Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability.
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PloS one
2024
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| _version_ | 1868266280142766083 |
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| author | Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen |
| author_facet | Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen |
| collection | PubMed - marine biology |
| contents | Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability. Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen Monophenol Monooxygenase Humans Polymorphism, Single Nucleotide Protein Stability Computational Biology Binding Sites Mutation Tyrosinase, a copper-containing oxidase, plays a vital role in the melanin biosynthesis pathway. Mutations in the tyrosinase gene can disrupt the hydroxylation of tyrosine, leading to decreased production of 3,4-dihydroxyphenylalanine (DOPA). Consequently, this impairs the subsequent formation of dopaquinone, a key precursor in melanin pigment synthesis. This study aimed to identify the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) within the TYR gene that exert an influence on the human TYR protein. Additionally, we evaluated the impact of 10 FDA-approved drugs on the protein stability of mutated structures, exploring the potential for inhibitory pharmaceutical interventions. Through various bioinformatics tools, we detected 47900 nsSNPs, particularly K142M, I151N, M179R, S184L, L189P, and C321R, which were found to be the most deleterious variants, decreasing the protein stability. These drugs (Sapropterin, Azelaic Acid, Menobenzone, Levodopda, Mequinol, Arbutin, Hexylresorcinol, Artenimol, Alloin and Curcumin) interacted with the binding sites in four mutant models K142M, I151N, M179R, and S184L proving that these ligands directly bind with the active site of mutant tyrosinase protein to inhibit it's working. On the other hand, two mutant models L189P and C321R did not show any binding site residue interaction with any ligands. In conclusion, this in-silico analysis of deleterious nsSNPs in the TYR gene, coupled with the evaluation of ligands/drugs on mutated tyrosinase structures not only advances our understanding of molecular variations but also highlights promising pathways for targeted inhibitory interventions in the intricate network of melanin biosynthesis. |
| format | Artículo científico |
| id | pubmed_39541331 |
| institution | PubMed |
| language | en |
| publishDate | 2024 |
| publisher | PloS one |
| record_format | pubmed |
| spellingShingle | Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability. Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen Monophenol Monooxygenase Humans Polymorphism, Single Nucleotide Protein Stability Computational Biology Binding Sites Mutation Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability. Fan, Wei Ji, Heng Li Kakar, Mohibullah Ahmed, Shabbir Alobaid, Hussah M Shakir, Yasmeen Monophenol Monooxygenase Humans Polymorphism, Single Nucleotide Protein Stability Computational Biology Binding Sites Mutation Tyrosinase, a copper-containing oxidase, plays a vital role in the melanin biosynthesis pathway. Mutations in the tyrosinase gene can disrupt the hydroxylation of tyrosine, leading to decreased production of 3,4-dihydroxyphenylalanine (DOPA). Consequently, this impairs the subsequent formation of dopaquinone, a key precursor in melanin pigment synthesis. This study aimed to identify the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) within the TYR gene that exert an influence on the human TYR protein. Additionally, we evaluated the impact of 10 FDA-approved drugs on the protein stability of mutated structures, exploring the potential for inhibitory pharmaceutical interventions. Through various bioinformatics tools, we detected 47900 nsSNPs, particularly K142M, I151N, M179R, S184L, L189P, and C321R, which were found to be the most deleterious variants, decreasing the protein stability. These drugs (Sapropterin, Azelaic Acid, Menobenzone, Levodopda, Mequinol, Arbutin, Hexylresorcinol, Artenimol, Alloin and Curcumin) interacted with the binding sites in four mutant models K142M, I151N, M179R, and S184L proving that these ligands directly bind with the active site of mutant tyrosinase protein to inhibit it's working. On the other hand, two mutant models L189P and C321R did not show any binding site residue interaction with any ligands. In conclusion, this in-silico analysis of deleterious nsSNPs in the TYR gene, coupled with the evaluation of ligands/drugs on mutated tyrosinase structures not only advances our understanding of molecular variations but also highlights promising pathways for targeted inhibitory interventions in the intricate network of melanin biosynthesis. |
| title | Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability. |
| topic | Monophenol Monooxygenase Humans Polymorphism, Single Nucleotide Protein Stability Computational Biology Binding Sites Mutation |
| url | https://pubmed.ncbi.nlm.nih.gov/39541331/ |