Work

Structure and Mechanisms of Assembly-Line Polyketide Synthases

Year: 2024

Type: review

Abstract: Three decades of studies on the multifunctional 6-deoxyerythronolide B synthase have laid a foundation for understanding the chemistry and evolution of polyketide antibiotic biosynthesis by a large family of versatile enzymatic assembly lines. Recent progress in applying chemical and structural biology tools to this prototypical assembly-line polyketide synthase (PKS) and related systems has highlighted several features of their catalytic cycles and associated protein dynamics. There is compelling evidence that multiple mechanisms have evolved in this enzyme family to channel growing polyketide chains along uniquely defined sequences of 10-100 active sites, each of which is used only once in the overall catalytic cycle of an assembly-line PKS. Looking forward, one anticipates major advances in our understanding of the mechanisms by which the free energy of a repetitive Claisen-like reaction is harnessed to guide the growing polyketide chain along the assembly line in a manner that is kinetically robust yet evolutionarily adaptable.

Source: Annual Review of Biochemistry

DOI: 10.1146/annurev-biochem-080923-043654

Authors: Alexander M. Soohoo, Dillon P. Cogan, Krystal L. Brodsky, Chaitan Khosla

Institutions: Stanford University, University of Southern California

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: hybrid

Funders: National Science Foundation, National Institutes of Health, National Institute of General Medical Sciences

Awards: G2911450482, Graduate Research Fellowship Program (GRFP), Mechanisms and Evolution of Assembly-Line Polyketide Synthases, Mechanistic Studies of Polyketide Synthases Enabled by Unnatural Amino Acids and Antibody Fragment Structural Tools