The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ·AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan).
The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ·AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan).
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DOI：
10.1021/acs.biochem.7b00509
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发表时间：
2017-09-19
期刊：
影响因子：
2.9
通讯作者：
Webb ME
中科院分区：
文献类型：
--
作者：
Arnott ZLP;Nozaki S;Monteiro DCF;Morgan HE;Pearson AR;Niki H;Webb ME
抗代谢物戊基泛酸酰胺具有广谱抗生素活性，但对大肠杆菌表现出增强的活性。PanDZ复合物被认为是调节E.通过响应辅酶A浓度限制β-丙氨酸的供应来抑制大肠杆菌。我们表明，激活的天冬氨酸脱羧酶（PanD）和PanZ之间形成这样的复合物导致螯合的乙酰丙酮辅因子作为酮水合物，并证明这两个PanZ过表达相关的β-丙氨酸营养缺陷型和戊基泛酸酰胺毒性是由于这种复合物的形成。这两者都表明PanDZ复合物在细胞环境中调节泛酸的生物合成，并验证了该复合物作为抗生素开发的靶点。
The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of β-alanine in response to coenzyme A concentration. We show that formation of such a complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked β-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development.
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