Altered main metabolites pathway and dysregulated urea cycle in AMN-SARS-CoV-2:
Pathway analysis conducted via PubChem and KEGG unveiled significantly dysregulated pathways, including arginine biosynthesis, arginine and proline metabolism, D-arginine and D-D-ornithine metabolism, glycine, serine, and threonine metabolism, and D-amino acid metabolism (Supplementary figure 1A and 1B). The dysregulated arginine metabolism pathway was pivotal in AMN-SARS-CoV-2. Specifically, the urea cycle, pivotal in arginine metabolism (Figure 2A), demonstrated a significant role in AMN-SARS-CoV-2. Although plasma arginine levels showed no significant variance between the AMN-SARS-CoV-2 and AMN-SARS-CoV-2-no AMN groups in this study, notable increases were observed in ornithine and citrulline levels within the AMN-SARS-CoV-2 group. Both are critical intermediate metabolites in the urea cycle (Figure 2B), indicative of urea cycle dysregulation in AMN-SARS-CoV-2. Furthermore, ornithine’s capacity to convert into proline, utilized for synthesizing structural proteins, particularly collagen involved in fibrosis, has been reported[18]. In this study, the AMN-SARS-CoV-2 group demonstrated significantly elevated proline levels compared to the AMN-SARS-CoV-2-no AMN group (Figure 2B). Receiver operating characteristic (ROC) analysis of ornithine, citrulline, and L-proline yielded an area under the curve (AUC) values of 0.7704, 0.7296, and 0.7704, respectively (Figure 2C).