COVID-19 and One-Carbon Metabolism

Abstract

Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B12 deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease.

Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology

“…Finally, we observed a modest, but significant increase (FC<1.5, p-value<0.05) in levels of serine in patients with mild/moderate and severe COVID-19, albeit to a lower extent in the latter group. Altered levels of serine associated with variable outcomes have been documented in other metabolomic analyses [ 68 , 86 , 87 ]. In this regard, it was shown that serine supplementation decreased ROS damage in mice with oxidative stress through direct involvement in GSH synthesis [ 88 ]; the property of promoting glycolysis and GSH production is apparently unique to this amino acid [ 89 ].…”

An Altered Metabolism in Leukocytes Showing in vitro igG Memory From SARS-CoV-2-Infected Patients

“…So since the methylation (capping) of viral RNA is necessary for its life cycle, a high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19 (Kryukov et al, 2021). Metabolomic analyses revealed that SAM was significantly elevated in critical cases of COVID-19 and those with a fatal outcome as compared to control, mild and moderate cases of COVID-19 (Roberts et al, 2021;Perła-Kaján and Jakubowski, 2022).…”

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…In the nucleus, following heterodimer complex formation with transcription factors, like small Maf proteins (G/F/K) and c-Jun, Nrf2 complexes bind to the antioxidant response element (ARE), a regulatory enhancer region within gene promoters that upregulate antioxidant and 10.3389/fmicb. 2022.979719 Frontiers in Microbiology 13 frontiersin.org anti-inflammatory defense processes (Cuadrado et al, 2019;McCord et al, 2020;Perła-Kaján and Jakubowski, 2022). Since SARS-CoV-2 mediates Nrf2 suppression and limits host anti-inflammatory response McCord et al, 2020;Olagnier et al, 2020;Emanuele et al, 2021;Fratta Pasini et al, 2021), targeting Nrf2 is therefore essential for the treatment of diseases characterized by enhanced oxidative stress and inflammation, such as aging and COVID-19-induced pneumonia and ARDS (Lewis et al, 2010;Lee, 2018;Robledinos-Antón et al, 2019;Schmidlin et al, 2019;Lin and Yao, 2020).…”

“…Since oxidative stress plays an important role in the pathogenesis of viral-associated cardiovascular and lung diseases, antioxidant intervention would be a rational approach to use for treating lower respiratory tract infections ( Komaravelli and Casola, 2014 ) and balancing oxidative damage by enhancing antioxidant defense ( Banjac et al, 2008 ; Chen et al, 2020 ; Sharifi-Rad et al, 2020 ; Perła-Kaján and Jakubowski, 2022 ) could be a major strategy for a successful intervention against SARS-CoV-2 infection and COVID-19 disease. Since SARS-CoV-2 activates mitochondrial ROS-mediated feedback loops that produce long-term changes in the redox status and endothelial function of the host, leading to cardiovascular disease and lung injury ( Chang et al, 2021 ), and endothelial cells are key players in inflammatory pathologies, such as acute respiratory distress syndrome, thrombosis, and atherosclerosis; the use of pro-GSH molecules ( Fraternale et al, 2006 ) and/or glutathione precursors like N-acetyl cysteine (NAC), glutamine, cysteine (cystine) and glycine, as well as nuclear factor erythroid 2 p45–related factor 2 (Nrf2) inducers like sulforaphane can enhance glutathione production and increase nuclear Nrf2 translocation and antioxidant response element (ARE) transcription ( Komaravelli and Casola, 2014 ; Atefi et al, 2020 ; Poe and Corn, 2020 ; Dominari et al, 2021 ; Obayan, 2021 ; Di Marco et al, 2022 ).…”

“…NRF2 inducers, like sulforaphane modify cysteine sensors of Keap1 and inactivate its repressor function. The liberation of Nrf2 from Keap1 allows Nrf2 accumulation and translocation to the nucleus ( Cuadrado et al, 2019 ; McCord et al, 2020 ; Perła-Kaján and Jakubowski, 2022 ). In the nucleus, following heterodimer complex formation with transcription factors, like small Maf proteins (G/F/K) and c-Jun, Nrf2 complexes bind to the antioxidant response element (ARE), a regulatory enhancer region within gene promoters that upregulate antioxidant and anti-inflammatory defense processes ( Cuadrado et al, 2019 ; McCord et al, 2020 ; Perła-Kaján and Jakubowski, 2022 ).…”