Computational Prediction of Phylogenetically Conserved Sequence Motifs for Five Different Candidate Genes in Type II Diabetic Nephropathy
Sindhu, T., Rajamanikandan, S., Srinivasan, P., Iranian Journal of Public Health
Background: Computational identification of phylogenetic motifs helps to understand the knowledge about known functional features that includes catalytic site, substrate binding epitopes, and protein-protein interfaces. Furthermore, they are strongly conserved among orthologs, indicating their evolutionary importance. The study aimed to analyze five candidate genes involved in type II diabetic nephropathy and to predict phylogenetic motifs from their corresponding orthologous protein sequences.
Methods: AKR1B1, APOE, ENPP1, ELMO1 and IGFBP1 are the genes that have been identified as an important target for type II diabetic nephropathy through experimental studies. Their corresponding protein sequences, structures, orthologous sequences were retrieved from UniprotKB, PDB, and PHOG database respectively. Multiple sequence alignments were constructed using ClustalW and phylogenetic motifs were identified using MINER. The occurrence of amino acids in the obtained phylogenetic motifs was generated using WebLogo and false positive expectations were calculated against phylogenetic similarity.
Results: In total, 17 phylogenetic motifs were identified from the five proteins and the residues such as glycine, leucine, tryptophan, aspartic acid were found in appreciable frequency whereas arginine identified in all the predicted PMs. The result implies that these residues can be important to the functional and structural role of the proteins and calculated false positive expectations implies that they were generally conserved in traditional sense.
Conclusion: The prediction of phylogenetic motifs is an accurate method for detecting functionally important conserved residues. The conserved motifs can be used as a potential drug target for type II diabetic nephropathy.
Keywords: Diabetic nephropathy, Conserved regions, Phylogenetic motifs, PHOG1.0, MINER
Diabetes mellitus is characterized by the metabolic disorders of carbohydrate, lipid, and protein. "Type II diabetes mellitus is one of the primary threats to human health due to increasing prevalence, chronic course and disabling complications" (1, 2). Diabetic nephropathy (DN) is a major microvascular complication that affects 30-40% of all diabetic patients and represents a major cause of morbidity and mortality, due to a serious gradual decline in renal function (3). Several genes, proteins, and environmental factors are likely to contribute to the onset of the disease DN (4). Several candidate genes have been identified for the association with DN using case-control studies. They were selected for their positional and/or functional characteristics and the contribution of the corresponding proteins in the pathophysiological axes (5).
The expression of AKR1B1 gene has been seen in human kidneys. It catalyzes the reduction of glucose to sorbitol. In hyperglycaemic condition, this pathway becomes activated by excess amount of glucose, whereas in case of normal condition, it is relatively inactive. High levels of sorbitol accumulation disrupt osmoregulation in kidney cells, which leads to kidney damage (6). ELMO1 is promoting excess transcription growth factor-β, collagen type 1, fibronectin and integrin-linked kinase expression and inhibiting cell adhesion when it is over expressed. ELMO1 is expressed in the presence of high glucose and it has a potential role in the pathogenesis of diabetic nephropathy (7). Insulin like growth factor binding proteins plays a major role in cell growth and metabolism. It influences cell adhesion and migration and interacts with α5β1. Over expression of IGFBP1 is associated with many glomerular diseases, including diabetic nephropathy (8).
Ectonucleotidepyrophosphate/ phosphodiesterase 1 is a candidate susceptibility gene for type 2 diabetes and obesity. It helps to catalyze the release of nucleoside 5- phosphatase from nucleotides and their products. ENPP1 is expressed in several tissues such as skeletal tissue, adipose tissue, liver and kidney tissues. …