Abstract
Product-releasing enzyme (PRE) domains in fungal non-reducing polyketide synthases (NR-PKSs) play a crucial role in catalysis and editing during polyketide biosynthesis, especially accelerating final biosynthetic reactions accompanied with product offloading. However, up to date, the systematic knowledge about PRE domains is deficient. In the present study, the relationships between sequences, structures, and functions of PRE domains were analyzed with 574 NR-PKSs of eight groups (I–VIII). It was found that the PRE domains in NR-PKSs could be mainly classified into three types, thioesterase (TE), reductase (R), and metallo-β-lactamase-type TE (MβL-TE). The widely distributed TE or TE-like domains were involved in NR-PKSs of groups I–IV, VI, and VIII. The R domains appeared in NR-PKSs of groups IV and VII, while the physically discrete MβL-TE domains were employed by most NR-PKSs of group V. The changes of catalytic sites and structural characteristics resulted in PRE functional differentiations. The phylogeny revealed that the evolution of TE domains was accompanied by complex functional divergence. The diverse sequence lengths of TE lid-loops affected substrate specificity with different chain lengths. The volume diversification of TE catalytic pockets contributed to catalytic mechanisms with functional differentiations. The above findings may help to understand the crucial catalysis of fungal aromatic polyketide biosyntheses and govern recombination of NR-PKSs to obtain unnatural target products.
Highlights
A great variety of fungal aromatic polyketides have an important impact on the pharmaceutical industry and agricultural production due to a wide range of biological products including clinical drugs as well as undesirable toxins and virulence factors (Hertweck, 2009; Crawford and Townsend, 2010; Chooi and Tang, 2012)
The resulting non-reducing polyketide synthases (NR-PKSs) phylogenetic tree (Figure 2A) clearly classified the collected sequences into eight major groups with NR-PKSs from basidiomycetes only appeared in group VIII, which was consistent with our previous study (Liu et al, 2015)
The results showed that the majority of conserved residue sites (ConSurf grade 7–9) in TE sequences of NR-PKSs in groups I–IV and VIII locate at the catalytic pockets (Figure 8A and Supplementary Table S5)
Summary
A great variety of fungal aromatic polyketides have an important impact on the pharmaceutical industry and agricultural production due to a wide range of biological products including clinical drugs as well as undesirable toxins and virulence factors (Hertweck, 2009; Crawford and Townsend, 2010; Chooi and Tang, 2012). As a class of crucial domains, the product-releasing related domains have been demonstrated to dominate the final step reaction to synthesize and release the products in many NR-PKSs (Crawford and Townsend, 2010; Chooi and Tang, 2012; Newman et al, 2014). During the biosynthesis of aromatic polyketides by NR-PKSs, the linear polyketide intermediates were regio-selectively cyclized by PT domains to form the polyketides containing one or two aromatic rings These aromatic polyketide intermediates were further processed and released by product-releasing related domains (Figure 1)
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