Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
Chem Soc Rev. 2021 Jun 21;50(12):6950-7008. doi: 10.1039/d1cs00065a.
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.
精神活性天然产物在现代世界中起着不可或缺的作用。这些分子所表现出的巨大结构复杂性赋予了它们多样化的生物活性，具有重要的药用价值和社会文化影响。因此，在过去的两个世纪中，人们付出了巨大的努力，试图了解植物、动物和真菌如何从简单的代谢前体合成复杂的天然产物。最近基因组学数据和分子生物学工具的爆炸式增长，使得能够鉴定出编码催化单个生物合成步骤的蛋白质的基因。一旦完全阐明，这些“生物合成途径”在优雅性和产率方面往往可与有机合成相媲美。此外，生物合成酶的发现为合成生物学应用提供了强大的催化剂，或者可以通过化学生物酶合成方法来实现。在这篇综述中，我们讨论了在四类精神活性天然产物（致幻剂、兴奋剂、大麻素和阿片类药物）的生物合成途径阐明方面所取得的进展。确定了具有不同生物合成来源的化合物（萜类、氨基酸、聚酮），并强调了关键支架转化步骤的显著机制。我们还描述了生物合成机制的后续应用，重点介绍了使异源生产成为可能的合成生物学和代谢工程策略。
