Discrete acyltransferases involved in polyketide biosynthesis

Musiol, Ewa Maria; Weber, Tilmann

doi:10.1039/c2md20048a

Cited by 30 publications

(23 citation statements)

References 187 publications

(288 reference statements)

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“…Although KirCII functionally resembles the trans-ATs DSZS and MCAT, the crystal structures of which are known (Keatinge-Clay, et al, 2003; Wong, et al, 2011), these two structures were not selected by Swiss-Model, likely due to poor sequence identity with KirCII (27% and 22% sequence identity to KirCII, respectively). This is in agreement with phylogenetic analyses, which showed that KirCII is more closely related to cis-AT’s than to malonate-specific trans-ATs (Musiol and Weber, 2012). In addition to the large and small AT subdomains typical of trans-AT’s, the modeled KirCII structure also includes a KS-AT linker domain that is usually associated with cis-acting AT domains from type I PKSs (Liew, et al, 2012; Tang, et al, 2006).…”

Section: Resultssupporting

confidence: 91%

“…One target, KirCII from kirromycin biosynthesis (Figure 2), is responsible for installation of the C28 ethyl moiety of kirromycin, via ethylmalonyl-CoA (Musiol, et al, 2011). KirCII has the distinction of being the only characterized trans-AT to naturally utilize a non-malonyl acyl-CoA substrate (Musiol and Weber, 2012). All other unusual trans-AT extender units are introduced into polyketides linked to ACP’s (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Reprogramming Acyl Carrier Protein Interactions of an Acyl-CoA Promiscuous trans-Acyltransferase

Musiol

Weber

et al. 2014

Chemistry & Biology

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SUMMARY Protein interactions between acyl carrier proteins (ACP’s) and trans-acting acyltransferase domains (trans-AT’s) are critical for regioselective extender unit installation by many polyketide synthases. Yet, little is known regarding the specificity of these interactions, particularly for trans-AT’s with unusual extender unit specificities. Currently, the best-studied trans-AT with non-malonyl specificity is KirCII from kirromycin biosynthesis. Here, we developed a new assay to probe ACP interactions based on leveraging the extender unit promiscuity of KirCII. The assay allows us to identify residues on the ACP surface that contribute to specific recognition by KirCII. This information proved sufficient to modify a non-cognate ACP from a different biosynthetic system to be a substrate for KirCII. The findings form a foundation for further understanding the specificity of trans-AT:ACP protein interactions, and for engineering modular polyketide synthases to produce analogues.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Reprogramming Acyl Carrier Protein Interactions of an Acyl-CoA Promiscuous trans-Acyltransferase

Musiol

Weber

et al. 2014

Chemistry & Biology

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“…Subsequently, a PKS consisting of two modules (VirF -S. virginiae; SnaE3-S. pristinaespiralis) is responsible for the addition of another two malonyl-CoA to the growing S A chain, to which a serine is attached to by the function of a hybrid PKS/NRPS (VirH -S. virginiae; SnaE4 -S. pristinaespiralis). Interestingly, all the reported streptogramin PKSs are of the trans-acyltransferase-type, which are characterized by the lack of the typical acyltransferase domain but instead are loaded by standalone acyltransferases (Mast et al, 2011a;Musiol and Weber, 2012). A final NRPS module (gene not identified in S. virginiae; SnaD -S. pristinaespiralis) introduces a proline residue into the precursor molecule and the C-terminal thioesterase domain of this NRPS catalyzes the release and cyclization reaction of the polyketide chain resulting in the S A end product (Pulsawat et al, 2007;Mast et al, 2011a).…”

Section: Streptogramin a Biosynthesis (Pii Vm)mentioning

confidence: 99%

Streptogramins – Two are better than one!

Mast

Wohlleben

2014

International Journal of Medical Microbiology

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“…These trans-AT PKSs include those responsible for production of the disorazoles [76,77], kirromycin [78 -80] and several others [75,81,82]. A potential engineering strategy involves the selective inactivation of a cis-AT domain and complementation using a trans-AT with differing specificity [9].…”

Section: Trans-acyltransferase Complementationmentioning

confidence: 99%

Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

Dunn

Khosla

2013

J. R. Soc. Interface.

107

114

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Polyketide natural products act as a broad range of therapeutics, including antibiotics, immunosuppressants and anti-cancer agents. This therapeutic diversity stems from the structural diversity of these small molecules, many of which are produced in an assembly line manner by modular polyketide synthases. The acyltransferase (AT) domains of these megasynthases are responsible for selection and incorporation of simple monomeric building blocks, and are thus responsible for a large amount of the resulting polyketide structural diversity. The substrate specificity of these domains is often targeted for engineering in the generation of novel, therapeutically active natural products. This review outlines recent developments that can be used in the successful engineering of these domains, including AT sequence and structural data, mechanistic insights and the production of a diverse pool of extender units. It also provides an overview of previous AT domain engineering attempts, and concludes with proposed engineering approaches that take advantage of current knowledge. These approaches may lead to successful production of biologically active 'unnatural' natural products.

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Discrete acyltransferases involved in polyketide biosynthesis

Cited by 30 publications

References 187 publications

Reprogramming Acyl Carrier Protein Interactions of an Acyl-CoA Promiscuous trans-Acyltransferase

Reprogramming Acyl Carrier Protein Interactions of an Acyl-CoA Promiscuous trans-Acyltransferase

Streptogramins – Two are better than one!

Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

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