Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID‐19 is exaggerated systemic inflammation, regarded as a “cytokine storm,” which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug‐metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin‐converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro‐inflammatory cytokine IL‐6 were upregulated in the lungs of SARS‐CoV‐2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P‐450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re‐purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS‐CoV‐2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.
Proper branching of neuronal dendrites is crucial for healthy brain function. We previously reported that cypin, a guanine deaminase, binds to tubulin heterodimers via its collapsin response mediator protein (CRMP) homology domain (amino acids 350‐403), promoting microtubule assembly in a cell‐free system. This increased microtubule assembly results in increased dendrite number and branching. Here, we ask how cypin alters microtubules in neurons. We found that overexpression of cypin increases the number of and decreases the spacing between microtubules. We also observed that overexpression of cypin increases microtubule polymerization as evidenced by increased movement of end‐binding protein 3 (EB3) comets. To determine whether cypin binds polymerized microtubules in addition to tubulin heterodimers, we performed a series of biochemical and computational experiments. We found that cypin binds to fully formed microtubules but does not prefer microtubule ends or shafts. In addition, preliminary protein‐protein docking strategies suggest that cypin binds to microtubules through several unreported residues near the N‐terminal end of cypin, which form a surface‐exposed loop with several bulky residues. We used structure‐based approaches through docking analyses of “straight” polymerized microtubules and of “curved” soluble tubulin heterodimers and found that cypin binds free heterodimers though its CRMP homology domain along with a small amino acid region near the N‐terminus (residues 43‐63). Molecular dynamics data also suggest that the region of residues 43‐63 is highly flexible and may bind protein partners. Our results suggest that cypin regulates the microtubule cytoskeleton by promoting assembly and stabilizing microtubules.
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