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Human active site nsSNV-containing genes have yeast orthologs with active site and pathway conservation: validation and analysis of potential for targeted metabolomics and diagnostics

Friday, November 08, 2013 — Poster Session III

10:00 a.m. – 12:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • H.M. Dingerdissen
  • P. Karp
  • D. Weaver
  • A. Vertes
  • V. Simonyan
  • R. Mazumder


We have previously identified the entire set of human genes with single-nucleotide variation causing a nonsynonymous variation in the residue at the active site of the corresponding proteins. A subset of 32 of these proteins was shown to have a 1:1:1 pathway:substrate:product relationship, making this group ideal as candidates for laboratory validation and downstream targeted metabolomics experiments. Here we used the reciprocal BLAST method, manual alignment and pathway comparison to identify 6 proteins which are mutual reciprocal best hits, have conserved active site residue and have the same annotated pathway, substrate and product. An in-depth manual inspection of these proteins and their pathways show that if the active sites were mutated in yeast then we should observe an increase in substrate and a decrease in product. As no enzymatic pathway occurs in isolation we attempted to further evaluate these 6 enzymes in the Yeast flux-balance model. We believe studies like these should be useful in the development of simple biochemical or mass-spectrometric assays to validate predictions and detect presence of known nsSNVs with deleterious outcomes, or to predict as yet unknown outcomes of active site nsSNVs for enzymes that are not yet well classified or annotated.

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