Biosynthesis and synthetic biology of psychoactive natural products

Jamieson, Cooper S.; Misa, Joshua; Tang, Yi; Billingsley, John M

doi:10.1039/d1cs00065a

Cited by 43 publications

(29 citation statements)

References 455 publications

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“…Thus, both En CYP81AN15 and CYP82M3 yield (+)- 7 from S - 3 and not (−)- 7 from R - 3 . Besides, R - 3 may undergo a dynamic kinetic resolution as R - 3 could be converted to S - 3 via the opening of a pyrrolidine ring (a retro aza-Michael/aza-Michael reaction) (Figure a). , Alternatively, spontaneous decarboxylation of unreacted R - 3 would lead to hygrine ( 11 ), which is also present in high concentrations in Erythroxylaceae plants …”

Section: Resultsmentioning

confidence: 99%

Discovery and Engineering of the Cocaine Biosynthetic Pathway

et al. 2022

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Cocaine, the archetypal tropane alkaloid from the plant genus Erythroxylum, has recently been used clinically as a topical anesthesia of the mucous membranes. Despite this, the key biosynthetic step of the requisite tropane skeleton (methylecgonone) from the identified intermediate 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid (MPOA) has remained, until this point, unknown. Herein, we identify two missing enzymes (EnCYP81AN15 and EnMT4) necessary for the biosynthesis of the tropane skeleton in cocaine by transient expression of the candidate genes in Nicotiana benthamiana. Cytochrome P450 EnCYP81AN15 was observed to selectively mediate the oxidative cyclization of S-MPOA to yield the unstable intermediate ecgonone, which was then methylated to form optically active methylecgonone by methyltransferase EnMT4 in Erythroxylum novogranatense. The establishment of this pathway corrects the longstanding (but incorrect) biosynthetic hypothesis of MPOA methylation first and oxidative cyclization second. Notably, the de novo reconstruction of cocaine was realized in N. benthamiana with the two newly identified genes, as well as four already known ones. This study not only reports a near-complete biosynthetic pathway of cocaine and provides new insights into the metabolic networks of tropane alkaloids (cocaine and hyoscyamine) in plants but also enables the heterologous synthesis of tropane alkaloids in other (micro)organisms, entailing significant implications for pharmaceutical production.

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Section: Resultsmentioning

confidence: 99%

Discovery and Engineering of the Cocaine Biosynthetic Pathway

et al. 2022

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“…Other challenges are oxygen delivery or using enzymes in flow. 602,605−609 The examples for a broad use of biocatalysts in API synthesis presented here indicate only the beginning of a prosperous future of biocatalysis: the identification of novel useful reactivities will be fueled by reactivities identified in the biosynthetic pathways continuously elucidated 610,611 and will be facilitated by the broad diversity of tools for enzyme identification, such as metagenomics, computational enzyme search and design, and (in-silico) high-throughput library screenings. 612−614 To get the biocatalyst fit for large-scale applications, rapid methods to evolve the catalysts need to be improved and will enable us to address the challenges of the large-scale synthesis, such as enzyme stability or inhibition, and to improve the tolerance of the enzyme to organic solvents or cosolvents, which are needed for substrate solubilization.…”

Section: Discussionmentioning

confidence: 99%

“…The examples for a broad use of biocatalysts in API synthesis presented here indicate only the beginning of a prosperous future of biocatalysis: the identification of novel useful reactivities will be fueled by reactivities identified in the biosynthetic pathways continuously elucidated , and will be facilitated by the broad diversity of tools for enzyme identification, such as metagenomics, computational enzyme search and design, and ( in-silico ) high-throughput library screenings. − …”

Section: Discussionmentioning

confidence: 99%

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

et al. 2021

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Biocatalysis, using enzymes for organic synthesis, has emerged as powerful tool for the synthesis of active pharmaceutical ingredients (APIs). The first industrial biocatalytic processes launched in the first half of the last century exploited whole-cell microorganisms where the specific enzyme at work was not known. In the meantime, novel molecular biology methods, such as efficient gene sequencing and synthesis, triggered breakthroughs in directed evolution for the rapid development of process-stable enzymes with broad substrate scope and good selectivities tailored for specific substrates. To date, enzymes are employed to enable shorter, more efficient, and more sustainable alternative routes toward (established) small molecule APIs, and are additionally used to perform standard reactions in API synthesis more efficiently. Herein, large-scale synthetic routes containing biocatalytic key steps toward >130 APIs of approved drugs and drug candidates are compared with the corresponding chemical protocols (if available) regarding the steps, reaction conditions, and scale. The review is structured according to the functional group formed in the reaction.

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“…It will also provide valuable guidance for enzymatic specificity determination and enzyme characterization. Whenever it was established that the polysaccharide biosynthesis cluster comprises cloning the entire biosynthesis cluster into a suitable heterologous host, recombinant development can be envisaged [ 78 ]. This is a modern approach established in accordance with the growth of synthetic biology [ 79 , 80 , 81 ].…”

Section: Targeted Polysaccharides Structures Modifications With Molecular Biology Toolsmentioning

confidence: 99%

Recent Advancements in Microbial Polysaccharides: Synthesis and Applications

et al. 2021

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Polysaccharide materials are widely applied in different applications including food, food packaging, drug delivery, tissue engineering, wound dressing, wastewater treatment, and bioremediation sectors. They were used in these domains due to their efficient, cost-effective, non-toxicity, biocompatibility, and biodegradability. As is known, polysaccharides can be synthesized by different simple, facile, and effective methods. Of these polysaccharides are cellulose, Arabic gum, sodium alginate, chitosan, chitin, curdlan, dextran, pectin, xanthan, pullulan, and so on. In this current article review, we focused on discussing the synthesis and potential applications of microbial polysaccharides. The biosynthesis of polysaccharides from microbial sources has been considered. Moreover, the utilization of molecular biology tools to modify the structure of polysaccharides has been covered. Such polysaccharides provide potential characteristics to transfer toxic compounds and decrease their resilience to the soil. Genetically modified microorganisms not only improve yield of polysaccharides, but also allow economically efficient production. With the rapid advancement of science and medicine, biosynthesis of polysaccharides research has become increasingly important. Synthetic biology approaches can play a critical role in developing polysaccharides in simple and facile ways. In addition, potential applications of microbial polysaccharides in different fields with a particular focus on food applications have been assessed.

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Biosynthesis and synthetic biology of psychoactive natural products

Abstract: The biosynthetic logic employed by Nature in the construction of psychoactive natural products is reviewed, in addition to biological activities, methodologies enabling pathway discovery, and engineering applications.

Cited by 43 publications

References 455 publications

Discovery and Engineering of the Cocaine Biosynthetic Pathway

Discovery and Engineering of the Cocaine Biosynthetic Pathway

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

Recent Advancements in Microbial Polysaccharides: Synthesis and Applications

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