Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK.
Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748). doi: 10.1098/rstb.2017.0068.
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 species involves the DesD-catalysed condensation of various -acylated derivatives of -hydroxycadaverine with two molecules of -succinyl--hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various -acyl--hydroxycadaverine substrates of DesD from -hydroxycadaverine has until now been unclear. Here we show that the gene of encodes the acyl transferase responsible for this process. DesC catalyses the -acylation of -hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the diverse array of desferrioxamines produced by The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of -succinyl--hydroxycadaverine and one of -acetyl--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'.
羟胺基团在各种天然产物的生物功能中起着关键作用。重要的例子包括曲古抑菌素 A，它通过与活性位点锌 (II) 离子配位来抑制组蛋白去乙酰化酶，以及去铁胺，它使用三个羟胺基团螯合三价铁。种的去铁胺生物合成涉及 DesD 催化的各种酰化 -羟基尸胺与两个分子的 -琥珀酰 -羟基尸胺缩合，形成一系列线性和大环三羟胺。然而，到目前为止，DesD 组装各种 -酰基 -羟基尸胺底物的机制尚不清楚。在这里，我们表明编码负责此过程的酰基转移酶的 基因。 DesC 催化 -羟基尸胺与乙酰基、琥珀酰基和肉豆蔻酰 -CoA 的酰化，解释了 产生的各种去铁胺。还确定了铁氧胺脂蛋白受体 DesE 与铁氧胺 B（由两个单位的 -琥珀酰 -羟基尸胺和一个 -乙酰 -羟基尸胺组成）的 X 射线晶体结构。这表明铁氧胺 B 的乙酰基暴露在溶剂中，表明较长链同系物中的相应酰基基团可以从结合口袋中伸出，这为它们的可能功能提供了线索。本文是“表观遗传化学生物学前沿”讨论会议的一部分。
