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Inhibition and Mechanism of Plasmodium falciparum Hypoxanthine–Guanine–Xanthine Phosphoribosyltransferase
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-11-22 , DOI: 10.1021/acschembio.2c00546 Yacoba V T Minnow 1 , Kajitha Suthagar 2 , Keith Clinch 2 , Rodrigo G Ducati 1 , Agnidipta Ghosh 1 , Joshua N Buckler 2 , Rajesh K Harijan 1 , Sean M Cahill 1 , Peter C Tyler 2 , Vern L Schramm 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-11-22 , DOI: 10.1021/acschembio.2c00546 Yacoba V T Minnow 1 , Kajitha Suthagar 2 , Keith Clinch 2 , Rodrigo G Ducati 1 , Agnidipta Ghosh 1 , Joshua N Buckler 2 , Rajesh K Harijan 1 , Sean M Cahill 1 , Peter C Tyler 2 , Vern L Schramm 1
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Plasmodium falciparum hypoxanthine–guanine–xanthine phosphoribosyltransferase (PfHGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state analogue inhibitors of PfHGXPRT are characterized by kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound 1, 9-deazaguanine linked to an acyclic ribocation phosphonate mimic, shows a kinetic Ki of 0.5 nM. Isothermal titration calorimetry (ITC) experiments of 1 binding to PfHGXPRT reveal enthalpically driven binding with negative cooperativity for the binding of two inhibitor molecules in the tetrameric enzyme. Crystal structures of 1 bound to PfHGXPRT define the hydrogen bond and ionic contacts to complement binding thermodynamics. Dynamics of ribosyl transfer from 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) to hypoxanthine were examined by 18O isotope exchange at the bridging phosphoryl oxygen of PRPP pyrophosphate. Rotational constraints or short transition state lifetimes prevent torsional rotation and positional isotope exchange of bridging to nonbridging oxygen in the α-pyrophosphoryl group. Thermodynamic analysis of the transition state analogue and magnesium pyrophosphate binding reveal random and cooperative binding to PfHGXPRT, unlike the obligatory ordered reaction kinetics reported earlier for substrate kinetics.
中文翻译：
恶性疟原虫次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶的抑制作用及其机制
恶性疟原虫次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶 ( Pf HGXPRT) 对于将次黄嘌呤补救为寄生虫嘌呤核苷酸至关重要。Pf HGXPRT 的过渡态类似物抑制剂的特征在于动力学分析、热力学参数和 X 射线晶体结构。化合物1，9-脱氮鸟嘌呤与无环核糖化膦酸酯模拟物连接，显示出 0.5 nM 的动力学K i。1与Pf HGXPRT结合的等温滴定量热法 (ITC) 实验揭示了焓驱动的结合与四聚体酶中两个抑制剂分子结合的负协同性。的晶体结构1绑定到Pf HGXPRT 定义氢键和离子接触以补充结合热力学。核糖基从 5-磷酸-α- d-核糖基1-焦磷酸 (PRPP) 转移到次黄嘌呤的动力学通过18 O 同位素交换在 PRPP 焦磷酸的桥磷酰氧处进行检查。旋转约束或较短的过渡态寿命可防止扭转旋转和桥接至 α-焦磷酰基中的非桥接氧的位置同位素交换。过渡态类似物和焦磷酸镁结合的热力学分析揭示了与Pf HGXPRT 的随机和协同结合，这与之前针对底物动力学报道的强制性有序反应动力学不同。
更新日期：2022-11-22
中文翻译：
恶性疟原虫次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖转移酶的抑制作用及其机制
恶性疟原虫次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶 ( Pf HGXPRT) 对于将次黄嘌呤补救为寄生虫嘌呤核苷酸至关重要。Pf HGXPRT 的过渡态类似物抑制剂的特征在于动力学分析、热力学参数和 X 射线晶体结构。化合物1，9-脱氮鸟嘌呤与无环核糖化膦酸酯模拟物连接，显示出 0.5 nM 的动力学K i。1与Pf HGXPRT结合的等温滴定量热法 (ITC) 实验揭示了焓驱动的结合与四聚体酶中两个抑制剂分子结合的负协同性。的晶体结构1绑定到Pf HGXPRT 定义氢键和离子接触以补充结合热力学。核糖基从 5-磷酸-α- d-核糖基1-焦磷酸 (PRPP) 转移到次黄嘌呤的动力学通过18 O 同位素交换在 PRPP 焦磷酸的桥磷酰氧处进行检查。旋转约束或较短的过渡态寿命可防止扭转旋转和桥接至 α-焦磷酰基中的非桥接氧的位置同位素交换。过渡态类似物和焦磷酸镁结合的热力学分析揭示了与Pf HGXPRT 的随机和协同结合，这与之前针对底物动力学报道的强制性有序反应动力学不同。
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