The biosynthetic community is working to decipher the logic of two large classes of enzymatic assembly lines that contain polyketide synthase (PKS) machinery - cis-acyltransferase (cis-AT) assembly lines that primarily rely on embedded ATs and trans-acyltransferase (trans-AT) assembly lines that primarily rely on separately-encoded ATs. From the sequencing of the erythromycin synthase in 1990 until 2017, the boundaries of the modules of cis-AT assembly lines were incorrectly defined - comparisons with the domain organization of the mammalian FAS had led to the module being defined with KS at its upstream boundary and ACP at its downstream boundary. The ACP domains of several cis-AT assembly lines are now known evolutionarily co-migrate with the KS downstream of them, leading to the redefinition of cis-AT modules as possessing a downstream KS. When trans-AT assembly lines started to be discovered fifteen years ago, often from difficult-to-culture, symbiotic bacteria, the use of cis-AT nomenclature resulted in their modules being incorrectly defined as well. Ironically, only a few years later KSs that accept similar substrates in trans-AT assembly lines were oberved to clade together, suggesting that they collaborate most closely with the domains preceding them, not following them.<br/><br/>In this seminar, bioinformatic analysis of 526 ACPs from 33 well-characterized trans-AT assembly lines will be presented. ACPs from the same module type are related to one another, reflective of their interactions with cognate processing enzymes that have been relatively conserved through evolution. KSs downstream of ACPs from the same module type also clade together, whereas KSs upstream do not, contrary to the traditional definition of a module. Beyond nomenclature, how the updated definition of a module impacts our understanding of modules, the evolution of assembly lines, pathway prediction, and assembly line engineering will be discussed.

Redefining polyketide synthase modules

255th National Meeting (2018)

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