Evaluating the Accuracy of the QCEIMS Approach for Computational Prediction of Electron Ionization Mass Spectra of Purines and Pyrimidines

Mass spectrometry is the most commonly used method for compound annotation in metabolomics. However, most mass spectra in untargeted assays cannot be annotated with specific compound structures because reference mass spectral libraries are far smaller than the complement of known molecules. Theoretically predicted mass spectra might be used as a substitute for experimental spectra especially for compounds that are not commercially available. For example, the Quantum Chemistry Electron Ionization Mass Spectra (QCEIMS) method can predict 70 eV electron ionization mass spectra from any given input molecular structure. In this work, we investigated the accuracy of QCEIMS predictions of electron ionization (EI) mass spectra for 80 purine and pyrimidine derivatives in comparison to experimental data in the NIST 17 database. Similarity scores between every pair of predicted and experimental spectra revealed that 45% of the compounds were found as the correct top hit when QCEIMS predicted spectra were matched against the NIST17 library of >267,000 EI spectra, and 74% of the compounds were found within the top 10 hits. We then investigated the impact of matching, missing, and additional fragment ions in predicted EI mass spectra versus ion abundances in MS similarity scores. We further include detailed studies of fragmentation pathways such as retro Diels–Alder reactions to predict neutral losses of (iso)cyanic acid, hydrogen cyanide, or cyanamide in the mass spectra of purines and pyrimidines. We describe how trends in prediction accuracy correlate with the chemistry of the input compounds to better understand how mechanisms of QCEIMS predictions could be improved in future developments. We conclude that QCEIMS is useful for generating large-scale predicted mass spectral libraries for identification of compounds that are absent from experimental libraries and that are not commercially available.

The Intersection of Purine and Mitochondrial Metabolism in Cancer

Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.

Nitrosative stress parameters and the level of oxidized DNA bases in patients with multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease with various factors affecting its etiology. Overproduction of nitric oxide and subsequent lesions of biopolymers are some of the possible causes of the disease. This study aimed to measure the most relevant nitrosative and oxidative stress biomarkers and the level of modified DNA bases in patients with MS. Each parameter was assayed in 25 patients with MS and 25 healthy controls. This study involved detecting blood plasma and serum nitric oxide metabolites by chemiluminescence detector Sievers NOA-280i, malondialdehyde (MDA) measurements with thiobarbituric acid reactive substance (TBARS) assay, detection of oxidized purines and pyrimidines with the enzyme-modified comet assay. Statistical analysis of the results was performed by one-way analysis of variance (ANOVA) and unpaired t test for the comparison of less than three data sets. DNA single-strand breaks, levels of modified purines and pyrimidines, as well as nitrite and nitrate levels in plasma and serum samples, were significantly higher in patients with MS than in healthy controls. On the contrary, MDA levels appeared to be lower in patients with MS.

Data Types and the Phylogeny of Neoaves

The phylogeny of Neoaves, the largest clade of extant birds, has remained unclear despite intense study. The difficulty associated with resolving the early branches in Neoaves is likely driven by the rapid radiation of this group. However, conflicts among studies may be exacerbated by the data type analyzed. For example, analyses of coding exons typically yield trees that place Strisores (nightjars and allies) sister to the remaining Neoaves, while analyses of non-coding data typically yield trees where Mirandornites (flamingos and grebes) is the sister of the remaining Neoaves. Our understanding of data type effects is hampered by the fact that previous analyses have used different taxa, loci, and types of non-coding data. Herein, we provide strong corroboration of the data type effects hypothesis for Neoaves by comparing trees based on coding and non-coding data derived from the same taxa and gene regions. A simple analytical method known to minimize biases due to base composition (coding nucleotides as purines and pyrimidines) resulted in coding exon data with increased congruence to the non-coding topology using concatenated analyses. These results improve our understanding of the resolution of neoavian phylogeny and point to a challenge—data type effects—that is likely to be an important factor in phylogenetic analyses of birds (and many other taxonomic groups). Using our results, we provide a summary phylogeny that identifies well-corroborated relationships and highlights specific nodes where future efforts should focus.

