Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction

Abstract

Brunner syndrome is a disorder characterized by intellectual disability and impulsive, aggressive behavior associated with deficient function of the monoamine oxidase A (MAO-A) enzyme. These symptoms (along with particularly high serotonin levels) have been reported in patients with two missense variants in MAO-A (p.R45W and p.E446K). Herein, we report molecular simulations of the rate-limiting step of MAO-A-catalyzed serotonin degradation for these variants. We found that the R45W mutation causes a 6000-fold slowdown of enzymatic function, whereas the E446K mutation causes a 450-fold reduction of serotonin degradation rate, both of which are practically equivalent to a gene knockout. In addition, we thoroughly compared the influence of enzyme electrostatics on the catalytic function of both the wild type MAO-A and the p.R45W variant relative to the wild type enzyme, revealing that the mutation represents a significant electrostatic perturbation that contributes to the barrier increase. Understanding genetic disorders is closely linked to understanding the associated chemical mechanisms, and our research represents a novel attempt to bridge the gap between clinical genetics and the underlying chemical physics.

Inhibitory mechanism of vortioxetine on CYP450 enzymes in human and rat liver microsomes

“…Similar paper could also be found that several minor structural differences of x-ray crystal structures of zebrafish P450s 17A1 and 17A2, as well as with human P450 17A1, may be critical in understanding the basis of lyase function ( Pallan et al, 2015a ). Moreover, serotonin levels are controlled beside reuptake by the enzyme monoamine oxidase A (MAO-A) and that impaired MAO A leads to pathology that cannot be treated pharmacologically ( Prah et al, 2020 ; Prah et al, 2022 ).…”

Monitoring Enzyme Activity Using Near-Infrared Fluorescent Single-Walled Carbon Nanotubes

“…While enzymes operate with high specificity in the biological regime, significant deviations from their specificity can occur depending on substrate concentration, reaction conditions, and the presence of other molecules . Additionally, genetic mutations can alter the enzyme structure, potentially leading to the formation of unwanted side products with possible harmful biological effects . Therefore, optical tools, particularly those operational in the biological transparency window that can offer real-time product fingerprinting of enzyme activity are of paramount importance in the field of disease diagnostics.…”

“… 128 Additionally, genetic mutations can alter the enzyme structure, potentially leading to the formation of unwanted side products with possible harmful biological effects. 129 Therefore, optical tools, particularly those operational in the biological transparency window that can offer real-time product fingerprinting of enzyme activity are of paramount importance in the field of disease diagnostics. While this approach offers the advantage of directly screening the product of enzyme activity, challenges may arise from possible limited stability of the product in a biological medium and its preferential reactivity with other chemical species present in complex biological environments.…”

Review of β‐carboline and its derivatives as selective MAO‐A inhibitors

“…In fact, electrostatic interactions are significantly affected when positively charged lysine (E446K) replaces a negatively charged glutamate, as in Brunner syndrome, where the Serotonin degradation is 450-fold slower as a result of this mutation. [25] It has been reported that the essential amino acids on the mutant protein's interface modify the interaction at the interface, which may result in altered interactions. [26] Figure 2 depicts the mechanism of the rate-limiting step in the MAO-A catalyzed serotonin breakdown that features the hydride transfer that is hypothesized by Prah et al [24] One such family of natural chemicals known as (MAO) inhibitors has been studied therapeutically as an antidepressant and as a therapy for Parkinson's disease (PD) and social anxiety.…”