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首页> 外文期刊>Biochemistry >Synthesis and Characterization of Allosteric Probes of Substrate Channeling in the Tryptophan Synthase Bienzyme Complex
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Synthesis and Characterization of Allosteric Probes of Substrate Channeling in the Tryptophan Synthase Bienzyme Complex

机译：色氨酸合酶双酶复合物中底物通道化的变构探针的合成与表征

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摘要

Allosteric interactions regulate substrate channeling in Salmonella typhimurium tryptophan synthase. The channeling of indole between the alpha- and betalpha-sites via the interconnecting 25 A tunnel is regulated by allosteric signaling arising from binding of ligand to the alpha-site, and covalent reaction of L-Ser at the beta-site. This signaling switches the alpha- and beta-subunits between open conformations of low activity and closed conformations of high activity. Our objective is to synthesize and characterize new classes of alpha-site ligands (ASLs) that mimic the binding of substrates, 3-indole-D-glycerol 3'-phosphate (IGP) or D-glyceraldehyde 3-phosphate (G3P), for use in the investigation of alpha-site-beta-site interactions. The new synthesized IGP analogues contain an aryl group linked to an O-phosphoethanolamine moiety through amide, sulfonamide, or thiourea groups. The G3P analogue, thiophosphoglycolohydroxamate, contains a hydroxamic acid group linked to a thiophosphate moiety. Crystal structures of the internal aldimine complexed with G3P and with three of the new ASLs are presented. These structural and solution studies of the ASL complexes with the internal aldimine form of the enzyme establish the following. (1) ASL binding occurs with high specificity and relatively high affinities at the alpha-site. (2) Binding of the new ASLs slows the entry of indole analogues into the beta-site by blocking the tunnel opening at the alpha-site. (3) ASL binding stabilizes the closed conformations of the beta-subunit for the a-aminoacrylate and quinonoid forms of the enzyme. (4) The new ASLs exhibit allosteric properties that parallel the behaviors of IGP and G3P.
机译：变构相互作用调节鼠伤寒沙门氏菌色氨酸合酶中的底物通道。 α-和betα-位点之间的吲哚经由相互连接的25 A通道通过配体与α-位点的结合以及L-Ser在β-位点的共价反应引起的变构信号调节。该信号转导在低活性的开放构象和高活性的封闭构象之间切换α和β亚基。我们的目标是合成和表征新型α-位配体（ASL），它们可模拟底物，3-吲哚-D-甘油3'-磷酸酯（IGP）或D-甘油醛3-磷酸酯（G3P）的结合，用于研究α-位-β-位的相互作用。新合成的IGP类似物包含通过酰胺，磺酰胺或硫脲基与O-磷酸乙醇胺部分连接的芳基。 G3P类似物，硫代磷酸羟基异羟肟酸酯，含有一个与硫代磷酸酯部分连接的异羟肟酸基团。介绍了与G3P和三种新ASL复合的内部醛亚胺的晶体结构。这些具有内部醛亚胺形式的酶的ASL配合物的结构和溶液研究建立了以下内容。 （1）ASL结合在α位点以高特异性和相对高亲和力发生。 （2）新的ASL的结合通过阻断α位点的通道开口而减慢了吲哚类似物进入β位点的速度。 （3）ASL结合稳定了酶的α-氨基丙烯酸酯和醌型形式的β-亚基的封闭构象。 （4）新的ASL具有与IGP和G3P相似的变构性质。

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