Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis

Ryan S. Nett (), Yaereen Dho, Chun Tsai, Daria Passow, Jaime Martinez Grundman, Yun-Yee Low and Elizabeth S. Sattely ()
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Ryan S. Nett: Stanford University
Yaereen Dho: Stanford University
Chun Tsai: Stanford University
Daria Passow: Stanford University
Jaime Martinez Grundman: Harvard University
Yun-Yee Low: Universiti Malaya
Elizabeth S. Sattely: Stanford University

Nature, 2023, vol. 624, issue 7990, 182-191

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06716-y

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