Computational screening of pathogenic missense nsSNPs in heme oxygenase 1 (HMOX1) gene and their structural and functional consequences.
Arvind Kumar YadavThirupathihalli Pandurangappa Krishna MurthyGangaraju DivyashriDurga Prasad NSriraksha PrakashVijaya Vaishnavi VRohit ShuklaTiratha Raj SinghPublished in: Journal of biomolecular structure & dynamics (2023)
Heme Oxygenase 1 (HMOX1) is a cytoprotective enzyme, exhibiting the highest activity in the spleen, catalyzing the heme ring breakdown into products of biological significance- biliverdin, CO, and Fe 2+ . In vascular cells, HMOX1 possesses strong anti-apoptotic, antioxidant, anti-proliferative, anti-inflammatory, and immunomodulatory actions. The majority of these activities are crucial for the prevention of atherogenesis. Single amino acid substitutions in proteins generated by missense non-synonymous single nucleotide polymorphism (nsSNPs) in the protein-encoding regions of genes are potent enough to cause significant medical challenges due to the alteration of protein structure and function. The current study aimed at characterizing and analyzing high-risk nsSNPs associated with the human HMOX1 gene. Preliminary screening of the total available 288 missense SNPs was performed through the lens of deleteriousness and stability prediction tools. Finally, a total of seven nsSNPs (Y58D, A131T, Y134H, F166S, F167S, R183S and M186V) were found to be most deleterious by all tools that are present at highly conserved positions. Molecular dynamics simulations (MDS) analysis explained the mutational effects on the dynamic action of the wild-type and mutant proteins. In a nutshell, R183S (rs749644285) was identified as a highly detrimental mutation that could significantly render the enzymatic activity of HMOX1. The finding of this computational analysis might help subject the experimental confirmatory analysis to characterize the role of nsSNPs in HMOX1. Communicated by Ramaswamy H. Sarma.
Keyphrases
- anti inflammatory
- molecular dynamics simulations
- amino acid
- genome wide
- wild type
- intellectual disability
- healthcare
- oxidative stress
- induced apoptosis
- transcription factor
- cell death
- dna methylation
- cell proliferation
- nitric oxide
- genome wide identification
- binding protein
- signaling pathway
- gene expression
- molecular docking
- endoplasmic reticulum stress
- pluripotent stem cells