Pyrophosphate and Irreversibility in Evolution, or why PPi Is Not an Energy Currency and why Nature Chose Triphosphates

The possible evolutionary significance of pyrophosphate (PPi) has been discussed since the early 1960s. Lipmann suggested that PPi could have been an ancient currency or a possible environmental source of metabolic energy at origins, while Kornberg proposed that PPi vectorializes metabolism because ubiquitous pyrophosphatases render PPi forming reactions kinetically irreversible. To test those ideas, we investigated the reactions that consume phosphoanhydride bonds among the 402 reactions of the universal biosynthetic core that generates amino acids, nucleotides, and cofactors from H2, CO2, and NH3. We find that 36% of the core’s phosphoanhydride hydrolyzing reactions generate PPi, while no reactions use PPi as an energy currency. The polymerization reactions that generate ~80% of cell mass – protein, RNA, and DNA synthesis – all generate PPi, while none use PPi as an energy source. In typical prokaryotic cells, aminoacyl tRNA synthetases (AARS) underlie ~80% of PPi production. We show that the irreversibility of the AARS reaction is a kinetic, not a thermodynamic effect. The data indicate that PPi is not an ancient energy currency and probably never was. Instead, PPi hydrolysis is an ancient mechanism that imparts irreversibility, as Kornberg suggested, functioning like a ratchet’s pawl to vectorialize the life process toward growth. The two anhydride bonds in nucleoside triphosphates offer ATP-cleaving enzymes an option to impart either thermodynamic control (Pi formation) or kinetic control (PPi formation) upon reactions. This dual capacity explains why nature chose the triphosphate moiety of ATP as biochemistry’s universal energy currency.

Biotechnological and Biomedical Applications of Enzymes Involved in the Synthesis of Nucleosides and Nucleotides

Nucleic acid derivatives are involved in cell growth and replication, but they are also particularly important as building blocks for RNA and DNA synthesis [...]

Profiling Ribonucleotide and Deoxyribonucleotide Pools Perturbed by Remdesivir in Human Bronchial Epithelial Cells

Remdesivir (RDV) has generated much anticipation for its moderate effect in treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the unsatisfactory survival rates of hospitalized patients limit its application to the treatment of coronavirus disease 2019 (COVID-19). Therefore, improvement of antiviral efficacy of RDV is urgently needed. As a typical nucleotide analog, the activation of RDV to bioactive triphosphate will affect the biosynthesis of endogenous ribonucleotides (RNs) and deoxyribonucleotides (dRNs), which are essential to RNA and DNA replication in host cells. The imbalance of RN pools will inhibit virus replication as well. In order to investigate the effects of RDV on cellular nucleotide pools and on RNA transcription and DNA replication, cellular RNs and dRNs concentrations were measured by the liquid chromatography-mass spectrometry method, and the synthesis of RNA and DNA was monitored using click chemistry. The results showed that the IC50 values for BEAS-2B cells at exposure durations of 48 and 72 h were 25.3 ± 2.6 and 9.6 ± 0.7 μM, respectively. Ten (10) μM RDV caused BEAS-2B arrest at S-phase and significant suppression of RNA and DNA synthesis after treatment for 24 h. In addition, a general increase in the abundance of nucleotides and an increase of specific nucleotides more than 2 folds were observed. However, the variation of pyrimidine ribonucleotides was relatively slight or even absent, resulting in an obvious imbalance between purine and pyrimidine ribonucleotides. Interestingly, the very marked disequilibrium between cytidine triphosphate (CTP) and cytidine monophosphate might result from the inhibition of CTP synthase. Due to nucleotides which are also precursors for the synthesis of viral nucleic acids, the perturbation of nucleotide pools would block viral RNA replication. Considering the metabolic vulnerability of endogenous nucleotides, exacerbating the imbalance of nucleotide pools imparts great promise to enhance the efficacy of RDV, which possibly has special implications for treatment of COVID-19.

The role of zinc in the synthesis and metabolism of thyroid hormones

About one third of the world’s population is deficient in one or more micronutrients, with the most common deficiencies in iodine, iron, zinc, vitamin A and folate. Deficiency of one or more essential vitamins and minerals is usually the result of poor nutrition and / or insufficient absorption of micronutrients as a result of infectious and inflammatory diseases. It is possible that the deficiency of certain trace elements, in turn, can aggravate iodine deficiency and contribute to dysfunction of the thyroid gland. There are assumptions about the relationship between the content of iodine, selenium, iron, zinc in the human body and the level of thyroid hormones. Zinc is a vital trace element for all living organisms, participating in many biochemical processes in cells, including cell differentiation and division, its growth, cell transport, transcription, protein synthesis, RNA and DNA synthesis, and DNA replication. Its role as an antioxidant and participation in the functioning of both innate (T, NK and NKT cells) and adaptive immunity (anti-inflammatory cytokines) are very important. This review will consider the role of zinc in the synthesis and metabolism of thyroid hormones.

The Effect of Mitochondrial Dysfunction on Cytosolic Nucleotide Metabolism

Several enzymes of the metabolic pathways responsible for metabolism of cytosolic ribonucleotides and deoxyribonucleotides are located in mitochondria. Studies described in this paper suggest dysfunction of the mitochondria to affect these metabolic pathways and limit the available levels of cytosolic ribonucleotides and deoxyribonucleotides, which in turn can result in aberrant RNA and DNA synthesis. Mitochondrial dysfunction has been linked to genomic instability, and it is possible that the limiting effect of mitochondrial dysfunction on the levels of nucleotides and resulting aberrant RNA and DNA synthesis in part can be responsible for this link. This paper summarizes the parts of the metabolic pathways responsible for nucleotide metabolism that can be affected by mitochondrial dysfunction.