Santos Ruda de Luna Almeida, Crovella Sergio, Celsi Fulvio
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 Trieste, Italy; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy.
Gene. 2015 Mar 15;559(1):99-101. doi: 10.1016/j.gene.2015.01.029. Epub 2015 Jan 22.
We performed molecular modeling analysis onto a novel mutation in the gene MVK, described by Santos et al., found to be causative of a severe form of Hyper-IgD/Mevalonate Kinase Deficiency. The mutation p.R277G, in our analysis, lowers the binding affinity for some enzyme's substrates. Interestingly, we found that p.R277G mutation inhibits binding of Isopentenyl Pyrophosphate (IPP) (binding free energy=0 kcal/mol), one of isoprenoids responsible for feedback-inhibition of MVK. IPP is known to be an activator of a specific class of T-cells and we can hypothesize that increased levels of this metabolite generate an aberrant immune system response. Indeed other experiments are needed to verify this hypothesis; however, this work demonstrates usefulness of molecular modeling in generating novel pathogenic hypothesis.
我们对桑托斯等人描述的基因MVK中的一种新突变进行了分子建模分析，该突变被发现是导致严重形式的高IgD/甲羟戊酸激酶缺乏症的原因。在我们的分析中，p.R277G突变降低了对某些酶底物的结合亲和力。有趣的是，我们发现p.R277G突变抑制了异戊烯基焦磷酸（IPP）（结合自由能 = 0千卡/摩尔）的结合，IPP是负责MVK反馈抑制的类异戊二烯之一。已知IPP是一类特定T细胞的激活剂，我们可以推测这种代谢物水平的升高会产生异常的免疫系统反应。确实需要其他实验来验证这一假设；然而，这项工作证明了分子建模在生成新的致病假设方面的有用性。
