Actinorhodin polyketide synthases

CW Carreras, R Pieper, C Khosla. Efficient synthesis of aromatic polyketides in vitro by the actinorhodin polyketide synthase. J Am Chem Soc 118 5158-5159, 1996. 

MP Crump, J Crosby, CE Dempsey, M Murray, DA Hopwood, TJ Simpson. Conserved secondary structure in the actinorhodin polyketide synthase acyl carrier pro-... 

A-L Matharu, RJ Cox, J Crosby, KJ Byrom, TJ Simpson. MCAT is not required for in vitro polyketide synthesis in a minimal actinorhodin polyketide synthase from Streptomyces coelicolor. Chem Biol 5 699-712, 1998. 

Crump, M.P., Crosby, J., Dempsey, C. E., Parkinson, J.A., Murray, M., Hopwood, D.A. Simpson, T. J. Solution stmcture of the actinorhodin polyketide synthase acyl carrier protein from Streptomyces coelicdor A3(2). Biochemistry 36, 6000-6008 (1997). 

D. Hopwood, T. Simpson, Solution structure of the actinorhodin polyketide synthase acyl carrier protein from Streptomyces coelicolor A3 (2), Biochemistry 1997, 36, 6000-6008. 

A. Actinorhodin, Tetracenomycin, Doxorubicin, and Other Bacterial Aromatic Polyketide Synthases... 

MA Fernandez-Moreno, E Martinez, L Boto, DA Hopwood, F Malpartida. Nucleotide sequence and deduced functions of a set of cotranscribed genes of Streptomyces coelicolor A3(2) including the polyketide synthase for the antibiotic actinorhodin. J Biol Chem 267 19278-19290, 1992. 

J Dreier, AN Shah, C Khosla. Kinetic analysis of the actinorhodin aromatic polyketide synthase. J Biol Chem 274 25108-25112, 1999. 

Figure 4. Organization of representative type 1, II, and III polyketide synthases. Upper modular arrangement of DEBS 1,2,3 subunits Center orientation and arrangement of open reading frames in actinorhodin gene cluster Lower chalcone synthase subunit. AT, acyltransferase ACP, acyl carrier protein KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyl reductase TE, thioesterase TA, tailoring enzyme R/T, regulatory/transport related AR aromatase CY, cyclase.

Fig. 5.2 Organization of polyketide synthases (PKSs). (A) The type I erythromycin PKS (DEBS) which catalyzes the biosynthesis of 6-dEB. The PKS consists of three polypeptides, DEBSl, DEBS2, and DEBS3, each possessing two modules. (B) The type I epothilone PKS consists of six polypeptides EpoA, EpoB [a non-ribosomal peptide synthase (NRPS)], EpoC, EpoD (possessing four modules), EpoE (possessing two modules), and EpoF. (C) The type II actinorhodin PKS con-...

Fig. 9.2-1 Polyketide and nonribosomal peptide structures described in the text. Erythromycin A is produced by a modular polyketide synthase. Actinorhodin and...

Since the PKS (polyketide synthase) gene cluster for actinorhodin (act), an antibiotic produced by Streptomyces coelicolor[ 109], was cloned, more than 20 different gene clusters encoding polyketide biosynthetic enzymes have been isolated from various organisms, mostly actinomycetes, and characterized [98, 100]. Bacterial PKSs are classified into two broad types based on gene organization and biosynthetic mechanisms [98, 100, 102]. In modular PKSs (or type I), discrete multifunctional enzymes control the sequential addition of thioester units and their subsequent modification to produce macrocyclic compounds (or complex polyketides). Type I PKSs are exemplified by 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of the macrolactone portion of erythromycin A, an antibiotic produced by Saccharopolyspora erythraea. There are 7 different active-site domains in DEBS, but a given module contains only 3 to 6 active sites. Three domains, acyl carrier protein (ACP), acyltransferase (AT), and P-ketoacyl-ACP synthase (KS), constitute a minimum module. Some modules contain additional domains for reduction of p-carbons, e.g., P-ketoacyl-ACP reductase (KR), dehydratase (DH), and enoyl reductase (ER). The thioesterase-cyclase (TE) protein is present only at the end of module 6. 

Fig. 6. In vitro synthesis of actinorhodin biosynthetic intermediates and its shunt metabolites from acetyl CoA and malonyl CoA by the ActIORFI,2,3 polyketide synthase complex, the Actlll ketoreductase, the ActVII aromatase, ActIV cyclase, and the TcmO methyltransferase...

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