Elucidating the mechanism of

12 Feb

Polyketides are a large family of bioactive natural products synthesized by polyketide synthase (PKS) enzyme complexes predominantly from acetate and propionate.

Given the structural diversity of compounds produced using these two simple building blocks, there has been longstanding interest in engineering the incorporation of alternative extender units.

We have been investigating the mechanism of fluorinated monomer insertion by three of the six different modules of the PKS involved in erythromycin biosynthesis (6-deoxyerythronolide B synthase, DEBS) to begin understanding the contribution of different steps, such as enzyme acylation, transacylation, C–C bond formation, and chain transfer, to the overall selectivity and efficiency of this process.

In these studies, we observe that inactivation of a -acyltransferase (AT) domain to circumvent its native extender unit preference leads concurrently to a change of mechanism in which chain extension with fluorine-substituted extender units switches largely to an acyl carrier protein (ACP)-independent mode.

A distinct group of antimicrobial peptides kills bacteria by interfering with internal cellular functions and without concurrent lytic effects on cell membranes.

Here we describe some methods to investigate the mechanisms of action of these antimicrobial peptides.

However, the optimization of polyketide structure for medicinal purposes can be difficult using chemical methods given their complexity.

Site-selective introduction of fluorine into polyketides and other natural products is a particularly interesting area of exploration given the demonstrated effectiveness of fluorine in modulating the behavior of small-molecule therapeutics.

By increasing the throughput of fluorinated extender units, we can produce multiply fluorinated polyketide products by chemoenzymatic synthesis and target the production of complex structures.

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Moreover, these mostly neglect the cooperativity exhibited by zinc fingers.

Here, we present an ab-initio method that is based on mutation of the key α-helical residues of individual fingers of the parent template for Zif-268 and its consensus sequence (PDB ID: 1AAY).