ArticleProceedings of the National Academy of Sciences of the United States of America2008
Genetic dissection of the biosynthetic route to gentamicin A2 by heterologous expression of its minimal gene set.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 62 citations in OpenAlex.
- Review
- Recent advances in the biosynthetic pathway and structural modification of gentamicin.Frontiers in microbiology · 2025Review
- Combinatorial biosynthesis of novel gentamicin derivatives with nonsense mutation readthrough activity and low cytotoxicity.Frontiers in pharmacology · 2025Article
- Recent advances in the biosynthesis and production optimization of gentamicin: A critical review.Synthetic and systems biotechnology · 2025Review
- Glycodiversification of gentamicins throughActa pharmaceutica Sinica. B · 2024Article
- Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes.Nature communications · 2022Article
- Pyridoxal-5'-phosphate-dependent enzyme GenB3 Catalyzes C-3',4'-dideoxygenation in gentamicin biosynthesis.Microbial cell factories · 2021Article
- Complete reconstitution of the diverse pathways of gentamicin B biosynthesis.Nature chemical biology · 2019Article
- Methyltransferases of gentamicin biosynthesis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Parallel pathways in the biosynthesis of aminoglycoside antibiotics.F1000Research · 2017Review
- C3'-Deoxygenation of Paromamine Catalyzed by a Radical S-Adenosylmethionine Enzyme: Characterization of the Enzyme AprD4 and Its Reductase Partner AprD3.Angewandte Chemie (International ed. in English) · 2016Article
- Assembly of a novel biosynthetic pathway for gentamicin B production in Micromonospora echinospora.Microbial cell factories · 2016Article
- Delineating the biosynthesis of gentamicin x2, the common precursor of the gentamicin C antibiotic complex.Chemistry & biology · 2015Article
- Genetic engineering combined with random mutagenesis to enhance G418 production in Micromonospora echinospora.Journal of industrial microbiology & biotechnology · 2014Article
- Specificity and promiscuity at the branch point in gentamicin biosynthesis.Chemistry & biology · 2014Article
- GenK-catalyzed C-6' methylation in the biosynthesis of gentamicin: isolation and characterization of a cobalamin-dependent radical SAM enzyme.Journal of the American Chemical Society · 2013Article
- An insight into the "-omics" based engineering of streptomycetes for secondary metabolite overproduction.BioMed research international · 2013Review
- Radical SAM enzymes in the biosynthesis of sugar-containing natural products.Biochimica et biophysica acta · 2012Review
- Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation.Nature chemical biology · 2011Article
- Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates.Applied and environmental microbiology · 2011Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Since the first use of streptomycin as an effective antibiotic drug in the treatment of tuberculosis, aminoglycoside antibiotics have been widely used against a variety of bacterial infections for over six decades. However, the pathways for aminoglycoside biosynthesis still remain unclear, mainly because of difficulty in genetic manipulation of actinomycetes producing this class of antibiotics. Gentamicin belongs to the group of 4,6-disubstituted aminoglycosides containing a characteristic core aminocyclitol moiety, 2-deoxystreptamine (2-DOS), and the recent discovery of its biosynthetic gene cluster in Micromonospora echinospora has enabled us to decipher its biosynthetic pathway. To determine the minimal set of genes and their functions for the generation of gentamicin A(2), the first pseudotrisaccharide intermediate in the biosynthetic pathway for the gentamicin complex, various sets of candidate genes from M. echinospora and other related aminoglycoside-producing strains were introduced into a nonaminoglycoside producing strain of Streptomyces venezuelae. Heterologous expression of different combinations of putative 2-DOS biosynthetic genes revealed that a subset, gtmB-gtmA-gacH, is responsible for the biosynthesis of this core aminocyclitol moiety of gentamicin. Expression of gtmG together with gtmB-gtmA-gacH led to production of 2'-N-acetylparomamine, demonstrating that GtmG acts as a glycosyltransferase that adds N-acetyl-d-glucosamine (GLcNA) to 2-DOS. Expression of gtmM in a 2'-N-acetylparomamine-producing recombinant S. venezuelae strain generated paromamine. Expression of gtmE in an engineered paromamine-producing strain of S. venezuelae successfully generated gentamicin A(2), indicating that GtmE is another glycosyltransferase that attaches d-xylose to paromamine. These results represent in vivo evidence elucidating the complete biosynthetic pathway of the pseudotrisaccharide aminoglycoside.
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