A. Y. Chen

Alekseyev

Andrusier

B. Lowry

Broadhurst

C. Khosla

Castonguay

Cortes

D. E. Cane

Donadio

Gokhale

Keatinge-Clay

Khosla

Menzella

Moss

S. Kapur

S. Kenthirapalan

S. Yuzawa

Schatz

Schneidman-Duhovny

Tang

Valenzano

Volchegursky

Wilkinson

Multimodular polyketide synthases (PKSs) have an assembly line architecture in which a set of protein domains, known as a module, participates in one round of polyketide chain elongation and associated chemical modifications, after which the growing chain is translocated to the next PKS module. The ability to rationally reprogram these assembly lines to enable efficient synthesis of new polyketide antibiotics has been a long-standing goal in natural products biosynthesis. We have identified a ratchet mechanism that can explain the observed unidirectional translocation of the growing polyketide chain along the 6-deoxyerythronolide B synthase. As a test of this model, module 3 of the 6-deoxyerythronolide B synthase has been reengineered to catalyze two successive rounds of chain elongation. Our results suggest that high selectivity has been evolutionarily programmed at three types of protein–protein interfaces that are present repetitively along naturally occurring PKS assembly lines.</jats:p

Shiven Kapur

Brian Lowry

Satoshi Yuzawa

Sanketha Kenthirapalan

Alice Y. Chen

David E. Cane

Chaitan Khosla

Crossref

Proceedings of the National Academy of Sciences

Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation

Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation

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