An In Silico Functional Analysis of Non-Synonymous Single-Nucleotide Polymorphisms of Bovine CMAH Gene and Potential Implication in Pathogenesis

Abstract

The sugar molecule N-glycolylneuraminic acid (Neu5Gc) is one of the most common sialic acids discovered in mammals. Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) catalyses the conversion of N-acetylneuraminic acid (Neu5Ac) to Neu5Gc, and it is encoded by the CMAH gene. On the one hand, food metabolic incorporation of Neu5Gc has been linked to specific human diseases. On the other hand, Neu5Gc has been shown to be highly preferred by some pathogens linked to certain bovine diseases. We used various computational techniques to perform an in silico functional analysis of five non-synonymous single-nucleotide polymorphisms (nsSNPs) of the bovine CMAH (bCMAH) gene identified from the 1000 Bull Genomes sequence data. The c.1271C>T (P424L) nsSNP was predicted to be pathogenic based on the consensus result from different computational tools. The nsSNP was also predicted to be critical based on sequence conservation, stability, and post-translational modification site analysis. According to the molecular dynamic simulation and stability analysis, all variations promoted stability of the bCMAH protein, but mutation A210S significantly promoted CMAH stability. In conclusion, c.1271C>T (P424L) is expected to be the most harmful nsSNP among the five detected nsSNPs based on the overall studies. This research could pave the way for more research associating pathogenic nsSNPs in the bCMAH gene with diseases.

Molecular Structural Analysis of Porcine CMAH–Native Ligand Complex and High Throughput Virtual Screening to Identify Novel Inhibitors

“…This can arise from various factors, among which is possible inherent protein flexibility, which could have impacted the convergence [76,77] and is associated with large conformational changes [76], multiple stable conformations [78], or intrinsically disordered regions [76]. Intrinsically disordered regions of the CMAH protein were also observed in our previous study on the predicted impacts of mutations on bovine CMAH [79].…”

Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis

“…Experimental investigation of the impact of various nsSNPs is an expensive, time-consuming, and challenging process. However, employing in silico analysis through web-based computational methods is a feasible, effective, and affordable approach for investigating numerous SNPs in specific genes 44 , 45 .…”