美国斯坦福大学Sattely, Elizabeth S.团队报道了植物类碳酸酐酶在神经活性生物碱生物合成中的作用。相关研究成果发表在2023年11月8日出版的国际知名学术期刊《自然》。

植物合成许多模拟动物神经递质的生物碱。生物碱结构的多样性是通过产生和剪裁独特的碳支架来实现的，然而许多神经活性生物碱属于一类支架，其生物合成途径或酶催化剂尚不清楚。

通过研究产生神经活性石松生物碱的植物中高度协调的组织特异性基因表达，研究人员确定了一类意想不到的生物碱生物合成酶：新功能化α-碳酸酐酶（CAHs）。研究人员发现，在石松生物碱的关键前体的生物合成途径中，通过催化立体特异性Mannich样缩合和随后的双环支架的产生，需要三种CAH样（CAL）蛋白。此外，研究人员描述了一系列支架剪裁步骤，这些步骤产生了石杉碱A5的最佳乙酰胆碱酯酶抑制活性。

研究结果表明，CAH样酶在专门的代谢中有更广泛的参与，并证明了连续的支架剪裁如何提高对抗神经蛋白质靶点的效力。研究人员展示了棒状苔藓中的神经活性生物碱是如何生物合成的，揭示了碳酸酐酶样酶在生物碱支架形成中的意想不到的作用。

附：英文原文

Title: Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis

Author: Nett, Ryan S., Dho, Yaereen, Tsai, Chun, Passow, Daria, Martinez Grundman, Jaime, Low, Yun-Yee, Sattely, Elizabeth S.

Issue&Volume: 2023-11-08

Abstract: Plants synthesize numerous alkaloids that mimic animal neurotransmitters1. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds2,3, yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids4, we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A5. Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target. We show how neuroactive alkaloids from clubmosses are biosynthesized, which reveals an unexpected role for carbonic anhydrase-like enzymes in alkaloid scaffold formation.

DOI: 10.1038/s41586-023-06716-y

Source: https://www.nature.com/articles/s41586-023-06716-y