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Serendipitous Discovery of α-Hydroxyalkyl Esters as β-Lactamase Substrates

机译：偶然发现α-羟烷基酯作为β-内酰胺酶底物

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O-(1-Carboxy-1-alkyloxycarbonyl) hydroxamates were found to spontaneously decarboxylate innaqueous neutral buffer to formO-(2-hydroxyalkylcarbonyl) hydroxamates.While the former molecules do not reactnrapidly with serine β-lactamases, the latter are quite good substrates of representative class A and C, but not D,nenzymes, and particularly of a class C enzyme. The enzymes catalyze hydrolysis of these compounds to a mixture ofnthe R-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather thatnhydroxamates are also substrates. Structure-activity experiments showed that the R-hydroxyl group was requirednfor any substantial substrate activity. Although bothD-and L-R-hydroxy acid derivatives were substrates, the formernwere preferred. The response of the class C activity to pH and to alternative nucleophiles (methanol andnD-phenylalanine) suggested that the same active site functional groups participated in catalysis as for classicalnsubstrates. Molecular modeling was employed to explore how the R-hydroxy group might interact with the class Cnβ-lactamase active site. Incorporation of theR-hydroxyalkylmoiety into novel inhibitorswill be of considerable interest.
机译：发现O-（1-羧基-1-烷氧基羰基）异羟肟酸酯可自发地将不饱和中性缓冲液脱羧形成O-（2-羟烷基羰基）异羟肟酸酯，尽管前一种分子不与丝氨酸β-内酰胺酶发生快速反应，但后者是β-内酰胺酶的良好底物。代表性的A和C类酶，但不包括D类酶，尤其是C类酶。所述酶催化这些化合物水解为R-羟基酸和异羟肟酸酯的混合物。含有芳氧基离去基团而不是异羟肟酸酯的类似化合物也是底物。结构活性实验表明，R-羟基对于任何基本的底物活性都是必需的。尽管D-和L-R-羟基酸衍生物都是底物，但前者是优选的。 C类活性对pH和其他亲核试剂（甲醇和nD-苯丙氨酸）的响应表明，与经典底物一样，相同的活性位点官能团也参与了催化。分子模型被用来探索R-羟基如何与Cnβ-内酰胺酶活性位点相互作用。将R-羟烷基部分掺入新型抑制剂中将是令人关注的。

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  • 来源
    《Biochemistry》 |2010年第49期|p.10496-10506|共11页
  • 作者

    Ryan B. Pelto and R. F. Pratt;

  • 作者单位

    Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459, United States;

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