Computational Insights into the Regeneration of Ovothiol and Ergothioneine and Their Selenium Analogues by Glutathione.

Ovothiol and ergothioneine are powerful antioxidants that readily react with oxidants by forming their respective disulfides. In fact, ovothiol is widely considered one of the most powerful natural antioxidants. However, for these antioxidants to be again involved in reacting with oxidants, they must be regenerated via the reduction of the disulfide bonds. In the present work, the regeneration of the antioxidants ovothiol and ergothioneine and their selenium analogues, by the closed-shell nucleophilic attack of glutathione, was investigated using density functional theory. From the calculated thermodynamic data, the attack of glutathione on OSSO and EYYE (where Y = S and/or Se) will readily occur in solution. Moreover, in comparison to the reference reaction GSH + GSSG → GSSG + GSH, all reactions are expected to be faster. Overall, the results presented herein show that the key antioxidant GSH should readily recycle ovothiol, ovoselenol, ergothioneine, and ergoseloneine from OYYO and EYYE (where Y = S and/or Se).

Metabolomics Pilot Study Identifies Desynchronization of 24-H Rhythms and Distinct Intra-patient Variability Patterns in Critical Illness: A Preliminary Report.

Background: Synchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites. Methods: We monitored daily rhythms in 5 healthy controls and 5 ICU patients for 24 h. Heart rate and blood pressure were measured every 30 min, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 h. Bedside sound levels were measured every minute. Twenty-four hours rhythms were evaluated in vitals and putatively identified plasma metabolites individually and in each group using the cosinor method. Results: ICU patient rooms were significantly louder than healthy controls' rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant 24-h rhythms individually and as a group. While a few ICU patients had significant 24-h rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient's samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls. Conclusions: In this pilot study, ICU patients' 24-h rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients' clinical courses longitudinally. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.

Density Functional Theory Investigation of As(III) S-Adenosylmethionine Methyltransferase.

Arsenic is one of the most pervasive environmental toxins. It enters our water and food supply through many different routes, including the burning of fossil fuels, the application of arsenic-based herbicides, and natural sources. Using a density functional theory (DFT) cluster approach, the mechanism of arsenic (III) S-adenosylmethionine methyltransferases and various selenium-containing analogues was investigated. Notably, the methylation of arsenic by arsenic (III) S-adenosylmethionine is proposed to be a way to remove arsenic from contaminated water or soil. From the DFT cluster results, it was found that the selective substitution of the active-site Cys44, Cys72, and Cys174 residues with selenocysteines had a marginal effect on the barrier for CH3 transfer. Specifically, the average Gibbs activation energy was calculated to be only 4.2 kJ mol-1 lower than the Gibbs activation energy of 107.4 kJ mol-1 for the WT enzyme. However, importantly, it was found that with selective mutation, the methylation process becomes considerably more exergonic, where the methylation reaction can be made to be 26.4 kJ mol-1 more exergonic than the reaction catalyzed by the WT enzyme. Therefore, we propose that the selective substitution of the active-site Cys44, Cys72 and Cys174 residues with selenocysteines could make the process of methylation and volatilization more advantageous for bioremediation.