Type II Polyketide Synthases

Aromatic polyketides are structurally diverse, often polycyclic molecules that are derived from unreduced polyketone chains. This group of compounds is produced with the help of type II polyketide synthase (PKS), a complex of enzymes that catalyzes the iterative decarboxylative condensation of malonyl-CoA extender units with an acyl starter unit [70], The carbon framework of aromatic polyketides is further decorated with different functionalities, and carbohydrates are often one of them. Their presence has profound effects on physico-chemical and biological properties of aromatic polyketides. For example, anthracycline aglycones are stable and unpolar, while polyglycosylated anthracyclines are quite polar and often... 

Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A (2007) Type II polyketide synthases gaining a deeper insight into enzymatic teamwork. Nat Prod Rep 24 162-190... 

W Bao, E Wendt-Pienkowski, CR Hutchinson. Reconstitution of the iterative type II polyketide synthase for tetracenomycin F2 biosynthesis. Biochemistry 37 8132-8138, 1998. 

RJX Zawada, C Khosla. Heterologous expression, purification, reconstitution and kinetic analysis of an extended type II polyketide synthase. Chem Biol 6 607-615, 1999. 

TS Hitchman, J Crosby, KJ Byrom, RJ Cox, TJ Simpson. Catalytic self-acylation of type II polyketide synthase acyl carrier proteins. Chem Biol 5 35-47, 1998. 

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],... 

This review covers the biosynthesis of terrestriai and marine polyethers and discusses their biologic properties and the molecular genetics and enzymology of the proteins responsible for their formation. The biosynthesis of monensin, nanchangmycin, nonactin, and the marine polyether ladders are discussed in detail. Novel enzymes found only in type I polyketide polyether gene clusters that are responsible for the epoxidation and cyclization of polyene biosynthetic intermediates are described. The macrotetrolide biosynthetic gene cluster, which is an ACP-less type II polyketide synthase that functions noniteratively is reviewed. 

Shen B, Kwon H-J. Macrotetrolide biosynthesis a novel type ii polyketide synthase. Chem. Rec. 2002 2 389-396. 

Type II polyketide synthases, also referred to as bacterial aromatic polyketide synthases (25) are involved in the biosynthesis of a number of clinically important bacterial aromatic polyketides products exhibiting antitumor or antibiotic activity, such as doxorubicin and oxytetracycline. As mentioned, type II synthases are evolutionarily and structurally related to type II FASs, which occurr as heteromultimeric complexes. In contrast to type I synthases however, where multiple catalytic sites occur within a given subunit, the polypeptides associated with type II synthase complexes are typically monofimctional and dissociable 20,30). 

The anthracycline core is assembled from acetyl imits in the form of malonyl-CoA by an iterative, type II polyketide synthase (Metsa-Ketela et al. Anthracycline Biosynthesis Genes, Enzymes and Mechanisms , this volume) followed by aromatase, cyclase and tailoring enzymes, which produce the tetracycUc ring structure from the imstable polyketide chain as shown in Scheme 1. 

The orf 1 and 2 of each type II polyketide synthase arc similar to each other, and each oifl/2 set from a different microorganism shows considerable similarity to other pair sets (e.g., 95). Orfl contains the active-site cysteine, to which the growing polyketide chain is assumed to be attached via an ACP intermediate. Thus, orfl has often been named the P-ketoacylrACP synthase subunit (abbreviated to KS). Whereas each orf2 has striking similarity to the o l that it is paired with, the various orf2 do not possess the... 

B. Hybrid Antibiotics Produced by Minipuletion of Iterative (Type II) Polyketide Synthase Genes... 

Schweeke T, Aparicio ]F, Molnar I, Konig A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortes J, Lester JB, Elohm GA, Staunton J, Leadlay PF. The biosynthesis gene duster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 1995 93 7839-7843, Decker H, Summers RG, Hutchinson CR. Overproduction of all of the components of a type II polyketide synthase or only the acyl carrier protein stimulates the production of tetra-cenomycin C biosynthetic intermediates In Streptomyees glaMcescens. J Amibioc 1994 47 54-63. 

Polyketide Antibiotics Produced By Type-II Polyketide Synthase Systems... 

Sandmarm A, Dickschat J, Jerike-Kodama H, Kunze B, Dittmann E, Muller R (2007) A type II polyketide synthase from the gram-negative bacterium Stigmatella aurantiaca is involved in aurachin alkaloid biosynthesis. Angew Chem Int Ed 46 2712-2716... 

R.J. Cox et al., Post-translational modification of heterologously expressed Streptomyces type II polyketide synthase acyl carrier proteins. FEBS Lett. 405, 267-272 (1997)... 

B. S. Moore and J, Piel, 2000, Engineering biodiversity with type II polyketide synthase genes,... 

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