During biosynthesis by the type I multienzyme polyketide synthases (PKSs), chain extension intermediates are tethered to small domains called acyl carrier proteins (ACPs). Analysis of a typical chain extension cycle reveals that the ACP must communicate with each of the other domains within the module, to either receive or present substrate. Thus, ACP-centered protein-protein interactions may be fundamental to assembly line biosynthesis of polyketides.¹

Aavailable evidence suggests that such a protein-protein complex is formed between the ACP and ketosynthase (KS) domains during chain extension.² However, ketoreductase (KR) domains exhibit a high degree of tolerance towards ACP partners, suggesting that the domains instead recognize the ACP-tethered acyl chain.³ Here, we present further evidence for this alternative mode of interaction though studies of a representative ACP domain and the thioesterase (TE) domain which lies downstream of it.⁴ Using a combination of enzymatic assay, binding analysis⁴ and solution phase NMR, we demonstrate that the interaction between the ACP and TE domains is weak (mM affinity), and centered on the acyl group. Thus, despite the obvious mechanistic similarities between type I and type II (discrete) PKS systems, there appear to be significant differences in key protein-protein interactions within these multienzymes. Together, these results motivate a model for ACP-based communication in modular PKS, which we present here.

^{1. K. J. Weissman & R. Müller, ChemBioChem, 2008, 9, 826–848.}

^{2. Y. Tang, et al. Chem. Biol. 2007, 14, 931–943.}

^{3. A. Y. Chen, et al. Chem. Biol. 2007, 14, 784–792.}

^{4. L. Tran, et al. ChemBioChem, 2008, 9, 905–915.}