14.167
1-hydroxy-13-O-acetyl-N-methylcanadine 8-hydroxylase
-
Papaver somniferum
1.14.14.167
CYP82X1
-
Papaver somniferum
Cofactor
EC Number
Cofactor
Commentary
Organism
Structure
1.14.14.166
cytochrome P-450
heme-thiolate enzyme
Papaver somniferum
1.14.14.167
cytochrome P-450
heme-thiolate enzyme
Papaver somniferum
Application (protein specific)
EC Number
Application
Commentary
Organism
1.1.1.415
synthesis
complete biosynthesis of noscapine and halogenated alkaloids in yeast and optimizing noscapine production toward scalable manufacturing. Engineered strain contains 25 heterologous plant, bacteria, and mammalian genes and 6 mutant or overexpressed yeast genes. The noscapine biosynthetic pathway incorporates seven endomembrane-localized plant enzymes, highlighting the ability of the yeast to functionally express and properly localize large numbers of heterologous enzymes into the endoplasm reticulum. Noscapine titers were improved by 18000fold (to low mg/l levels) via a combination of enzyme engineering, pathway and strain engineering, and fermentation optimization. Microbial fermentation can be used to produce halogenated alkaloid derivatives, which can ultimately serve as potential drug leads, through feeding amino acid derivatives to strains
Papaver somniferum
1.14.14.163
synthesis
de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself, including 7 plant endoplasmic reticulum (ER)-localized enzymes. Optimization directed to tuning expression of pathway enzymes, host endogenous metabolic pathways, and fermentation conditions led to an over 18,000-fold improvement from initial noscapine titers to 2.2 mg/l
Papaver somniferum
2.3.1.285
synthesis
de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself. Optimization of conditions leads to an over 18,000fold improvement from initial noscapine titers to about2.2 mg/l. By feeding modified tyrosine derivatives to the optimized noscapine-producing strain, microbial production of halogenated benzylisoquinoline alkaloids is possible
Papaver somniferum
Cloned(Commentary) (protein specific)
EC Number
Commentary
Organism
1.1.1.415
Saccharomyces cerevisiae CSY1060 and CSY1061 strains are used as the base strain for construction of the de novo noscapine biosynthetic strains
Papaver somniferum
1.14.14.166
expression in Saccharomyces cerevisiae
Papaver somniferum
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
1.14.14.166
cytochrome P-450
heme-thiolate enzyme
Papaver somniferum
1.14.14.167
cytochrome P-450
heme-thiolate enzyme
Papaver somniferum
Natural Substrates/ Products (Substrates) (protein specific)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
ID
1.1.1.415
narcotine hemiacetal + NAD+
Papaver somniferum
-
noscapine + NADH + H+
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine is a 10-gene cluster
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
Papaver somniferum
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
?
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
ID
1.1.1.415
narcotine hemiacetal + NAD+
-
749191
Papaver somniferum
noscapine + NADH + H+
-
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.163
(S)-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
749191
Papaver somniferum
(13S,14R)-1,13-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.166
(S)-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine is a 10-gene cluster
749191
Papaver somniferum
(S)-1-hydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
-
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1.14.14.167
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + [reduced NADPH-hemoprotein reductase] + O2
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1,8-dihydroxy-N-methylcanadine + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
2.3.1.285
acetyl-CoA + (13S,14R)-1,13-dihydroxy-N-methylcanadine
-
749191
Papaver somniferum
(13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + CoA
-
-
-
?
General Information
EC Number
General Information
Commentary
Organism
1.14.14.163
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum
1.14.14.166
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum
1.14.14.167
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum
General Information (protein specific)
EC Number
General Information
Commentary
Organism
1.14.14.163
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum
1.14.14.166
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum
1.14.14.167
metabolism
the enzyme participates in the biosynthesis of the isoquinoline alkaloid noscapine
Papaver somniferum