However, the organelles in Recon 1 usually have values below the reference line, due mainly to a higher difficulty to annotate reactions specific to an organelle. The separate organelle meta bolic networks are less connected. The exception is the mitochondria, which is well studied and has a very important and complex metabolic role. selleck chemicals Imatinib The metabolite connectivity of the erythrocyte net work is very similar to the less connected organelles in Recon 1. This similarity is due to either 1 the erythro cyte biology or 2 the lack of complete proteomic profil ing. First, as Inhibitors,Modulators,Libraries the erythrocyte circulates in blood, it has access to many types of metabolites. As the erythrocyte is relatively simple, it is possible that the reconstructed metabolic network is complete as different types of metabolites do not have to be created and can easily be transported into or out of the cell.
However, the network simplicity of the in silico erythrocyte model may also be attributed Inhibitors,Modulators,Libraries to the limita tions of proteomic techniques. As coverage of proteomic data Inhibitors,Modulators,Libraries is typically not as complete as transcriptomics, the reconstructed metabolic network may reflect this limita tion. Thus, deeper proteomic profiling could be of great use to further elucidate the role of the erythrocyte in systemic metabolism and the complexity of its own metabolic network. In silico simulations show a greater physiological func tionality of erythrocyte metabolism. The additional func tionality is not evident from the proteomic data alone. However, metabolite connectivity analysis shows that iAB RBC 283 explicitly accounts for the genetic basis of the enzymes and transporters that it represents.
To determine the capability of the in silico erythrocyte as a potential biomarker, we cross referenced morbid SNPs from the OMIM and nearly 4800 drugs from the DrugBank database with the 281 enzymes accounted for in iAB RBC Inhibitors,Modulators,Libraries 283. 142 morbid SNPs were found in 90 of the erythrocyte enzymes. In addition, 232 FDA approved, FDA withdrawn, and experimental drugs have known protein targets in the human erythrocyte. Only 35 of the 142 morbid SNPs are related to pathol ogies unique to the erythrocyte, mainly dealing with hemolytic anemia. The majority of the morbid SNPs deal with pathologies that are peripheral to the red blood cell and to the blood system. The remaining non erythrocyte related pathologies are classified in Table 1 using the Merck Manual.
Most of the observed SNPs are causal and simple targeted assays could be used as diagnostic tools. We also cross referenced the enzymes in iAB RBC 283 with the DrugBanks known protein targets of phar maceuticals. Inhibitors,Modulators,Libraries 85 FDA approved, 4 FDA withdrawn, and 143 experimental drugs have known targets in the human erythrocyte. These medications target enzymes for the treatment of a wide range of diseases including additional targeted proteomics http://www.selleckchem.com/products/Roscovitine.html are of interest. During the manual curation steps we noted that portions of the TCA cycle were detected but not functional.