Genomic mining and diversity of assembly line polyketide synthases

Kishore, Shreya; Khosla, Chaitan

doi:10.1098/rsob.230096

Cited by 3 publications

(1 citation statement)

References 62 publications

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“…With the increasing availability of whole genome sequencing, a growing number of PKS gene clusters and their products have been characterized [ 19 ]. To assess and evaluate the sequence–stereoselectivity relationship of KRs, here we have collected 1,762 KR sequences from modular cis -AT PKS gene clusters, whose product structures have been verified using spectroscopic and/or chemical methods.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

Xiang,

Yao,

Wang

et al. 2024

Beilstein J. Org. Chem.

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Polyketides are a major class of natural products, including bioactive medicines such as erythromycin and rapamycin. They are often rich in stereocenters biosynthesized by the ketoreductase (KR) domain within the polyketide synthase (PKS) assembly line. Previous studies have identified conserved motifs in KR sequences that enable the bioinformatic prediction of product stereochemistry. However, the reliability and applicability of these prediction methods have not been thoroughly assessed. In this study, we conducted a comprehensive bioinformatic analysis of 1,762 KR sequences from cis-AT PKSs to reevaluate the residues involved in conferring stereoselectivity. Our findings indicate that the previously identified fingerprint motifs remain valid for KRs in β-modules from actinobacteria, but their reliability diminishes for KRs from other module types or taxonomic origins. Additionally, we have identified several new motifs that exhibit a strong correlation with the stereochemical outcomes of KRs. These updated fingerprint motifs for stereochemical prediction not only enhance our understanding of the enzymatic mechanisms governing stereocontrol but also facilitate accurate stereochemical prediction and genome mining of polyketides derived from modular cis-AT PKSs.

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Section: Introductionmentioning

confidence: 99%

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

Xiang,

Yao,

Wang

et al. 2024

Beilstein J. Org. Chem.

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Structure and Mechanisms of Assembly-Line Polyketide Synthases

Soohoo,

Cogan,

Brodsky

et al. 2024

Annual Review of Biochemistry

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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.

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Enzyme Databases in the Era of Omics and Artificial Intelligence

Prešern,

Goličnik

2023

IJMS

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Enzyme research is important for the development of various scientific fields such as medicine and biotechnology. Enzyme databases facilitate this research by providing a wide range of information relevant to research planning and data analysis. Over the years, various databases that cover different aspects of enzyme biology (e.g., kinetic parameters, enzyme occurrence, and reaction mechanisms) have been developed. Most of the databases are curated manually, which improves reliability of the information; however, such curation cannot keep pace with the exponential growth in published data. Lack of data standardization is another obstacle for data extraction and analysis. Improving machine readability of databases is especially important in the light of recent advances in deep learning algorithms that require big training datasets. This review provides information regarding the current state of enzyme databases, especially in relation to the ever-increasing amount of generated research data and recent advancements in artificial intelligence algorithms. Furthermore, it describes several enzyme databases, providing the reader with necessary information for their use.

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Genomic mining and diversity of assembly line polyketide synthases

Cited by 3 publications

References 62 publications

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

Structure and Mechanisms of Assembly-Line Polyketide Synthases

Enzyme Databases in the Era of Omics and Artificial Intelligence

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