Assembly Line Polyketide Synthases: Mechanistic Insights and Unsolved Problems

摘要: Two hallmarks of assembly line polyketide synthases have motivated an interest in these unusual multienzyme systems, their stereospecificity and capacity for directional biosynthesis. In this review, we summarize the state knowledge regarding mechanistic origins two remarkable features, using 6-deoxyerythronolide B synthase as a prototype. Of 10 stereocenters B, stereochemistry nine carbon atoms is directly set by ketoreductase domains, which catalyze epimerization and/or diastereospecific reduction reactions. The 10th stereocenter established sequential action three enzymatic domains. Thus, problem has been reduced to challenge mainstream enzymology, where fundamental gaps remain our understanding structural basis exquisite stereochemical control relatively well-defined active sites. contrast, testable hypotheses phenomenon vectorial biosynthesis are only just beginning emerge. Starting from elegant theoretical framework coupled processes biology [Jencks, W. P. (1980) Adv. Enzymol. Relat. Areas Mol. Biol. 51, 75–106], present simple model that can explain process. Our model, highlights important role domain–domain interactions, not consistent with recent observations but also amenable further experimental verification refinement. Ultimately, definitive view coordinated motions within between modules will require combination structural, kinetic, spectroscopic, computational tools could be one most exciting frontiers 21st Century enzymology.