Ferrier Research Institute, Victoria University of Wellington, Wellington 6140, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand.
Philos Trans R Soc Lond B Biol Sci. 2023 Feb 27;378(1871):20220039. doi: 10.1098/rstb.2022.0039. Epub 2023 Jan 11.
Anthranilate phosphoribosyltransferase catalyses the second reaction in the biosynthesis of tryptophan from chorismate in microorganisms and plants. The enzyme is homodimeric with the active site located in the hinge region between two domains. A range of structures in complex with the substrates, substrate analogues and inhibitors have been determined, and these have provided insights into the catalytic mechanism of this enzyme. Substrate 5-phospho-d-ribose 1-diphosphate (PRPP) binds to the C-terminal domain and coordinates to Mg, in a site completed by two flexible loops. Binding of the second substrate anthranilate is more complex, featuring multiple binding sites along an anthranilate channel. This multi-modal binding is consistent with the substrate inhibition observed at high concentrations of anthranilate. A series of structures predict a dissociative mechanism for the reaction, similar to the reaction mechanisms elucidated for other phosphoribosyltransferases. As this enzyme is essential for some pathogens, efforts have been made to develop inhibitors for this enzyme. To date, the best inhibitors exploit the multiple binding sites for anthranilate. This article is part of the theme issue 'Reactivity and mechanism in chemical and synthetic biology'.
色氨酸合酶（Anthranilate phosphoribosyltransferase）能够催化微生物和植物中从分支酸合成色氨酸的第二步反应。该酶是同源二聚体，其活性位点位于两个结构域之间的铰链区。目前已经确定了一系列与底物、底物类似物和抑制剂结合的结构，这些结构为该酶的催化机制提供了深入了解。底物 5-磷酸-D-核糖-1-二磷酸（PRPP）结合在 C 末端结构域上，并与 Mg 配位，该配位由两个柔性环完成。另一个底物邻氨基苯甲酸的结合更为复杂，在邻氨基苯甲酸通道上有多个结合位点。这种多模式结合与在高浓度邻氨基苯甲酸时观察到的底物抑制一致。一系列结构预测了该反应的解联机制，类似于其他磷酸核糖基转移酶阐明的反应机制。由于该酶对一些病原体是必需的，因此人们一直在努力开发该酶的抑制剂。迄今为止，最好的抑制剂利用了邻氨基苯甲酸的多个结合位点。本文是主题为“化学反应和合成生物学中的反应性和机制”的一部分。
