Callahan Brian P, Lomino Joseph V, Wolfenden Richard
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA.
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3802-5. doi: 10.1016/j.bmcl.2006.04.024. Epub 2006 May 5.
2,3-Dihydroxybenzohydroxamoyl adenylate (I) was prepared as a potential product analog inhibitor of EntE (EC# 2.7.7.58), a 2,3-dihydroxybenzoate AMP ligase from Escherichia coli that is required for the biosynthesis of enterobactin. This compound, obtained by the aqueous reaction of imidazole-activated adenosine 5'-phosphate and 2,3-dihydroxybenzohydroxamic acid, is a competitive inhibitor with a Ki value of 4.5 x 10(-9)M. Deletion of the catecholic 3-OH group of (I), in compound (II), reduced inhibitory activity by a factor of 3.5, whereas, removal of both the 3-OH and 2-OH groups, in (III), reduced inhibitory activity by a factor of approximately 2000. Acetohydroxamoyl adenylate (IV), in which the entire catechol moiety of (I) is replaced by a hydrogen atom, gave <or= 10% inhibition at 6 x 10(-4)M, indicating a reduction in affinity by more than 10(5). The binding free energy of (I) is nearly equivalent to the sum of the corresponding values for adenosine 5'-phosphate and 2,3-dihydroxybenzoate.
2,3 - 二羟基苯甲酰氧肟酸腺苷酸（I）被制备为EntE（EC编号2.7.7.58）的潜在产物类似物抑制剂，EntE是一种来自大肠杆菌的2,3 - 二羟基苯甲酸AMP连接酶，是肠杆菌素生物合成所必需的。该化合物通过咪唑活化的5'-磷酸腺苷与2,3 - 二羟基苯甲羟肟酸的水相反应获得，是一种竞争性抑制剂，Ki值为4.5×10⁻⁹M。在化合物（II）中，（I）的邻苯二酚3 - OH基团缺失，抑制活性降低了3.5倍，而在（III）中，3 - OH和2 - OH基团都被去除，抑制活性降低了约2000倍。乙酰氧肟酸腺苷酸（IV）中，（I）的整个邻苯二酚部分被氢原子取代，在6×10⁻⁴M时抑制率≤10%，表明亲和力降低了超过10⁵倍。（I）的结合自由能几乎等同于5'-磷酸腺苷和2,3 - 二羟基苯甲酸相应值的总和。
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