Desferrioxamine biosynthesis: diverse hydroxamate assembly by substrate-tolerant acyl transferase DesC
Autor: | Jade L. Ronan, Lona M. Alkhalaf, James H. Naismith, Gregory L. Challis, Stephen A. McMahon, Nadia Kadi |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Stereochemistry Iron Streptomyces coelicolor Deferoxamine Hydroxamic Acids Ferric Compounds General Biochemistry Genetics and Molecular Biology Fungal Proteins Acylation 03 medical and health sciences chemistry.chemical_compound Biosynthesis medicine Transferase Receptors Lipoprotein Hydroxamic acid 030102 biochemistry & molecular biology biology Chemistry Active site Articles biology.organism_classification QR 030104 developmental biology Trichostatin A biology.protein General Agricultural and Biological Sciences Acyltransferases Acyl group medicine.drug |
Zdroj: | Philosophical Transactions of the Royal Society B, Biological Sciences. 373(1748) |
ISSN: | 1471-2970 0962-8436 |
Popis: | Hydroxamate groups play key roles in the biological function of diverse natural products. Important examples include trichostatin A, which inhibits histone deacetylases via coordination of the active site zinc(II) ion with a hydroxamate group, and the desferrioxamines, which use three hydroxamate groups to chelate ferric iron. Desferrioxamine biosynthesis in Streptomyces species involves the DesD-catalysed condensation of various N -acylated derivatives of N -hydroxycadaverine with two molecules of N -succinyl- N -hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various N -acyl- N -hydroxycadaverine substrates of DesD from N -hydroxycadaverine has until now been unclear. Here we show that the desC gene of Streptomyces coelicolor encodes the acyl transferase responsible for this process. DesC catalyses the N -acylation of N -hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the diverse array of desferrioxamines produced by S. coelicolor . The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of N -succinyl- N -hydroxycadaverine and one of N -acetyl- N -hydroxycadaverine) was also determined. This showed that the acetyl group of ferrioxamine B is solvent exposed, suggesting that the corresponding acyl group in longer chain congeners can protrude from the binding pocket, providing insights into their likely function. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology'. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’. |
Databáze: | OpenAIRE |
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