Diverse evolutionary origins of microbial [4 + 2]-cyclases in natural product biosynthesis

Natural [4 + 2]-cyclases catalyze concerted cycloaddition during biosynthesis of over 400 natural products reported. Microbial [4 + 2]-cyclases are structurally diverse with a broad range of substrates. Thus far, about 52 putative microbial [4 + 2]-cyclases of 13 different types have been characterized, with over 20 crystal structures. However, how these cyclases have evolved during natural product biosynthesis remains elusive. Structural and phylogenetic analyses suggest that these different types of [4 + 2]-cyclases might have diverse evolutionary origins, such as reductases, dehydratases, methyltransferases, oxidases, etc. Divergent evolution of enzyme function might have occurred in these different families. Understanding the independent evolutionary history of these cyclases would provide new insights into their catalysis mechanisms and the biocatalyst design.