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Retrobiosynthesis of unnatural lactams via reprogrammed polyketide synthase

ABSTRACT: Using discovery global proteomics to study the retrobiosynthesis of unnatural lactams via reprogrammed polyketide synthase.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Pseudomonas Putida Kt2440 (ncbitaxon:160488)

SUBMITTER: Young-Mo Kim Kristin E. Burnum-Johnson

PROVIDER: MSV000096981 | MassIVE | Tue Jan 28 14:47:00 GMT 2025

REPOSITORIES: MassIVE

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Project description:Background: Among the nineteen polyketide synthases encoded by the genome of Mycobacterium tuberculosis, Pks13 was identified as the condensase required for the final condensation step of two long acyl chains. This leads to mycolic acids, which are essential components of the cell envelope of Corynebacterineae species. The single polypeptide chain of Pks13 comprises five catalytic domains, including two functional acyl carrier protein domains, separated by linkers comprising up to ca. 200 amino acid residues. In many aspects, Pks13 is an atypical polyketide synthase. It has been validated as a promising druggable target and its structure is badly needed to speed up drug discovery to fight against tuberculosis. Results: We report here a quasi-atomic model of Pks13 obtained using small angle X-ray scattering of the entire protein and various molecular subspecies combined with known high-resolution structures of Pks13 domains or structural homologues. In addition, the structural changes induced by the loading of a substrate analogue have been challenged. As a comparison, the low-resolution structures of two other mycobacterial polyketide synthases, Mas and PpsA from Mycobacterium bovis BCG, are also presented. This study highlights an identical and elongated structure of the apo and holo forms at the resolution probed. Catalytic domains are segregated into two parts, which correspond to the condensation reaction per se and to the release of the product, a pivot for the enzyme flexibility being at the interface. The two acyl carrier protein domains are found at opposite sides of the ketosynthase domain and display distinct characteristics in terms of flexibility. Apo-Pks13 is in our conditions in a monomeric state, but loading of a substrate analogue push the enzyme towards the functional dimeric state. Conclusions: The Pks13 model provides the first structural information on the molecular mechanism of this complex enzyme and open up new perspectives to develop inhibitors that target the interactions with its enzymatic partners or between catalytic domains within Pks13 itself.

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Retrobiosynthesis of unnatural lactams via reprogrammed polyketide synthase

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