Crystallographic evidence for the action of potassium, thallium, and lithium ions on fructose-1,6-bisphosphatase.
Crystallographic evidence for the action of potassium, thallium, and lithium ions on fructose-1,6-bisphosphatase.
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钾、铊和锂离子对果糖 1,6-二磷酸酶作用的晶体学证据。
DOI：
10.1073/pnas.92.19.8916
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发表时间：
1995
影响因子：
11.1
通讯作者：
Lipscomb,WN
中科院分区：
文献类型：
--
作者：
Villeret,V;Huang,S;Fromm,HJ;Lipscomb,WN
果糖-1,6-二磷酸水解酶（fru -1,6- pase； d -果糖-1,6-二磷酸1-磷酸水解酶，EC 3.1.3.11）需要两个二价金属离子来水解α - d -果糖1,6-二磷酸。虽然不是催化所必需的，但一价阳离子可以修饰酶的活性；K+和Tl+离子是活化剂，而Li+离子是抑制剂。它们的作用机制尚不清楚。本文报道了猪肾fru -1,6- pase与K+、Tl+或Tl+和Li+络合的晶体结构。在T形式的fru -1,6- pase与底物类似物2,5-无水- d -葡糖醇1,6-二磷酸（ahg -1,6- p2）和Tl+或K+离子络合时，发现了三个Tl+或K+结合位点。位点1由Glu-97、Asp-118、Asp-121、Glu-280和ahg -1,6- p2的1-磷酸氧定义；位点2由Glu-97、Glu-98、Asp-118和Leu-120定义。最后，位点3由Arg-276、Glu-280和ahg -1,6- p2的1-磷酸基定义。位1和位2上的Tl+或K+离子与先前确定的二价金属离子的位置非常接近。位点3对K+或Tl+有特异性。在二价金属离子配合物中，位3被Arg-276的胍基占据。这些观察结果表明，Tl+或K+离子可以在活性位点取代Arg-276，使1-磷酸基团极化，从而促进对磷中心的亲核攻击。在T型与Tl+和Li+离子配合时，Li+取代了金属位1上的Tl+。锂的抑制作用很可能发生，因为它与该位点结合，从而延缓了周转或磷酸盐的释放。本研究为肌醇单磷酸酶的抑制机制提供了结构基础，肌醇单磷酸酶是锂离子治疗躁狂抑郁症的潜在靶点之一。
Fructose-1,6-bisphosphatase (Fru-1,6-Pase; D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) requires two divalent metal ions to hydrolyze alpha-D-fructose 1,6-bisphosphate. Although not required for catalysis, monovalent cations modify the enzyme activity; K+ and Tl+ ions are activators, whereas Li+ ions are inhibitors. Their mechanisms of action are still unknown. We report here crystallographic structures of pig kidney Fru-1,6-Pase complexed with K+, Tl+, or both Tl+ and Li+. In the T form Fru-1,6-Pase complexed with the substrate analogue 2,5-anhydro-D-glucitol 1,6-bisphosphate (AhG-1,6-P2) and Tl+ or K+ ions, three Tl+ or K+ binding sites are found. Site 1 is defined by Glu-97, Asp-118, Asp-121, Glu-280, and a 1-phosphate oxygen of AhG-1,6-P2; site 2 is defined by Glu-97, Glu-98, Asp-118, and Leu-120. Finally, site 3 is defined by Arg-276, Glu-280, and the 1-phosphate group of AhG-1,6-P2. The Tl+ or K+ ions at sites 1 and 2 are very close to the positions previously identified for the divalent metal ions. Site 3 is specific to K+ or Tl+. In the divalent metal ion complexes, site 3 is occupied by the guanidinium group of Arg-276. These observations suggest that Tl+ or K+ ions can substitute for Arg-276 in the active site and polarize the 1-phosphate group, thus facilitating nucleophilic attack on the phosphorus center. In the T form complexed with both Tl+ and Li+ ions, Li+ replaces Tl+ at metal site 1. Inhibition by lithium very likely occurs as it binds to this site, thus retarding turnover or phosphate release. The present study provides a structural basis for a similar mechanism of inhibition for inositol monophosphatase, one of the potential targets of lithium ions in the treatment of manic depression.