Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy

Dastmalchi, Mehran; Chen, Xue; Hagel, Jillian M.; Chang, Lihong; Chen, Rongji; Ramasamy, Sukanya; Yeaman, Sam; Facchini, Peter J.

doi:10.1038/s41589-019-0247-0

Cited by 68 publications

(104 citation statements)

References 38 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…A target of 5 g L −1 has been set forth for commercial-scale production of opioids 16 and although our titers are commensurate with this benchmark, morphine is synthesized several enzymatic steps downstream of (S)-reticuline. The efficiency of these reactions within a high titer production host remains unknown, yet the recent discovery of dedicated thebaine and neopinone biosynthetic enzymes 43,44 primes our engineered yeast for production of opioid pharmaceuticals at scale. Beyond BIAs, our microbial production platform also enables the production of diverse THIQ molecules and could be leveraged to identify new medicines derived from the THIQ structural moiety.…”

Section: Discussionmentioning

confidence: 99%

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

et al. 2020

View full text Add to dashboard Cite

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L −1 , a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.

show abstract

Section: Discussionmentioning

confidence: 99%

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

et al. 2020

View full text Add to dashboard Cite

show abstract

“…175 Recently, two more PR10s involved in BIA biosynthesis have been identied: thebaine synthase 176 and neopinone isomerase. 177 Outside BIA metabolism, PR10s have roles in defence responses 178 and binding intermediates in secondary metabolism pathways. 179,180 NCS contains an N-terminal signal peptide, which targets the enzyme to the vacuole via the endoplasmic reticulum.…”

Section: Aromatic Amino-acid Derivedmentioning

confidence: 99%

“…This has been highlighted recently with the identication of enzymes for steps in BIA biosynthesis previously thought to be spontaneous. 176,177 Enzymes that have evolved to catalyse a "spontaneous" reaction are somewhat unusual in that they oen evolve from protein families with no obvious connection to the reaction or pathway (e.g. NCS, SS).…”

Section: Enzyme Evolutionmentioning

confidence: 99%

The scaffold-forming steps of plant alkaloid biosynthesis

Lichman

2021

Nat. Prod. Rep.

131

View full text Add to dashboard Cite

show abstract

“…Although our titers are commensurate with this benchmark, morphine is synthesized several enzymatic steps downstream of (S)-reticuline. The efficiency of these reactions within a high titer production host remains unknown, yet the recent discovery of dedicated thebaine and neopinone biosynthetic enzymes 41,42 primes our engineered yeast for production of opioid pharmaceuticals at scale.…”

Section: Discussionmentioning

confidence: 99%

A yeast platform for high-level synthesis of natural and unnatural tetrahydroisoquinoline alkaloids

Kevvai

Ps³

et al. 2019

Preprint

View full text Add to dashboard Cite

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogues. The plant kingdom manufactures more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space.Here we report a THIQ platform by increasing yeast production of the central BIA intermediate (S)-reticuline to more than 3 g L -1 , a 38,000-fold improvement over our first-generation strain.Gains in BIA output coincided with the formation of several substituted THIQs derived from host amino acid catabolism. Enabled by this activity, we repurposed the yeast Ehrlich pathway and demonstrate the synthesis of an array of unnatural THIQ scaffolds. This work provides a blueprint for synthesizing new privileged structures and will enable the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.

show abstract

Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy

Cited by 68 publications

References 38 publications

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

The scaffold-forming steps of plant alkaloid biosynthesis

A yeast platform for high-level synthesis of natural and unnatural tetrahydroisoquinoline alkaloids

Contact Info

Product

Resources

About