Small Structural Differences in Proline-Rich Decapeptides Have Specific Effects on Oxidative Stress-Induced Neurotoxicity and L-Arginine Generation by Arginosuccinate Synthase

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 17; no. 7; p. 931
• Main Authors: Alberto-Silva, Carlos, da Silva, Brenda Rufino, da Silva, Julio Cezar Araujo, Cunha E Silva, Felipe Assumpção da, Kodama, Roberto Tadashi, da Silva, Wilmar Dias, Costa, Maricilia Silva, Portaro, Fernanda Calheta Vieira
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.07.2024
• Subjects: Amino acids; bioactive peptide; Cells; Kinases; Metabolism; Metabolites; neuroprotective; Neurotoxicity; Oxidative stress; PC12 cells; Peptides; Polyamines; proline-rich peptide; snake venom; Snakes; Toxicity; snake venom; proline-rich peptide; bioactive peptide; neuroprotective; PC12 cells; oxidative stress
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17070931

The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuroprotective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, <ENWPRPKIPP; Bn-PRO-10a-MK, <ENWPRPKIPPMK; and, Bn-PRO-10c, <ENWPRPKVPP) identified from snake venom, with a high degree of similarity to Bj-PRO-10c, on oxidative stress-induced toxicity in neuronal PC12 cells and L-arginine metabolite generation via AsS activity regulation. Cell integrity, metabolic activity, reactive oxygen species (ROS) production, and arginase activity were examined after 4 h of PRO pre-treatment and 20 h of H O -induced damage. Only Bn-PRO-10a-MK and Bn-PRO-10c restored cell integrity and arginase function under oxidative stress settings, but they did not reduce ROS or cell metabolism. The MK dipeptide in Bn-PRO-10a-MK and valine (V8) in Bn-PRO-10c are important to these effects when compared to Bn-PRO-10a. Bj-PRO-10c is not neuroprotective in PC12 cells, perhaps because of their limited NMDA-type glutamate receptor activity. The PROs interaction analysis on AsS activation can be rated as follows: Bj-PRO-10c > Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10c potentiated their affinity for AsS. Our investigation provides the first insights into the structure and molecular interactions of PROs with AsS, which could possibly further their neuropharmacological applications.