2006
DOI: 10.1016/j.str.2006.01.009
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The Structure of a Ketoreductase Determines the Organization of the β-Carbon Processing Enzymes of Modular Polyketide Synthases

Abstract: The structure of the ketoreductase (KR) from the first module of the erythromycin synthase with NADPH bound was solved to 1.79 A resolution. The 51 kDa domain has two subdomains, each similar to a short-chain dehydrogenase/reductase (SDR) monomer. One subdomain has a truncated Rossmann fold and serves a purely structural role stabilizing the other subdomain, which catalyzes the reduction of the beta-carbonyl of a polyketide and possibly the epimerization of an alpha-substituent. The structure enabled us to def… Show more

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Cited by 202 publications
(321 citation statements)
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“…6). We also note that the recently reported structure of a DEBS KR domain (33), and the proposed model of the ␤-carbon processing dehydratase, KR, and enoylreductase domains, is fully consistent with the upper arms containing the homologous reductive domains of the low resolution FAS structure and indicates how the structure of the minimal PKS module, represented by the KS-AT didomain, can be expanded to include additional domains without fundamental reorganization of the core KS-AT topology (Fig. 7).…”
Section: Interaction Between the Acp Domain And The Ks-at Fragment: Notmentioning
confidence: 63%
“…6). We also note that the recently reported structure of a DEBS KR domain (33), and the proposed model of the ␤-carbon processing dehydratase, KR, and enoylreductase domains, is fully consistent with the upper arms containing the homologous reductive domains of the low resolution FAS structure and indicates how the structure of the minimal PKS module, represented by the KS-AT didomain, can be expanded to include additional domains without fundamental reorganization of the core KS-AT topology (Fig. 7).…”
Section: Interaction Between the Acp Domain And The Ks-at Fragment: Notmentioning
confidence: 63%
“…To test this hypothesis, the KR-T 3 -T 4 region of PksJ was heterologously overexpressed (12). Tests of the KR domain catalytic action as a canonical ␤-KR used the model ␤-ketoacyl substrate bis-acetoacetyl (Acac)-S-PksJ(KR-T 3 -T 4 ) generated by incubation of apo-PksJ(KR-T 3 -T 4 ) with Acac-CoA (CoA) and Sfp (10).…”
Section: Resultsmentioning
confidence: 99%
“…A suite of ␤-KR active-site residues has been identified to determine the stereochemical course of ketoreduction with ''Btype'' (D-hydroxy-specific) ␤-KRs possessing a conserved LeuAsp-Asp motif and catalyzing ␤-ketoreductions with the same stereochemical sense as the PksJ-KR, and ''A-type'' (L-hydroxyspecific) ␤-KRs possessing a conserved tryptophan residue and yielding products epimeric to the PksJ-KR ␤-hydroxyacyl product (12,(16)(17)(18). The PksJ-KR has a completely different set of residues lining the active site, suggesting a different recognition ''code.''…”
Section: Discussionmentioning
confidence: 99%
“…KR domains were divided into two groups based on whether they generated an A-type ('S' configuration of the β-hydroxy residue when C24C4) or B-type ('R' configuration of the β-hydroxy residue when C24C4) alcohol stereochemistry. 28,29 A-and B-type KR sequences were aligned to allow for the identification of residues characteristic of each group. The multiple alignment and phylogenetic analysis was applied to compare bafilomycin KRs.…”
Section: Region Encoding Bafilomycin Pksmentioning
confidence: 99%