Purines and Pyrimidines: Metabolism, Function and Potential as therapeutic options in neurodegenerative diseases

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

Data Types and the Phylogeny of Neoaves

The phylogeny of Neoaves, the largest clade of extant birds, has remained unclear despite intense study. The difficulty associated with resolving the early branches in Neoaves is likely driven by the rapid radiation of this group. However, conflicts among studies may be exacerbated by the hypothesis that relationships are sensitive to the data type analyzed. For example, analyses of coding exons typically yield trees that place Strisores (nightjars and allies) sister to the remaining Neoaves, while analyses of non-coding data typically yield trees where Mirandornites (flamingos and grebes) is the sister of the remaining Neoaves. Our understanding of data type effects is hampered by the fact that previous analyses have used different taxa, loci, and types of non-coding data. Herein, we provide strong corroboration of the data type effects hypothesis for Neoaves by comparing trees based on coding and non-coding data derived from the same taxa and gene regions. A simple analytical method known to minimize biases due to base composition (coding nucleotides as purines and pyrimidines) resulted in coding exon data with increased congruence to the non-coding topology using concatenated analyses. These results improve our understanding of the resolution of neoavian phylogeny and point to a challenge - data type effects - that is likely to be an important factor in phylogenetic analyses of birds (and many other taxonomic groups). Using our results, we provide a summary phylogeny that identifies well-corroborated relationships and highlights specific nodes where future efforts should focus.

The Role of Purinergic Receptors in the Circadian System

The circadian system is an internal time-keeping system that synchronizes the behavior and physiology of an organism to the 24 h solar day. The master circadian clock, the suprachiasmatic nucleus (SCN), resides in the hypothalamus. It receives information about the environmental light/dark conditions through the eyes and orchestrates peripheral oscillators. Purinergic signaling is mediated by extracellular purines and pyrimidines that bind to purinergic receptors and regulate multiple body functions. In this review, we highlight the interaction between the circadian system and purinergic signaling to provide a better understanding of rhythmic body functions under physiological and pathological conditions.

Effect of Laser Radiation on Biomolecules

Time of flight laser photoionization has been used to study the response of some molecules of biological interest under laser radiation. One of the questions of great interest today is the effect of radiation on DNA and RNA molecules. Damage to these molecules can be caused directly by radiation or indirectly by secondary electrons created by radiation. As response of the radiation field fragmentation process can occur producing different ions with kinetic energies of a few electron volts. In this paper we present the results of the interaction of 355nm laser with the nitrogen bases adenine(A) and uracil(U) using time-of-flight spectrometry and the comparison of experimental results on the effects of laser radiation in (A) and (U) belonging to two different ring groups, purines and pyrimidines respectively,which are linked to form the AU pair of the RNA.

Potential Therapeutic Applications of P2 Receptor Antagonists: From Bench to Clinical Trials

Background: Extracellular purines and pyrimidines have important physiological functions in mammals. Purines and pyrimidines act on P1 and P2 purinergic receptors, which are widely expressed in the plasma membrane in various cell types. P2 receptors act as important therapeutic targets and are associated with several disorders, such as pain, neurodegeneration, cancer, inflammation, and thrombosis. However, the use of antagonists for P2 receptors in clinical therapy, with the exception of P2Y12, is a great challenge. Currently, many research groups and pharmaceutical companies are working on the development of specific antagonist molecules for each receptor subtype that could be used as new medicines to treat their respective disorders. Objective: The present review compiles some interesting findings on the application of P2 receptor antagonists in different in vitro and in vivo experimental models as well as the progress of advanced clinical trials with these compounds. Conclusion: Despite all of the exciting results obtained on the bench, few antagonists of P2 receptors advanced to the clinical trials, and once they reach this stage, the effectiveness of the therapy is not guaranteed, as in the example of P2X7 antagonists. Despite this, P2Y12 receptor antagonists have a history of success and have been used in therapy for at least two decades to prevent thrombosis in patients at risk for myocardial infarctions. This breakthrough is the motivation for scientists to develop new drugs with antagonistic activity for the other P2 receptors; thus, in a matter of years, we will have an evolution in the field of purinergic therapy.