Volume 16, Issue 11, Pages (November 2009)

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Volume 16, Issue 11, Pages 1180-1189 (November 2009) Biosynthesis of the Aminocyclitol Subunit of Hygromycin A in Streptomyces hygroscopicus NRRL 2388 Nadaraj Palaniappan, Vidya Dhote, Sloan Ayers, Agata L. Starosta, Daniel N. Wilson, Kevin A. Reynolds Chemistry & Biology Volume 16, Issue 11, Pages 1180-1189 (November 2009) DOI: 10.1016/j.chembiol.2009.10.013 Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 1 Relationship between Hygromycin A Analogs and the Biosynthetic Pathway Leading to the Aminocyclitol Moiety The three structural moieties, 5-dehydro-α-L-fucofuranose (subunit A), (E)-3-(3,4-dihydroxyphenyl)-2-methylacrylic acid (subunit B), and 2L-2-amino-2-deoxy-4,5-O-methylene-neo-inositol (subunit C) are indicated. Chemistry & Biology 2009 16, 1180-1189DOI: (10.1016/j.chembiol.2009.10.013) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 2 Effect of Methyltransferase gene (hyg6, hyg29) Disruptions on Hygromycin A Production (A) Reverse-phase HPLC analysis of fermentation broths of wild-type, Δhyg29, and Δhyg6 strains. Disruption of hyg29 caused a decrease in hygromycin A production. Disruption of hyg6 resulted in the generation of new metabolites with shorter retention times than hygromycin A. (B) Mass spectrometric analysis (negative mode) of Δhyg6 fermentation broth. Two new species were identified with [M-H]- values of 498 and 500 corresponding to desmethylenehygromycin A (5) and 5″-dihydrodesmethylenehygromycin A (6), respectively. Chemistry & Biology 2009 16, 1180-1189DOI: (10.1016/j.chembiol.2009.10.013) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 3 Effect of hyg7 Gene Disruption on Hygromycin A Production (A) Reverse-phase HPLC analysis of Δhyg7 fermentation broth. The Δhyg7 strain produced only compound 3. Restoration of HA production was observed upon subunit C supplementation as seen in the HPLC chromatogram “Δhyg7-C.” (B) HPLC analysis of Δhyg7 fermentation supplemented with C subunit in the presence of [2-3H] myo-inositol or [carboxyl-14C] 4-hydroxybenzoic acid. Δhyg7-C-MI(UV) and Δhyg7-C-pHBA(UV) are UV traces of fermentation broth of Δhyg7 supplemented with subunit C in the presence of [2-3H] myo-inositol and [carboxyl-14C] 4-hydroxybenzoic acid, respectively. Δhyg7-C-MI(R) and Δhyg7-C-pHBA(R) represent the radiolabeled traces recorded by Beta-Ram (R) radioactivity quantization system for their respective UV traces. This analysis clearly indicated the role of hyg7 in the cyclization step of methylenedioxy bridge formation. Chemistry & Biology 2009 16, 1180-1189DOI: (10.1016/j.chembiol.2009.10.013) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 4 Effect of Hygromycin A and Derivatives on In Vitro Transcription-Translation (A) Detection of template-dependent synthesis of GFP using fluorescence in the absence or presence of increasing concentrations (μM) of the antibiotic hygromycin A (HA), methoxyhygromycin A (3), desmethylenehygromycin A (5), or 5″-dihydroAB subunit (7) (see Figure 1 for structures). (B) Quantitation of (A). GFP fluorescence is given as a percentage where 100% is defined as the fluorescence detected in the absence of the antibiotic. Chemistry & Biology 2009 16, 1180-1189DOI: (10.1016/j.chembiol.2009.10.013) Copyright © 2009 Elsevier Ltd Terms and Conditions