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Structural and functional dissection of aminocoumarin antibiotic biosynthesis: a review

DOI: 10.1007/s10969-012-9138-2 DOI Help

Authors: David Lawson (John Innes Centre) , Clare Stevenson (John Innes Centre)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Structural And Functional Genomics , VOL 13 , PAGES 125 - 133

State: Published (Approved)
Published: May 2012
Diamond Proposal Number(s): 303

Abstract: Aminocoumarin antibiotics are natural products of soil-dwelling bacteria called Streptomycetes. They are potent inhibitors of DNA gyrase, an essential bacterial enzyme and validated drug target, and thus have attracted considerable interest as potential templates for drug development. To date, aminocoumarins have not seen widespread clinical application on account of their poor pharmacological properties. Through studying the structures and mechanisms of enzymes from their biosynthetic pathways we will be better informed to redesign these compounds through rational pathway engineering. Novobiocin, the simplest compound, requires at least seventeen gene products to convert primary metabolites into the mature antibiotic. We have solved the crystal structures of four diverse biosynthetic enzymes from the novobiocin pathway, and used these as three-dimensional frameworks for the interpretation of functional and mechanistic data, and to speculate about how they might have evolved. The structure determinations have ranged from the routine to the challenging, necessitating a variety of different approaches.

Journal Keywords: Antibiotic Biosynthesis; Enzyme Evolution; Structure Determination; Streptomyces

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography

Other Facilities: SRS Daresbury

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