Fig. 3.

Evolutionary role of GRINS in assembly-line PKSs. (A) Seven homologous PKSs. For each module, the extender unit specificity of its AT domain is specified: mm, methylmalonyl extender; m, malonyl; em, ethylmalonyl; moxm, methoxymalonyl. Each color shows a different group of GRINS within a PKS (>80% DNA sequence identity within group) and their locations. Molecules biosynthesized by these PKSs are shown to the right. Each color shows the differences in chemical structure, all of which can be attributed to the different extender unit incorporated by the GRINS-encoded AT domains. (B) Phylogenetic tree of AT domains (Left) and their extender unit specificity (Right). Fatty acid synthase (FAS) and trans-AT PKS AT sequences were used as an outgroup. Sequence alignment performed using ClustalOmega (10); phylogenetic tree constructed using RAxML (30). (C) Proposed role of GRINS in assembly-line PKS evolution. Extender unit specificity of AT domains devoid of GRINS allows reconstruction of the most likely ancestral PKS and its product (Left), whose AT domain specificity differs in multiple modules from modern-day PKSs such as tylactone synthase. These differences would likely have involved several AT domain recombination events and consequently a long evolutionary path, if they occurred independently. Through gene conversion, GRINS allow concerted changes in multiple PKS modules, resulting in a more rapid polyketide diversification path.