Volume 9, Issue 2, Pages (February 2002)

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Volume 9, Issue 2, Pages 203-214 (February 2002) Generation of Multiple Bioactive Macrolides by Hybrid Modular Polyketide Synthases in Streptomyces venezuelae Yeo Joon Yoon, Brian J Beck, Beom Seok Kim, Han-Young Kang, Kevin A Reynolds, David H Sherman Chemistry & Biology Volume 9, Issue 2, Pages 203-214 (February 2002) DOI: 10.1016/S1074-5521(02)00095-9

Figure 1 Modular Organization and the Products of Pik PKS, Tyl PKS, and Erythromycin PKS Modular organization and the products of (A) Pik PKS, (B) Tyl PKS, and (C) erythromycin (DEBS) PKS (6-deoxyerythronolide B synthase). Each protein subunit is shown as a broad arrow, with the domains indicated by symbols explained in the text. Each module catalyzes one cycle of chain elongation and associated β-keto processing for the biosynthesis of corresponding macrolactones. Pik PKS produces 10-deoxymethynolide (1) and narbonolide (2). Final products are methymycin (3), neomethymycin (4), pikromycin (5), and narbomycin (6). Tyl PKS generates tylactone (7), which is modified further to tylosin (8). DEBS PKS produces 6-deoxyerythronolide B, which is converted to erythromycin A, B, C, and D (10, 11, 12, and 13, respectively). Post-polyketide modifications are highlighted in different colors: hydroxylation, pink; glycosylation, red. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 2 Organization of the pik Cluster in Wild-Type S. venezuelae and Pik PKS Deletion Mutants Organization of the pik cluster in (A) wild-type S. venezuelae, (B) pikAIV deletion mutant HK954, (C) pikAIII-pikAIV deletion mutant YJ004, and (D) pikAI deletion mutant BB138. Each arrow represents an ORF. The direction of transcription and relative sizes of the ORFs are indicated. aphII and pikAV encode the kanamycin resistance gene [25] and type II thioesterase [13], respectively. After PKS gene deletion, pikAV and other downstream genes remain intact and can still be expressed. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 3 Polyketides Produced by Functional Replacement of PikAIV and Partial Sequence Alignment of PikAIV and TylGV Polyketides produced by complementation of PikAIV with native and hybrid TylGV (B–D) and partial sequence alignment of PikAIV and TylGV. Alternative ribosome binding sites and start codons are shown in blue and red text, respectively (E). Domains from Pik PKS are marked in yellow, and those from Tyl PKS (A–D) are in red. Des represents all eight enzymes for desosamine biosynthesis and transfer [13], and PikC is the cytochrome P450 monooxygenase responsible for hydroxylation [14]. Alternative ribosome binding sites and start codons are shown in blue and red text, respectively. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 4 LC/MS and MS/MS Analyses of Aglycones Produced from S. venezuelae Wild-Type and HK954/pDHS3007 Strains Comparison of LC/MS and MS/MS analyses of aglycones produced from S. venezuelae wild-type (A–D) and HK954/pDHS3007 (E–H) strains. (A) LC/MS selected for amu = 297, corresponding to compound 1 produced from the S. venezuelae wild-type strain. (B) LC/MS selected for amu = 353, corresponding to compound 2 produced from the S. venezuelae wild-type strain. (C) MS/MS spectrum corresponding to compound 1 produced from S. venezuelae wild-type strain. (D) MS/MS spectrum corresponding to compound 2 produced from S. venezuelae wild-type strain. (E) LC/MS selected for amu = 297, corresponding to compound 1 produced from HK954/pDHS3007 strain. (F) LC/MS selected for amu = 341, corresponding to compound 14 produced from HK954/pDHS3007 strain. (G) MS/MS spectrum corresponding to compound 1 produced from HK954/pDHS3007 strain. (H) MS/MS spectrum corresponding to compound 14 produced from HK954/pDHS3007 strain (see text for a detailed description of the MS/MS signals). Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 5 Polyketides Produced by Functional Replacement of PikAI Domains from Pik PKS are marked in yellow, and those from Tyl PKS are in red. Des represents all eight enzymes for desosamine biosynthesis and transfer [13], and PikC is the cytochrome P450 monooxygenase responsible for hydroxylation [14]. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 6 Polyketides Produced by Functional Replacement of PikAI Domains from Pik PKS are marked in yellow, those from Tyl PKS are in red, and those from DEBS PKS are in blue. Des represents all eight enzymes for desosamine biosynthesis and transfer [13], and PikC is the cytochrome P450 monooxygenase responsible for hydroxylation [14]. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)

Figure 7 Biological Activity of Fractionated Organic Solvent Extracts from Strains Containing Hybrid PKSs The text below each TLC spot indicates the strain name from which the extract was prepared. The multiple zones of growth inhibition demonstrate the generation of multiple macrolides by a single engineered biosynthetic pathway. Chemistry & Biology 2002 9, 203-214DOI: (10.1016/S1074-5521(02)00095-9)