Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis.
Nature
; 624(7990): 182-191, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-37938780
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plantas
/
Anidrases Carbônicas
/
Alcaloides
/
Modelos Neurológicos
Limite:
Animals
Idioma:
En
Revista:
Nature
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos