Strauss Erick, Begley Tadhg P
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York, 14853, USA.
J Biol Chem. 2002 Dec 13;277(50):48205-9. doi: 10.1074/jbc.M204560200. Epub 2002 Oct 7.
Pantothenic acid (vitamin B(5)) is the natural precursor of coenzyme A (CoA), an essential cofactor in all organisms. The pantothenic acid antimetabolite N-pentylpantothenamide inhibits the growth of Escherichia coli with a minimum inhibitory concentration of 2 microm. In this study, we examine the mechanism of this inhibition. Using the last five enzymes of the CoA biosynthetic pathway in E. coli we demonstrate that N-pentylpantothenamide does not inhibit the CoA biosynthetic enzymes but instead acts as an alternative substrate, forming the CoA analog ethyldethia-CoA. We show that N-pentylpantothenamide is converted to ethyldethia-CoA 10.5 times faster than CoA is biosynthesized from pantothenic acid, demonstrating that ethyldethia-CoA biosynthesis can effectively compete with CoA biosynthesis in the cell. We conclude that the mechanism of toxicity of N-pentylpantothenamide is most likely due to its biosynthetic conversion to the CoA analog ethyldethia-CoA, which may act as an inhibitor of CoA- and acetyl-CoA-utilizing enzymes.
泛酸（维生素B5）是辅酶A（CoA）的天然前体，CoA是所有生物体中一种必需的辅助因子。泛酸抗代谢物N-戊基泛酰胺抑制大肠杆菌的生长，最低抑菌浓度为2微摩尔。在本研究中，我们研究了这种抑制作用的机制。利用大肠杆菌中CoA生物合成途径的最后五种酶，我们证明N-戊基泛酰胺并不抑制CoA生物合成酶，而是作为一种替代底物，形成CoA类似物乙二硫代CoA。我们表明，N-戊基泛酰胺转化为乙二硫代CoA的速度比泛酸生物合成CoA的速度快10.5倍，这表明乙二硫代CoA的生物合成可以有效地在细胞内与CoA的生物合成竞争。我们得出结论，N-戊基泛酰胺的毒性机制很可能是由于其生物合成转化为CoA类似物乙二硫代CoA，后者可能作为CoA和乙酰CoA利用酶的抑制剂。
