Halim Mohammad A, Almatarneh Mansour H, Poirier Raymond A
Department of Chemistry, Memorial University , St. John's, NL, Canada A1B 3X7.
J Phys Chem B. 2014 Mar 6;118(9):2316-30. doi: 10.1021/jp4107266. Epub 2014 Feb 21.
Glutamine--a popular nutritional supplement, non-toxic amino acid, and an essential interorgan and intercellular ammonia transporter--can destroy the neurons' mitochondria. When glutamine enters (like a Trojan horse) into the mitochondria, in the presence of glutaminase, it reacts with water and yields glutamate and excess ammonia which opens gates in the membrane of the mitochondria and thereby destroys it. The mechanistic details underlying the molecular basis of the catabolic production of excess ammonia remain unclear. In the present paper, both 5-oxoproline-mediated and direct pathways for glutamine deamidation are studied using wave function and density functional theories. The mechanisms are studied both in the gas phase and in aqueous solution using the polarizable continuum model (PCM) and solvent model on density (SMD) solvation models. Among three glutamine deamidation pathways, a two-step pathway, GDB, shows the lowest gas phase barrier height of 189 kJ/mol with the G3MP2B3 level of theory. Incorporation of solvent through PCM and SMD models reduces the barrier height to 183 and 174 kJ/mol, respectively. For the hydrolysis of 5-oxoproline, a two-step mechanism, pathway PH-B, provides a lower gas phase energy barrier (187 kJ/mol) compared to one-step (201 kJ/mol) and three-step (227 kJ/mol) pathways at G3MP2B3. Although direct hydrolysis with OH(-), pathway DHE, has the lowest gas phase barrier of 135 kJ/mol, the solvent has little effect on the barrier. For the direct hydrolysis with OH(-)/H2O, pathway DHF, the overall barrier is 143 kJ/mol, in the gas phase at G3MP2B3. In aqueous solution, the overall barrier decreases to 76 and 75 kJ/mol with PCM and SMD, respectively, at B3LYP/6-31+G(d,p), making this the most plausible mechanism. Compared to PCM, SMD predicts lower barriers for nearly all pathways investigated.
谷氨酰胺——一种广受欢迎的营养补充剂、无毒氨基酸以及重要的器官间和细胞间氨转运体——会破坏神经元的线粒体。当谷氨酰胺（如特洛伊木马般）进入线粒体后，在谷氨酰胺酶的作用下，它与水反应生成谷氨酸和过量的氨，这些氨会打开线粒体膜上的通道，从而破坏线粒体。过量氨分解代谢产生的分子基础背后的机制细节仍不清楚。在本文中，使用波函数和密度泛函理论研究了5-氧代脯氨酸介导的和谷氨酰胺脱酰胺的直接途径。在气相和水溶液中使用极化连续介质模型（PCM）和密度溶剂化模型（SMD）研究了这些机制。在三种谷氨酰胺脱酰胺途径中，两步途径GDB在G3MP2B3理论水平下显示出最低的气相势垒高度，为189 kJ/mol。通过PCM和SMD模型引入溶剂后，势垒高度分别降至183和174 kJ/mol。对于5-氧代脯氨酸的水解，两步机制途径PH-B在G3MP2B3水平下比一步（201 kJ/mol）和三步（227 kJ/mol）途径提供了更低的气相能垒（187 kJ/mol）。尽管与OH(-)的直接水解途径DHE具有最低的气相势垒135 kJ/mol，但溶剂对势垒的影响很小。对于与OH(-)/H2O的直接水解途径DHF，在G3MP2B3气相中总势垒为143 kJ/mol。在水溶液中，在B3LYP/6-31+G(d,p)水平下，使用PCM和SMD时总势垒分别降至76和75 kJ/mol，这使其成为最合理的机制。与PCM相比，SMD预测几乎所有研究途径的势垒更低。
