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Literature summary extracted from

  • Li, Y.; Li, S.; Thodey, K.; Trenchard, I.; Cravens, A.; Smolke, C.
    Complete biosynthesis of noscapine and halogenated alkaloids in yeast (2018), Proc. Natl. Acad. Sci. USA, 115, E3922-E3931 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment 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 (Comment) 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 Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
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 Comment 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 Comment Substrates Organism Products Comment (Products) Rev. Reac.
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 (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 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
-
 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 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
-
 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 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
-
 Papaver somniferum (13S,14R)-13-O-acetyl-1-hydroxy-N-methylcanadine + CoA
-
 ?

Synonyms

EC Number Synonyms Comment 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 Comment 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

General Information

EC Number General Information Comment 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