Abstract
The product template (PT) domains, specifically in fungal non-reducing polyketide synthases (NR-PKSs), mediate the regioselective cyclization of polyketides dominating the final structures. However, up to date, the systematic knowledge about PT domains has been insufficient. In present study, the relationships between sequences, structures and functions of the PT domains were analyzed with 661 NR-PKS sequences. Based on the phylogenetic analysis, the PT domains were classified into prominent eight groups (I–VIII) corresponding with the representative compounds and cyclization regioselectivity (C2-C7, C4-C9, and C6-C11). Most of the cavity lining residue (CLR) sites in all groups were common, while the regional CLR site mutations resulted in the appearance of finger-like regions with different orientation. The cavity volumes and shapes, even the catalytic dyad positions of PT domains in different groups were corresponding with characteristic cyclization regioselectivity and compound sizes. The conservative residues in PT sequences were responsible for the cyclization functions and the evolution of the key residues resulted in the differentiations of cyclization functions. The above findings may help to better understand the cyclization mechanisms of PT domains and even predict the structural types of the aromatic polyketide products.
Highlights
polyketide synthase (PKSs) domains, additional functional domains including the starter unit-acyl carrier protein (ACP) transacylase (SAT) domain, product template (PT) domain, and thioesterase (TE) releasing domain are unique to the NR-PKSs1,7,8
Only one PT domain crystal structure has been studied from Aspergillus parasiticus PksA, which participates in aflatoxin B1 biosynthesis[12]
The collected NR-PKSs dataset comprised of 661 sequences, of which 627 sequences were derived from 187 strains of ascomycetes and 34 sequences from 29 strains of basidiomycetes
Summary
PKS domains, additional functional domains including the starter unit-ACP transacylase (SAT) domain, product template (PT) domain, and thioesterase (TE) releasing domain are unique to the NR-PKSs1,7,8. Subclade III was characterized by a methyltransferase (CMeT) domain located after the acyl carrier protein (ACP) domain. Later, based on a phylogenetic analysis of PT domains in subclades I and II from known functional NR-PKSs, the PT domains were classified into five groups (groups I–V) corresponding to the cyclization regioselectivity at C2-C7, C4-C9, and C6-C11 as well as compound sizes[9]. The PT domains with associated metabolites in subclade III were further classified into two groups (groups VI and VII) responsible to produce aromatics with C2-C7 cyclization[11]. The NR-PKS phylogenetic tree and PT phylogenetic tree were established based on all known fungal NR-PKSs protein sequences. The three-dimensional structures of different PT domains were modeled, and the relationships between catalytic pocket shapes and sizes, regioselective cyclization, and compound sizes were analyzed. The influence of the PT domain sequence variations on the differentiations of structures and functions was discussed
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