TY - JOUR
T1 - Model-based identification of drug targets that revert disrupted metabolism and its application to ageing
AU - Yizhak, Keren
AU - Gabay, Orshay
AU - Cohen, Haim
AU - Ruppin, Eytan
N1 - Funding Information:
We thank Matthew Oberhardt, Tuvik Beker, Gideon Y. Stein, Shiri Stempler, Allon Wagner and Yoav Teboulle for their helpful comments on the manuscript. K.Y. is partially supported by a fellowship from the Edmond J. Safra Bioinformatics center at Tel-Aviv University and is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship; E.R. acknowledges the generous support of grants from the Israeli Science Foundation (ISF) and the Israeli Cancer Research Fund (ICRF) for this research; H.C. acknowledges the generous support of grants from the Israeli Ministry of Health and the ERC; E.R. and H.C. acknowledge the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant number 41/11).
PY - 2013
Y1 - 2013
N2 - The growing availability of 'omics' data and high-quality in silico genome-scale metabolic models (GSMMs) provide a golden opportunity for the systematic identification of new metabolic drug targets. Extant GSMM-based methods aim at identifying drug targets that would kill the target cell, focusing on antibiotics or cancer treatments. However, normal human metabolism is altered in many diseases and the therapeutic goal is fundamentally different - to retrieve the healthy state. Here we present a generic metabolic transformation algorithm (MTA) addressing this issue. First, the prediction accuracy of MTA is comprehensively validated using data sets of known perturbations. Second, two predicted yeast lifespan-extending genes, GRE3 and ADH2, are experimentally validated, together with their associated hormetic effect. Third, we show that MTA predicts new drug targets for human ageing that are enriched with orthologs of known lifespan-extending genes and with genes downregulated following caloric restriction mimetic treatments. MTA offers a promising new approach for the identification of drug targets in metabolically related disorders.
AB - The growing availability of 'omics' data and high-quality in silico genome-scale metabolic models (GSMMs) provide a golden opportunity for the systematic identification of new metabolic drug targets. Extant GSMM-based methods aim at identifying drug targets that would kill the target cell, focusing on antibiotics or cancer treatments. However, normal human metabolism is altered in many diseases and the therapeutic goal is fundamentally different - to retrieve the healthy state. Here we present a generic metabolic transformation algorithm (MTA) addressing this issue. First, the prediction accuracy of MTA is comprehensively validated using data sets of known perturbations. Second, two predicted yeast lifespan-extending genes, GRE3 and ADH2, are experimentally validated, together with their associated hormetic effect. Third, we show that MTA predicts new drug targets for human ageing that are enriched with orthologs of known lifespan-extending genes and with genes downregulated following caloric restriction mimetic treatments. MTA offers a promising new approach for the identification of drug targets in metabolically related disorders.
UR - http://www.scopus.com/inward/record.url?scp=84886670153&partnerID=8YFLogxK
U2 - 10.1038/ncomms3632
DO - 10.1038/ncomms3632
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C2 - 24153335
AN - SCOPUS:84886670153
SN - 2041-1723
VL - 4
JO - Nature Communications
JF - Nature Communications
M1 - 2632
ER -