INSILICO INVESTIGATION OF MISSENSE MUTATIONS IN SDH5 GENE USING DIFFERENT GENOMIC ALGORITHMS
Objective: Nonsynonymous single nucleotide polymorphism (nsSNP) has a deleterious effect on a protein, thereby leading to a disease. Succinate dehydrogenase complex 5 (SDH5) gene, which encodes for a mitochondrial protein is responsible for the flavination of succinate dehydrogenase complex and also plays a major role in Kreb's cycle. Mutations in this gene lead to the cancerous diseases such as paraganglioma and pheochromocytoma. The aim of this paper is to excavate the deleterious mutations in SDH5.
Method: The deleterious mutations in SDH5is evaluated by assorted genomic algorithmsand to find the drug binding affinity by docking the current drug against the mutated protein using Molecular docking Server. A total of 20 mutation were retrieved from SNP NCBI. The structural and the functional aspectsof these 20 mutations were analysed by using various genomics algorithmssuch as SIFT, PolyPhen2.0, I-Mutant 2.0, SNPs & GO, PANTHER and PhD-SNP, which helped us narrowing down our search to G78R and L80S as the deleterious missense mutations. The drug cyclophosphamide, used for the treatment of these cancerous diseases was considered for our study. Drug-protein interactions were studied using protein docking server. Binding efficiency of the cyclophosphamide drug with the most deleterious mutations was calculated.
Result: G78Rwas found to be deleterious and confirmed that the mutation decrease the stability of the protein.
Conclusion: Our findings lead to the better understanding of the deleterious mutations in SDH5, providing immense knowledge on the cancerous diseases, such as paraganglioma and pheochromocytoma, and drug docking mechanisms which will be extremely useful in the discovery of new treatmentsagainst such diseases.Keywords: Cyclophosphamide, Molecular docking, Paraganglioma, Pheochromocytoma, SDH5 gene
Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP,
Kunst H, et al. SDH5, a gene required for flavination of
succinate dehydrogenase, is mutated in paraganglioma. Science
Kim HJ, Winge DR. Emerging concepts in the flavinylation of succinate
dehydrogenase. Biochim Biophys Acta 2013;1827(5):627-36.
Grimm S. Respiratory chain complex II as general sensor for apoptosis.
Biochim Biophys Acta 2013;1827(5):565-72.
Opocher G, Schiavi F. Functional consequences of succinate
dehydrogenase mutations. Endocr Pract 2011;17 Suppl 3:64-71.
Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma:
Understanding the complexities of the genetic background. Cancer
Liu J, Gao L, Zhang H, Wang D, Wang M, Zhu J, et al. Succinate
dehydrogenase 5 (SDH5) regulates glycogen synthase kinase
ÃŸ-ÃŸ-catenin-mediated lung cancer metastasis. J Biol Chem
Nadeau JH. Single nucleotide polymorphisms: Tackling complexity.
Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs:
Server and survey. Nucleic Acids Res 2002;30(17):3894-900.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding nonsynonymous
variants on protein function using the SIFT algorithm. Nat
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect
protein function. Nucleic Acids Res 2003;31(13):3812-4.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A,
Bork P, et al. A method and server for predicting damaging missense
mutations. Nat Methods 2010;7(4):248-9.
Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: Predicting stability
changes upon mutation from the protein sequence or structure. Nucleic
Acids Res 2005;33:W306-10.
Capriotti E, Fariselli P, Rossi I, Casadio R. A three-state prediction of
single point mutations on protein stability changes. BMC Bioinformatics
;9 Suppl 2:S6.
Mi H, Dong Q, Muruganujan A, Gaudet P, Lewis S, Thomas PD.
Panther version 7: Improved phylogenetic trees, orthologs and
collaboration with the Gene Ontology Consortium. Nucleic Acids Res
Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R,
et al. Panther: A library of protein families and subfamilies indexed by
function. Genome Res 2003;13(9):2129-41.
Capriotti E, Calabrese R, Casadio R. Predicting the insurgence of
human genetic diseases associated to single point protein mutations with
support vector machines and evolutionary information. Bioinformatics
Schwede T, Kopp J, Guex N, Peitsch MC. Swiss-model: An
automated protein homology-modeling server. Nucleic Acids Res
Kimura S, Iwai M, Fukuda T, Akamatsu T, Ochi F, Masugi J, et al.
Combination chemotherapy for malignant paraganglioma. Intern Med
Bikadi Z, Hazai E Application of the PM6 semi-empirical method
to modeling proteins enhances docking accuracy of AutoDock.
J Cheminform 2009;1:15.
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