The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A.
The structure of the PanD/PanZ protein complex reveals negative feedback regulation of pantothenate biosynthesis by coenzyme A.
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DOI：
10.1016/j.chembiol.2015.03.017
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发表时间：
2015-04-23
影响因子：
--
通讯作者：
Webb ME
中科院分区：
文献类型：
--
作者：
Monteiro DCF;Patel V;Bartlett CP;Nozaki S;Grant TD;Gowdy JA;Thompson GS;Kalverda AP;Snell EH;Niki H;Pearson AR;Webb ME
辅酶A(CoA)是由泛酸前体合成的一种普遍存在的必需辅因子。维生素的生物合成途径通常受到严格的调控，包括从泛酸到辅酶A的途径。然而，目前还没有发现泛酸生物合成的调控。我们最近描述了泛酸生物合成途径中的一个额外成分PanZ，它促进酶原PanD的激活，以辅酶A依赖的方式形成天冬氨酸α-脱羧酶(ADC)。在这里，我们报道了PanZ与PanD络合物的结构，揭示了这种相互作用和激活依赖CoA的结构基础。此外，我们还发现PanZ是一种依赖CoA的ADC催化抑制剂。这种抑制作用可以有效地调节泛酸的生物合成途径，从而调节辅酶A的生物合成。这代表了一种以前未观察到的代谢调节模式，即利用辅因子的蛋白质负面调节同一辅因子的生物合成。报道了PanD-PanZ的结构。AcCoA需要AcCoA与PanZ结合才能形成PanZ/PanZ界面。AcCoA通过选择PanD PanZ的反应性构象来激活PanD。AcCoA抑制激活的酶，调节泛酸的生物合成。Monteiro等人确定了PanD与其激活因子PanZ的络合物的结构，揭示了这种相互作用依赖CoA的基础。这种依赖CoA的相互作用被证明抑制了激活的酶的催化作用。这是有关泛酸生物合成调控的首次报道。
Coenzyme A (CoA) is an ubiquitous and essential cofactor, synthesized from the precursor pantothenate. Vitamin biosynthetic pathways are normally tightly regulated, including the pathway from pantothenate to CoA. However, no regulation of pantothenate biosynthesis has been identified. We have recently described an additional component in the pantothenate biosynthetic pathway, PanZ, which promotes the activation of the zymogen, PanD, to form aspartate α-decarboxylase (ADC) in a CoA-dependent manner. Here we report the structure of PanZ in complex with PanD, which reveals the structural basis for the CoA dependence of this interaction and activation. In addition, we show that PanZ acts as a CoA-dependent inhibitor of ADC catalysis. This inhibitory effect can effectively regulate the biosynthetic pathway to pantothenate, and thereby also regulate CoA biosynthesis. This represents a previously unobserved mode of metabolic regulation whereby a cofactor-utilizing protein negatively regulates the biosynthesis of the same cofactor. Structure of the PanD-PanZ.AcCoA complex is reported at a resolution of 1.6 Å Binding of AcCoA to PanZ is required to form the PanZ/PanD interface PanZ.AcCoA activates PanD via selection of a reactive conformation of PanD PanZ.AcCoA inhibits the activated enzyme, regulating pantothenate biosynthesis The structure of the complex of PanD and its activating factor PanZ is determined by Monteiro et al., revealing the basis for the CoA dependence of this interaction. This CoA-dependent interaction is shown to inhibit catalysis by the activated enzyme. This is the first report of regulation of pantothenate biosynthesis.
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影响因子：
3.4
作者：
Nozaki, Shingo;Webb, Michael E.;Niki, Hironori
通讯作者：
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通讯作者：
Svergun DI