Network reconstruction of platelet metabolism identifies metabolic signature for aspirin resistance.
Recently there has not been a systematic, objective assessment of the metabolic capabilities of the human platelet. A manually curated, functionally tested, and validated biochemical reaction network of platelet metabolism, iAT-PLT-636, was reconstructed using 33 proteomic datasets and 354 literature references. The network contains enzymes mapping to 403 diseases and 231 FDA approved drugs, alluding to an expansive scope of biochemical transformations that may affect or be affected by disease processes in multiple organ systems. The effect of aspirin (ASA) resistance on platelet metabolism was evaluated using constraint-based modeling, which revealed a redirection of glycolytic, fatty acid, and nucleotide metabolism reaction fluxes in order to accommodate eicosanoid synthesis and reactive oxygen species stress. These results were confirmed with independent proteomic data. The construction and availability of iAT-PLT-636 should stimulate further data-driven, systems analysis of platelet metabolism towards the understanding of pathophysiological conditions including, but not strictly limited to, coagulopathies.
1] Department of Bioinformatics and Systems Biology, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [2] University of California, San Diego, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412.
Alex
A
Thomas
1] Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [2] University of California, San Diego, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412.
Sorena
S
Rahmanian
1] Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [2] University of California, San Diego, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412.
Aarash
A
Bordbar
1] Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [2] Institute of Engineering and Medicine, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [3] University of California, San Diego, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412.
Bernhard Ø
BØ
Palsson
1] Institute of Engineering and Medicine, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [2] University of California, San Diego, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412 [3] Department of Radiological Sciences, University of California, Los Angeles, BOX 951721, Los Angeles, CA 90095-1721.
Neema
N
Jamshidi
D001241:Aspirin / Q000494:pharmacology*; D001669:Biochemical Phenomena / Q000187:drug effects / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009711:Nucleotides / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism
D015777:Eicosanoids; D005227:Fatty Acids; D009711:Nucleotides; D020543:Proteome; D017382:Reactive Oxygen Species; D001241:Aspirin