Type I Polyketide Synthases

It is very likely that a similar Type I polyketide synthase constructs the naphthoate fragment of azinomycin B. This will be a very interesting enzyme to study, since it will need to perform an unprecedented three regioselective reduction reactions, as well as controlling the polyketide chain length and directing its cycliza-tion. 

The biosynthesis of maduropeptin has not been studied in detail, but an iterative type I polyketide synthase gene predicted to be responsible for forming the enediyne core structure has been identified [188]. 

Liu, W., Nonaka, K., Nie, L. et al. (2005) The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases. Chemistry Biology, 12, 293. 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

A multifunctional biosynthetic machinery mediates the synthesis of these complex natural products from acetyl- and propionyl-coenzyme A [3). In the case of type I polyketide-synthases, the )8-oxo-esters made by polycondcnsa-tion steps are modified for example by reduction or dehydration after the chain elongation. Additional specific enzymatic transformations, e.g. oxidations and glycosylations, usually take place after the decoupling at the completed macrocyclic ring framework [1,3],... 

Chan YA, Boyne MT, Podevels AM, Klimowicz AK, Handelsman J, Kelleher NL, Thomas MG (2006) Hydroxymalonyl-Acyl Carrier Protein (ACP) and Aminomalonyl-ACP are Two Additional Type I Polyketide Synthase Extender Units. Proc Natl Acad Sci USA 103 14349... 

Chen AY, Cane DE, Khosla C (2007) Structure-Based Dissociation of a Type I Polyketide Synthase Module. Chem Biol 14 784... 

Figure 2 Conventional modular type I PKS paradigm, (a) Individual domains in a full type I polyketide synthase extension module. Homodimeric contacts are made in the N-terminal docking, ketosynthase, dehydratase, enoyi reductase, and C-terminal docking domains, (b) PKS system for 10-deoxymethynolide and narbonolide generation.

Research on modular type I polyketide synthases in the Sherman laboratory is supported generously by grants from the National Institutes of Health (GM076477, CA108874, TW007404), the Hans and Ella McCollum Vahlteich Research Fund at the University of Michigan College of Pharmacy, and the H.W. 

Cheng YQ, Tang GL, Shen B. Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 2003 100 3149-3154. 

The modular organization of type I polyketide synthases was first recognized by sequencing the gene cluster for the biosynthesis of the antibiotic erythromycin... 

We have identified a clone fi-om a cosmid library of So. cellulosum So ce26 that contains genes involved in soraphen A biosynthesis (10). Gene knockouts conducted with several restriction fiagments fi om this cosmid led to the abolition of soraphen A production in So ce26. One of these fragments was sequenced, and found to encode two incomplete modules from a Type I polyketide synthase (PKS). The coverage of the soraphen A locus was extended... 

Swan, D. G., Rodriguez, A. M., Vilches, C., Mendes, C., and Salas, J. A. (1994). Characterisation of a Streptomyces antibioticus gene encoding a type I polyketide synthase which has an unusual coding sequence. Mol. Gen. Genet. 242, 358-362. 

Yu, J.-H., and Leonard, T. J. (1995). Sterigmatocystin biosynthesis in Aspergillus nidulans requires a novel type I polyketide synthase. J. Bacterial. 177, 4792-4800. 

A. Hybrid Antibiotics Produced 1 ManipulaHon of Modular (Type I) Polyketide Synthase Genes... 

A. Ginolhac et al.. Type I polyketide synthases may have evolved through horizontal gene transfer. J. Mol. Evolut. 60, 716-725 (2005)... 

A.T. Keatinge-Clay, The structures of type I polyketide synthases. Nat. Prod. Rep. 29, 1050-... 

W. Xu, K. Qiao and Y. Tang, Structural Analysis of Protein-Protein Interactions in Type I Polyketide Synthases, Crit. Rev. Biochem. Mol. Biol., 2013, 48, 98. 

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