I have decided to make public the preliminary models and kinetic results from my thesis. I will post some code here, but most likely I will upload the files (Fortran files and Mathematica notebooks, unfortunately I am not going to be able to do it 100% on FLOSS) somewhere. The title of the thesis is: "Control y regulación de la Glicólisis en Trypanosoma cruzi: Un enfoque teórico-práctico", which translated would be something like "Control and regulation of Trypanosoma cruzi's Glycolysis: A theoretical-practical approach". I will make a model of T. cruzi's Glycolisis based on Ordinary Differential Equations and an Metabolic Control Analysis of the model, trying to find which enzymes and/or transporters comprise the majority of the control of the glycolytic flux of the pathway. According to Solomon Nwaka and Alan Hudson, in their paper Innovative lead discovery strategies for tropical diseases, published in Nature RFeviews, Drug Discovery, November 2006 finding proper targets is important because:
Many compounds active in protein-based assays are inactive in whole cells.My favorite analogy to explain to my family what the hell I am doing is to ask them if they have a gun, few bullets and a car is coming to them at 100 kph, will they aim to the rear-view mirrors? I tell them I try to find the vital parts of the parasite that can be targeted in a safe way, without risk to us in order to not waste bullets against non relevant targets, since resources for research are scarce here. We have chosen to model T. cruzi's glycolysis because this pathway is very particular in trypanosomatids, it is physically located inside an special organelle called the glycosome. the enzymes are regulated in a non traditional
This can be due to failure to enter intact cells but can
also occur because the chosen molecular targets are not
in fact essential to the microbes. The latter issue sug-
gests that more work on target validation is needed to
increase confidence levels in the selection of protein
candidates for Hight-Throughput Screening campaigns. The initial challenge of
identifying molecular targets that are crucial to parasite
survival, coupled with the identification of whole-cell
active compounds, is formidable (...)
fashion, do not share a lot of similarity with mammalian enzymes and glycolysis is essential for the survival of the parasite. Besides this, there is a whole research line on these kind of models for other trypanosomatids, but not in T. cruzi. I have spotted some mistakes on the kinetic equations of some of the models I am basing my work on and therefore, improved models of other kinetoplastids could be developed too, if there is enough time. And I think that besides replicating the work for T. cruzi, it is also possible to develop some original research concerning these models. Stay in touch.
PS: Around the weekend I should post/upload a corrected version (minor details of transcription and nomenclature) of Daniel Guerra's model of Trypanosoma brucei's glycolysis in his doctoral thesis from 2005, Glucose Metabolism of Trypanosoma brucei and Leishmania mexicana.