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Proteome-wide analysis of non-synonymous single-nucleotide variations in active sites of human proteins.
MedLine Citation:
PMID:  23350563     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
An enzyme's active site is essential to normal protein activity such that any disruptions at this site may lead to dysfunction and disease. Non-synonymous single nucleotide variations (nsSNVs), which alter the amino acid sequence, are one type of disruption that can alter the active site. When this occurs, it is assumed enzyme activity will vary because of the criticality of the site to normal protein function. We integrate nsSNV data and active site annotations from curated resources to identify all active-site-impacting-nsSNVs in the human genome and search for all pathways observed to be associated with this dataset to assess the likely consequences. We find that there are 934 unique nsSNVs that occur at the active sites of 559 proteins. Analysis of the nsSNV data shows an over-representation of arginine and an under-representation of cysteine, phenylalanine and tyrosine when comparing the list of nsSNV-impacted active site residues to the list of all possible proteomic active site residues, implying a potential bias for or against variation of these residues at the active site. Clustering analysis shows an abundance of hydrolases and transferases. Pathway and functional analysis shows several pathways over- or under-represented in the dataset with the most significantly affected pathways involved in carbohydrate metabolism. We provide a table of 32 variation-substrate/product pairs that can be used in targeted metabolomics experiments to assay the effects of specific variations. Additionally, we report the significant prevalence of aspartic acid to histidine variation in 8 proteins associated with 9 diseases including Glycogen storage diseases, Lacrimo-auriculo-dento-digital syndrome, Parkinson's disease and several cancers. © 2013 The Authors Journal compilation © 2013 FEBS.
Authors:
Hayley Dingerdissen; Mona Motwani; Konstantinos Karagiannis; Vahan Simonyan; Raja Mazumder
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-28
Journal Detail:
Title:  The FEBS journal     Volume:  -     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors Journal compilation © 2013 FEBS.
Affiliation:
Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC, 20037, United States of America.
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