酶
生物合成
碳酸酐酶
生物化学
生物碱
化学
立体专一性
生物
立体化学
催化作用
作者
Ryan S. Nett,Yaereen Dho,Chun J. Tsai,Daria Passow,Jaime E. Martinez Grundman,Yun‐Yee Low,Elizabeth S. Sattely
出处
期刊:Nature
[Nature Portfolio]
日期:2023-11-08
卷期号:624 (7990): 182-191
被引量:23
标识
DOI:10.1038/s41586-023-06716-y
摘要
Abstract Plants synthesize numerous alkaloids that mimic animal neurotransmitters 1 . The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds 2,3 , 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 alkaloids 4 , 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 A 5 . 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.
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