Data in support of substrate flexibility of a mutated acyltransferase domain and implications for polyketide biosynthesis

Klopries, Stephan; Bravo-Rodríguez, Kenny; Koopmans, Kyra R.M.; Sundermann, Uschi; Yahiaoui, Samir; Arens, J. F.; Kushnir, Susanna; Sánchez-García, Elsa; Schulz, Frank

doi:10.1016/j.dib.2015.09.052

Cited by 3 publications

(2 citation statements)

References 7 publications

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“…In other studies, the prototypical PKS (DEBS) was subjected to mutagenesis and the generated active site-mutant library was screened for substrate selectivity [ 61 , 63 , 64 , 65 ]. Several single amino acid substitutions, having an impact on the selectivity of the PKS, were identified.…”

Section: Strategies Of Acyltransferase-based Polyketide Engineerinmentioning

confidence: 99%

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Acyltransferases as Tools for Polyketide Synthase Engineering

Musiol-Kroll

Wohlleben

2018

Antibiotics

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Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the stepwise polyketide biosynthesis. The acyltransferase (AT) domains and their “partners”, the acyl carrier proteins (ACPs), thereby play an essential role. The AT loads the building blocks onto the “substrate acceptor”, the ACP. Thus, the AT dictates which building blocks are incorporated into the polyketide structure. The precursor- and occasionally the ACP-specificity of the ATs differ across the polyketide pathways and therefore, the ATs contribute to the structural diversity within this group of complex natural products. Those features make the AT enzymes one of the most promising tools for manipulation of polyketide assembly lines and generation of new polyketide compounds. However, the AT-based PKS engineering is still not straightforward and thus, rational design of functional PKSs requires detailed understanding of the complex machineries. This review summarizes the attempts of PKS engineering by exploiting the AT attributes for the modification of polyketide structures. The article includes 253 references and covers the most relevant literature published until May 2018.

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Section: Strategies Of Acyltransferase-based Polyketide Engineerinmentioning

confidence: 99%

“…Bravo-Rodriguez et al used a combined approach, which involved molecular modelling and mutagenesis of the AT6 of DEBS and showed that the V295A mutation of this AT leads to a wider active site and improves the promiscuity for non-native substrates [ 61 , 63 , 64 ].…”

Section: Strategies Of Acyltransferase-based Polyketide Engineerinmentioning

confidence: 99%

Acyltransferases as Tools for Polyketide Synthase Engineering

Musiol-Kroll

Wohlleben

2018

Antibiotics

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Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis

Bravo-Rodríguez

Klopries

Koopmans

et al. 2015

Chemistry & Biology

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Polyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme-substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification.

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