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Curated Papers > In recent years, high-impact research in "synthetic biology" (IF≥30, past 5 years)

Biosynthesis and synthetic biology of psychoactive natural products. ​

Literature Information ​

DOI10.1039/d1cs00065a
PMID33908526
JournalChemical Society reviews
Impact Factor39.0
JCR QuartileQ1
Publication Year2021
Times Cited20
KeywordsBiosynthesis, Psychoactive Natural Products, Synthetic Biology, Metabolic Engineering
Literature TypeJournal Article, Review
ISSN0306-0012
Pages6950-7008
Issue50(12)
AuthorsCooper S Jamieson, Joshua Misa, Yi Tang, John M Billingsley

TL;DR ​

This review highlights the recent advancements in understanding the biosynthetic pathways of psychoactive natural products, including hallucinogens, stimulants, cannabinoids, and opioids, by leveraging genomics and molecular biology tools to identify key enzymes and mechanisms involved in their synthesis. The findings underscore the potential for these biosynthetic pathways to be applied in synthetic biology and metabolic engineering, enhancing the production of complex natural compounds with significant medicinal and sociocultural relevance.

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Biosynthesis · Psychoactive Natural Products · Synthetic Biology · Metabolic Engineering

Abstract ​

Psychoactive natural products play an integral role in the modern world. The tremendous structural complexity displayed by such molecules confers diverse biological activities of significant medicinal value and sociocultural impact. Accordingly, in the last two centuries, immense effort has been devoted towards establishing how plants, animals, and fungi synthesize complex natural products from simple metabolic precursors. The recent explosion of genomics data and molecular biology tools has enabled the identification of genes encoding proteins that catalyze individual biosynthetic steps. Once fully elucidated, the "biosynthetic pathways" are often comparable to organic syntheses in elegance and yield. Additionally, the discovery of biosynthetic enzymes provides powerful catalysts which may be repurposed for synthetic biology applications, or implemented with chemoenzymatic synthetic approaches. In this review, we discuss the progress that has been made toward biosynthetic pathway elucidation amongst four classes of psychoactive natural products: hallucinogens, stimulants, cannabinoids, and opioids. Compounds of diverse biosynthetic origin - terpene, amino acid, polyketide - are identified, and notable mechanisms of key scaffold transforming steps are highlighted. We also provide a description of subsequent applications of the biosynthetic machinery, with an emphasis placed on the synthetic biology and metabolic engineering strategies enabling heterologous production.

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Primary Questions Addressed ​

  1. What are the specific biosynthetic pathways for different classes of psychoactive natural products, and how do they compare in terms of complexity and efficiency?
  2. How can the identification of biosynthetic enzymes be leveraged to enhance the production of psychoactive compounds through synthetic biology?
  3. What role do genomics and molecular biology tools play in the discovery and characterization of biosynthetic pathways for psychoactive natural products?
  4. How do metabolic engineering strategies differ when applied to the production of hallucinogens versus cannabinoids or opioids?
  5. What are the potential applications of heterologous production systems in the development of new psychoactive compounds or therapeutic agents?

Key Findings ​

Research Background and Purpose ​

Psychoactive natural products, derived from plants, fungi, and animals, have significant medicinal and sociocultural implications. The complexity of these compounds and their biosynthetic pathways has garnered substantial interest, particularly in the context of synthetic biology and metabolic engineering. This review aims to synthesize recent advancements in understanding the biosynthesis of four classes of psychoactive natural products: hallucinogens, stimulants, cannabinoids, and opioids.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive analysis of biosynthetic pathways for psychoactive natural products, utilizing recent genomic data and molecular biology techniques to elucidate the enzymatic processes involved. The authors emphasize the importance of identifying key enzymes and metabolic pathways, enabling the heterologous production of these compounds.

