Université de Paris, BFA, UMR 8251, CNRS, 75013, Paris, France; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
Université de Paris, BFA, UMR 8251, CNRS, 75013, Paris, France.
Biochem Biophys Res Commun. 2020 Apr 30;525(2):308-312. doi: 10.1016/j.bbrc.2020.02.082. Epub 2020 Feb 20.
Transglutaminases (TG) and arylamine N-acetyltransferases (NAT) are important family of enzymes. Although they catalyze different reactions and have distinct structures, these two families of enzymes share a spatially conserved catalytic triad (Cys, His, Asp residues). In active TGs, a conserved Trp residue located close to the triad cysteine is crucial for catalysis through stabilization of transition states. Here, we show that in addition to sharing a similar catalytic triad with TGs, functional NAT enzymes also possess in their active site an aromatic residue (Phe, Tyr or Trp) occupying a structural position similar to the Trp residue of active TGs. More importantly, as observed in active TGs, our data indicates that in functional NAT enzymes this conserved aromatic residue is also involved in stabilization of transition states. These results thus indicate that in addition to the three triad residues, these two families of enzymes also share a spatially conserved aromatic amino acid position important for catalysis. Identification of residues involved in the stabilization of transition states is important to develop potent inhibitors. Interestingly, NAT enzymes have been shown as potential targets of clinical interest.
转谷氨酰胺酶（TG）和芳香胺 N-乙酰基转移酶（NAT）是重要的酶家族。虽然它们催化不同的反应且具有不同的结构，但这两个酶家族共享空间保守的催化三联体（Cys、His、Asp 残基）。在活性 TG 中，靠近三联体半胱氨酸的保守色氨酸残基对于通过稳定过渡态至关重要。在这里，我们表明，除了与 TG 共享相似的催化三联体外，功能性 NAT 酶在其活性位点还具有芳香族残基（Phe、Tyr 或 Trp），其占据与活性 TG 的 Trp 残基相似的结构位置。更重要的是，正如在活性 TG 中观察到的那样，我们的数据表明，在功能性 NAT 酶中，这个保守的芳香族残基也参与了过渡态的稳定。因此，这些结果表明，除了三个三联体残基外，这两个酶家族还共享一个对催化重要的空间保守芳香族氨基酸位置。确定参与稳定过渡态的残基对于开发有效的抑制剂很重要。有趣的是，NAT 酶已被证明是具有临床意义的潜在靶点。
