Products Cited in Publications Worldwide A pyridoxal 5'-phosphate-dependent Mannich cyclase

A pyridoxal 5'-phosphate-dependent Mannich cyclase

Gao, Jinmin; Liu, Shaonan; Zhou, Chen; Lara, Darwin; Zou, Yike; Hai, Yang

DOI:

Abstract

Pyridoxal 5′-phosphate (PLP)-dependent enzymes catalyze a diverse range of chem. transformations. Despite their extraordinary functional diversity, no PLP-dependent enzyme is known to catalyze Mannich-type reactions, an important carbon-carbon bond-forming reaction in synthetic organic chem. Here we report the discovery of a biosynthetic enzyme LolT, a PLP-dependent enzyme catalyzing a stereoselective intramol. Mannich reaction to construct the pyrrolizidine core scaffold in loline alkaloids. Importantly, its versatile catalytic activity is harnessed for stereoselective synthesis of a variety of conformationally constrained α,α-disubstituted α-amino acids, which bear vicinal quaternary-tertiary stereocentres and various aza(bi)cyclic backbones, such as indolizidine, quinolizidine, pyrrolidine and piperidine. Furthermore, crystallog. and mutagenesis anal. and computational studies together provided mechanistic insights and structural basis for understanding LolT′s catalytic activity and stereoselectivity. Overall, this work expands the biocatalytic repertoire of carbon-carbon bond-forming enzymes and increases our knowledge of the catalytic versatility of PLP-dependent enzymes.

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