Rajić Martina, Stare Jernej
Theory Department, Laboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
J Chem Inf Model. 2025 Apr 14;65(7):3439-3450. doi: 10.1021/acs.jcim.4c01698. Epub 2025 Mar 26.
Brunner syndrome is a rare genetic disorder characterized by impulsive aggressiveness and intellectual disability, which is linked to impaired function of the monoamine oxidase A (MAO-A) enzyme. Patients with specific point mutations in the gene have been reported to exhibit these symptoms, along with notably elevated serotonin levels, which suggest a decreased catalytic performance of the mutated MAO-A enzymes. In this study, we present multiscale molecular simulations focusing on the rate-limiting step of MAO-A-catalyzed serotonin degradation for the C266F and V244I variants that are reportedly associated with pathologies characteristic of the Brunner syndrome. We found that the C266F mutation causes an approximately 18,000-fold slowdown of enzymatic function, which is equivalent to a gene knockout. For the V244I mutant, a somewhat smaller, yet still significant 300-fold slowdown has been estimated. Furthermore, we conducted a comprehensive comparison of the impact of enzyme electrostatics on the catalytic function of the wild-type (WT) MAO-A and both aforementioned mutants (C266F and V244I), as well as on the E446K mutant investigated in one of our earlier studies. The results have shown that the mutation induces a noteworthy change in electrostatic interactions between the reacting moiety and its enzymatic surroundings, leading to a decreased catalytic performance in all of the considered MAO-A variants. An analysis of mutation effects supported by geometry comparison of mutants and the wild-type enzyme at a residue level suggests that a principal driving force behind the altered catalytic performance of the mutants is subtle structural changes scattered along the entire enzyme. These shifts in geometry also affect domains most relevant to catalysis, where structural offsets of few tenths of an Å can significantly change contribution to the barrier of the involved residues. These results are in full agreement with the reasoning derived from clinical observations and biochemical data. Our research represents a step forward in the attempts of using fundamental principles of chemical physics in order to explain genetically driven pathologies. In addition, our results support the view that the catalytic function of enzymes is crucially driven by electrostatic interactions.
布鲁纳综合征是一种罕见的遗传性疾病，其特征为冲动攻击性和智力残疾，与单胺氧化酶A（MAO - A）功能受损有关。据报道，该基因发生特定点突变的患者会出现这些症状，同时血清素水平显著升高，这表明突变的MAO - A酶催化性能下降。在本研究中，我们针对据报道与布鲁纳综合征特征性病理相关的C266F和V244I变体，开展了聚焦于MAO - A催化血清素降解限速步骤的多尺度分子模拟。我们发现，C266F突变导致酶功能减慢约18000倍，这相当于基因敲除。对于V244I突变体，估计减慢程度稍小，但仍显著，为300倍。此外，我们全面比较了酶静电对野生型（WT）MAO - A以及上述两个突变体（C266F和V244I）催化功能的影响，以及对我们早期一项研究中所研究的E446K突变体的影响。结果表明，突变导致反应部分与其酶环境之间的静电相互作用发生显著变化，从而导致所有考虑的MAO - A变体的催化性能下降。在残基水平上对突变体和野生型酶进行几何比较所支持的突变效应分析表明，突变体催化性能改变背后的主要驱动力是沿整个酶分散的细微结构变化。这些几何结构的变化也会影响与催化最相关的结构域，在这些结构域中，几十分之一埃的结构偏移会显著改变相关残基对能垒的贡献。这些结果与临床观察和生化数据得出的推断完全一致。我们的研究代表了在尝试运用化学物理基本原理来解释基因驱动的病理学方面向前迈进的一步。此外，我们的结果支持了酶的催化功能关键由静电相互作用驱动这一观点。
