Skipping in a Hybrid Polyketide Synthase

Thomas, Iain P; Martin, Christine; Wilkinson, C. D. W.; Staunton, James; Leadlay, Peter F.

doi:10.1016/s1074-5521(02)00164-3

Cited by 63 publications

(50 citation statements)

References 34 publications

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“…These SAT domains involved in the production of bikaverin and emodin may have been maintained for structural reasons, or they function by an alternative mechanism. ACP-to-ACP transfer between modules has been deduced in modular type I PKSs with an erythromycin͞rapamycin hybrid PKS (43) and others (44). The flexible ACPs with their extended pantetheine arms allow for these acyl transfers.…”

Section: Discussionmentioning

confidence: 99%

Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase

Crawford

Dancy

Hill

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

167

184

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Polyketides are a class of natural products that exhibit a wide range of functional and structural diversity. They include antibiotics, immunosuppressants, antifungals, antihypercholesterolemics, and cytotoxins. Polyketide synthases (PKSs) use chemistry similar to fatty acid synthases (FASs), although building block variation and differing extents of reduction of the growing polyketide chain underlie their biosynthetic versatility. In contrast to the well studied sequential modular type I PKSs, less is known about how the iterative type I PKSs carry out and control chain initiation, elongation, folding, and cyclization during polyketide processing. Domain structure analysis of a group of related fungal, nonreducing PKSs has revealed well defined N-terminal domains longer than commonly seen for FASs and modular PKSs. Predicted structure of this domain disclosed a region similar to malonyl-CoA:acyl-carrier protein (ACP) transacylases (MATs). MATs play a key role transferring precursor CoA thioesters from solution onto FASs and PKSs for chain elongation. On the basis of site-directed mutagenesis, radiolabeling, and kinetics experiments carried out with individual domains of the norsolorinic acid PKS, we propose that the Nterminal domain is a starter unit:ACP transacylase (SAT domain) that selects a C6 fatty acid from a dedicated yeast-like FAS and transfers this unit onto the PKS ACP, leading to the production of the aflatoxin precursor, norsolorinic acid. These findings could indicate a much broader role for SAT domains in starter unit selection among nonreducing iterative, fungal PKSs, and they provide a biochemical rationale for the classical acetyl ''starter unit effect.'' aflatoxin biosynthesis ͉ fatty acid synthase

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Section: Discussionmentioning

confidence: 99%

Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase

Crawford

Dancy

Hill

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

167

184

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show abstract

“…The need for two mACPs to have access to TE may not be a problem, because the flexibility of TE to dock or loop back to modules/ACPs away from the terminal module/ACP has been reported in picromycin/methymycin PKS (37). The transfer of intermediates from one ACP to an another ACP is conceivable if the prosthetic groups are in proximity as ACP to ACP skipping has been previously reported in pikromycin (38) and an hybrid PKS of erythromycin and rapamycin (39).…”

Section: Role Of Tandemly Repeated Acyl Carrier Proteinsmentioning

confidence: 97%

Tandemly Duplicated Acyl Carrier Proteins, Which Increase Polyketide Antibiotic Production, Can Apparently Function Either in Parallel or in Series

Rahman

Hothersall

Crosby

et al. 2005

Journal of Biological Chemistry

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Polyketide biosynthesis involves the addition of subunits commonly derived from malonate or methylmalonate to a starter unit such as acetate. Type I polyketide synthases are multifunctional polypeptides that contain one or more modules, each of which normally contains all the enzymatic domains for a single round of extension and modification of the polyketide backbone. Acyl carrier proteins (ACP(s)) hold the extender unit to which the starter or growing chain is added. Normally there is one ACP for each ketosynthase module. However, there are an increasing number of known examples of tandemly repeated ACP domains, whose function is as yet unknown. For the doublet and triplet ACP domains in the biosynthetic pathway for the antibiotic mupirocin from Pseudomonas fluorescens NCIMB10586 we have inactivated ACP domains by inframe deletion and amino acid substitution of the active site serine. By deletion analysis each individual ACP from a cluster can provide a basic but reduced activity for the pathway. In the doublet cluster, substitution analysis indicates that the pathway may follow two parallel routes, one via each of the ACPs, thus increasing overall pathway flow. In the triplet cluster, substitution in ACP5 blocked the pathway. Thus ACP5 appears to be arranged "in series" to ACP6 and ACP7. Thus although both the doublet and triplet clusters increase antibiotic production, the mechanisms by which they do this appear to be different and depend specifically on the biosynthetic stage involved. The function of some ACPs may be determined by their location in the protein rather than absolute enzymic activity.

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“…[257,258] Dieser Befund ist in Einklang mit Untersuchungen von Leadlay et al zu einem Skipping-Prozess in einer Hybrid-PKS, die den Nachweis für einen ACP-zu-ACP-Kettentransfer erbrachten. [259] Schema 48. Komplexe Polyketide, die sich aus der programmierten Wiederholung in bakteriellen modularen PKS ergeben.…”

Section: "Stottern" Und Programmierte Iterationunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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Molekulares Lego: Polyketide bilden eine äußerst vielfältige Gruppe von Naturstoffen mit faszinierenden Kohlenstoffgerüsten (siehe Beispiele), die aus einfachen Acyl‐Bausteinen synthetisiert werden. Das Zusammenspiel von Chemie, Biochemie und Genetik lieferte wichtige Einblicke in die Programmierung des Polyketid‐Aufbaus und die beteiligten, komplexen Enzymsysteme. Dieser Aufsatz behandelt aktuelle Entwicklungen auf diesem Forschungsgebiet.magnified imagePolyketide bilden eine der größten Naturstoffklassen. Viele dieser Verbindungen – oder Derivate davon – sind wichtige Therapeutika, aber viele sind auch berüchtigte, Lebensmittel verderbende Toxine oder Virulenzfaktoren. Besonders bemerkenswert ist, dass sich die Verbindungen dieser heterogenen Gruppe, zu denen Polyether, Polyene, Polyphenole, Makrolide und Endiine gehören, hauptsächlich von einem der einfachsten natürlichen Bausteine ableiten: Essigsäure. Chemische, genetische und biochemische Untersuchungen haben Aufschluss über die Biosyntheseprogramme gegeben, die zur enormen Strukturvielfalt von Polyketiden führen. Dieser Aufsatz behandelt kürzlich aufgeklärte Biosynthesemechanismen, nach denen höchst unterschiedliche und komplexe Moleküle synthetisiert werden.

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Skipping in a Hybrid Polyketide Synthase

Cited by 63 publications

References 34 publications

Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase

Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase

Tandemly Duplicated Acyl Carrier Proteins, Which Increase Polyketide Antibiotic Production, Can Apparently Function Either in Parallel or in Series

Die biosynthetische Grundlage der Polyketid‐Vielfalt

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