Technical Route ​

Mermaid diagram

Key Results and Findings ​

  1. Hallucinogens: Pathways for compounds like psilocybin and DMT were elucidated, revealing critical enzymatic steps and potential therapeutic applications.
  2. Stimulants: The biosynthesis of caffeine and nicotine was characterized, highlighting the importance of specific enzymes in their metabolic pathways.
  3. Cannabinoids: Cannabigerolic acid (CBGA) serves as a precursor for THC and CBD, with the review detailing the enzymatic transformations leading to these compounds.
  4. Opioids: The review outlines the complex pathways from simple precursors to morphine and its derivatives, emphasizing the significance of specific P450 enzymes in the biosynthesis.

Main Conclusions/Significance/Innovation ​

The review underscores the intricate relationship between natural product biosynthesis and synthetic biology, demonstrating how understanding these pathways can facilitate the development of sustainable production methods for psychoactive compounds. It advocates for a more nuanced view of the therapeutic potential of these substances, particularly in light of evolving legal and ethical considerations.

Research Limitations and Future Directions ​

The review acknowledges limitations in fully elucidating all biosynthetic pathways and the regulatory challenges surrounding psychoactive natural products. Future research should focus on:

  • Expanding the understanding of enzyme functions and interactions.
  • Developing robust heterologous systems for the production of complex natural products.
  • Addressing ethical and legal frameworks to facilitate research and application in medicinal contexts.

This synthesis of knowledge positions the field for significant advancements in the sustainable production and therapeutic application of psychoactive natural products.

References ​

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Literatures Citing This Work ​

  1. Recent Advancements in Microbial Polysaccharides: Synthesis and Applications. - Yehia A-G Mahmoud;Mehrez E El-Naggar;Ahmed Abdel-Megeed;Mohamed El-Newehy - Polymers (2021)
  2. Engineered Production of Strictosidine and Analogues in Yeast. - Joshua Misa;John M Billingsley;Kanji Niwa;Rachel K Yu;Yi Tang - ACS synthetic biology (2022)
  3. Leveraging yeast to characterize plant biosynthetic gene clusters. - Yinan Wu;Franklin L Gong;Sijin Li - Current opinion in plant biology (2023)
  4. Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart. - Hannes Jacob;Pauline Braekow;Rebecca Schwarz;Christian Höhm;Uwe Kirchhefer;Britt Hofmann;Joachim Neumann;Ulrich Gergs - International journal of molecular sciences (2023)
  5. Investigation of Small-Molecule Constituents in Voacanga africana Seeds and Mapping of Their Spatial Distributions Using Laser Ablation Direct Analysis in Real-Time Imaging-Mass Spectrometry (LADI-MS). - Allix Marie Coon;Rabi Ann Musah - ACS omega (2023)
  6. Unveiling the Psychedelic Journey: An Appraisal of Psilocybin as a Profound Antidepressant Therapy. - Fatima Iftikhar Shah;Somia Shehzadi;Fatima Akram;Ikram Ul Haq;Benish Javed;Sadeed Sabir;Yasha Kazim;Sehrish Ashfaq - Molecular biotechnology (2025)
  7. Aconitine and its derivatives: bioactivities, structure-activity relationships and preliminary molecular mechanisms. - Pengyu Zhao;Ye Tian;Yuefei Geng;Chenjuan Zeng;Xiuying Ma;Jie Kang;Lin Lu;Xin Zhang;Bo Tang;Funeng Geng - Frontiers in chemistry (2024)
  8. Polyphenolic Platform Ameliorated Sanshool for Skin Photoprotection. - Tianyou Wang;Linghong Guo;Shuwei Wu;Yuanyuan Xu;Junmei Song;Yi Yang;Hengjie Zhang;Dongcui Li;Yiwen Li;Xian Jiang;Zhipeng Gu - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
  9. Effects of hallucinogenic drugs on the human heart. - Joachim Neumann;Stefan Dhein;Uwe Kirchhefer;Britt Hofmann;Ulrich Gergs - Frontiers in pharmacology (2024)
  10. The protective effect of natural medicines in rheumatoid arthritis via inhibit angiogenesis. - Chang Gao;Xiao-Di Song;Fang-Hui Chen;Gui-Lin Wei;Chun-Yu Guo - Frontiers in pharmacology (2024)

... (10 more literatures)

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