Ketoreductase domain, polyketide synthase

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

CM Kao, M McPherson, R McDaniel, H Fu, DE Cane, C Khosla. Alcohol stereochemistry in polyketide backbones is controlled by the (3-ketoreductase domains of modular polyketide synthases. J Am Chem Soc 120 2478-2479, 1998. 

IE Holzbaur, RC Harris, M Bycroft, J Cortes, C Bisang, J Staunton, BAM Rudd, PF Leadlay. Molecular basis of Celmer s rules the role of two ketoreductase domains in the control of chirality by the erythromycin modular polyketide synthase. Chem Biol 6 189-195, 1999. 

Baerga-Ortiz A, Popovic B, Siskos AP, O Hare HM, Spiteller D, Williams MG, Campillo N, Spencer JB, Leadlay PF (2006) Directed Mutagenesis Alters the Stereochemistry of Catalysis by Isolated Ketoreductase Domains from the Erythromycin Polyketide Synthase. Chem Biol 13 277... 

Reid R, Piagentini M, Rodriguez E, Ashley G, Viswanathan N, Carney J, Santi DV, Hutchinson CR, McDaniel R (2003) A Model of Structure and Catalysis for Ketoreductase Domains in Modular Polyketide Synthases. Biochemistry 42 72... 

Predicting Ketoreductase Domain Stereospecificity in Modular Polyketide Synthase... 

Figure 1 Hypothetical pentaketide biosynthetic system, which illustrates the enzymatic logic of type I modular polyketide synthases (PKSs) and the catalytic role of acyl transferase (AT) domains. Each AT domain selects substrates from the cellular pool and tethers them as thioesters to acyl carrier protein (ACP) domains. In a typical PKS module, the AT and ACP domains are present in all modules. The ketosynthase (KS) domain is present in all chain extension modules. The dehydratase (DH), enoyl reductase (ER), and ketoreductase (KR) domains are optional domains. The final thioesterase (TE) domain catalyzes the release of the product from the PKS.

Modular PKSs are large multifunctional enzymes. Active sites (domains) within these enzymes ketosynthases (KS), acyltransferases (AT), dehydratases (DH), enoyl reductases (ER), ketoreductases (KR), acyl carrier proteins (AGP) and thioesterases (TE) are organized into modules such that each module catalyzes the stereospecific addition of a new monomer onto a growing polyketide chain and also sets the reduction level of the carbon atoms of the resulting intermediate [70]. In 1994, the heterologous expression of the complete erythromycin polyketide synthase was accomplished. The recombinant... 

Biosynthesis of erythromycin represents a typical polyketide pathway and structural organization of PKSs. Erythromycin PKS (6-deoxyerythronolide B synthase, DEBS) uses propionyl-CoA as a priming unit and six methylmalonyl-CoA molecules as extender units. Each module in a modular PKS contains domains for one round of chain elongation (KS, AT, ACP) and p-keto modification (ketoreductase, KR dehy-drase, DH enoylreductase, ER). DEBS consists of six modules (mod 1 -6) encoded on three separate polypeptide subunits. 

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