A pyridoxal 5'-phosphate-dependent Mannich cyclase

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

doi:10.1038/s41929-023-00963-y

A pyridoxal 5'-phosphate-dependent Mannich cyclase

Journal Article · Thu Jun 08 00:00:00 EDT 2023 · Nature Catalysis

DOI:https://doi.org/10.1038/s41929-023-00963-y· OSTI ID:2005075

Gao, Jinmin ^[1]; Liu, Shaonan ^[1]; Zhou, Chen ^[1]; Lara, Darwin ^[1]; ^[2]; ^[1]

Univ. of California, Santa Barbara, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Pyridoxal 5'-phosphate (PLP)-dependent enzymes catalyse a diverse range of chemical transformations. Despite their extraordinary functional diversity, no PLP-dependent enzyme is known to catalyse Mannich-type reactions, an important carbon–carbon bond-forming reaction in synthetic organic chemistry. Here we report the discovery of a biosynthetic enzyme LolT, a PLP-dependent enzyme catalysing a stereoselective intramolecular 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, crystallographic and mutagenesis analysis and computational studies together provided mechanistic insights and structural basis for understanding LolT’s catalytic activity and stereoselectivity. As a whole, this work expands the biocatalytic repertoire of carbon–carbon bond-forming enzymes and increases our knowledge of the catalytic versatility of PLP-dependent enzymes.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: NIH; NSF; USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515; AC52-07NA27344

OSTI ID:: 2005075

Report Number(s):: LLNL-JRNL--839219; 1059916

Journal Information:: Nature Catalysis, Journal Name: Nature Catalysis Journal Issue: 6 Vol. 6; ISSN 2520-1158

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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A pyridoxal 5'-phosphate-dependent Mannich cyclase

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