The Diels-Alder reaction is a chemical process where a conjugated diene reacts with a dienophile to form cyclohexene.This reaction can generate up to four adjacent chiral centers and two carbon-carbon bonds simultaneously,making it an effective method to form C—C bonds.Therefore,it has attracted wide attention.Hetero-Diels-Alder(HDA)reactions,which involve heteroatoms,are an important tool for synthesizing natural heterocyclic rings.HAD reaction types are classified according to the heteroatoms involved,with the most common types being oxa Diels-Alder reaction and aza Diels-Alder reaction.At present,non-enzyme catalysts have been successfully applied to catalyze HDA reactions,which are catalyzed by chemical catalysts such as Lewis acids,metal ions,and organic molecules can do.However,compared to chemical catalysis,enzyme-catalyzed HDA reactions are favored due to their green,mild,efficient,and highly selective properties.With the discovery of enzyme-catalyzed HDA reactions in natural product biosynthetic pathways,uncovering the stereoselectivity and substrate specificity of HDA-related enzymes promotes our understandings of the relationship between sequences and functions.Additionally,it lays the foundation for further mining and modification of enzymes.However,there are several challenges need to be tackled.Firstly,although a few HDA enzymes have been studied,the vast majority are remained to be isolated and characterized.Secondly,the catalytic mechanisms of most reported HDA enzymes are not clear,and more information about their structures,key residues and catalytic processes remains to be uncovered.Thirdly,all reported cases present rather narrow substrate spectra,and the stereoselectivity is rather poor.Here,we summarize the currently known enzyme-catalyzed HDA reactions in heterocyclic natural product biosynthetic pathways,focusing mainly on those involved in the biosynthesis of pyridines and indole alkaloids.By summarizing and analyzing the entire biocatalytic pathways and catalytic mechanisms,we expect to guide further research and engineering of HAD enzymes to improve their activity and selectivity.We also hope to inspire the development of new biocatalysts for the synthesis of non-natural heterocyclic products.
NETL
NSTL
万方数据
