Mechanisms of Type III Polyketide SynthaseFunctional Diversity: From `Steric Modulation'to the 'Reaction Partitioning' Model

摘要

Subtle active site changes often result in the redirection of typeIII polyketide synthase (PKS) reaction pathway intermediatestoward different product fates. Complementary insights fromtwo of our recently published structural and mechanisticstudies prompt us to revise the existing steric modulation'mechanistic model for type III PKS functional divergence andresultant product specificity. Besides allowing for the activecontrol of the reactivity of polyketide intermediates throughmechanisms other then pure steric shape-dependent factors,our new 'reaction partitioning' model of functional divergencealso recognizes the mechanistic importance of intramolecularchemical features of an extended polyketide that control theintrinsic reactivities of these highly reactive enzyme generatedintermediates. This new model better explains how subtleactive site changes can alter catalytic steps downstream ofalternative reaction pathway branch points. Althoughformulated based upon work on type III PKS productspecificity, the concept of 'reaction partitioning' can be usedto describe control mechanisms in many other PKSbiosynthetic systems that do not employ complete reduction ofthe growing polyketide intermediates.