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Pathways Prediction and analysis 12-05-01 What is a pathway? A series of interconected enzymatic steps linked by the production of intermediates that are used in the next enzymatic step (Note this definition will change) May also include signaling pathways as well were one input may cause several effects Why is it good to find pathways? Better understand the physiology of the organism Predict the effect of a drug Predict the weaknesses or side effects of a drug Predict good or bad drug combinations Understand disease processes Gene function assignment Make a “perfect” simulation of cellular function to use as an experimental model A high level of understanding Many tools “feed” into this understanding Microarrays Homology tools (BLAST, alignments COGS) Biochemical Genomic literature sequence Any holes in these tools lead to problems in the pathway analysis A complex problem 35,000 genes either on or off (huge simplification!!!!) would have 2^35,000 solutions Things can be simplified by grouping and finding key genes which regulate many other genes and genes which may only interact with on other gene Lots of subtile interactions Two ways of looking at the problem Top down or bottom up Either look at the whole organism and abstract large portions of it Or try to understand each small piece and then after understanding every small piece assemble into the whole Bottom up is traditionally how it is done You would study a pathway in detail not worrying about how that pathway might interact with other elements in the cell. You would strive to understand a gene or pathway in great detail, eventually you might extend this knowledge to other organisms and compare and contrast. With top down you need other tools... Graph theory, networks Two types of networks Exponential and scale free Most cellular networks are scale free It makes the most sense to study the interactions of the central nodes not the outer nodes A better definition of a pathway: Voet and Voet say:a series of consecutive enzymatic reactions that produce specific products. Does this include pathways that feed into this pathway or branches to the pathway or ..... A more rigorous definition is needed A set of pathways could be defined as the possible routes through a “black box” given a set of enzymes and metabolic inputs Elementary modes A minimal set of enzymes that could operate at steady state with the enzymes weighted by the relative flux the need to carry for the node to function If one enzyme is removed the steady state would be destroyed How to transform this Into this... Several methods for doing this: Steps for reducing the matrix: Left hand side metabolites Right hand side keeps track of the origin Top reversable Bottom irreversable Linear combination is done to further reduce the set Different types go to irreversable 00100|1000 0-1 0 2 0 | 0 1 0 0 ____________________ 0 0 0-1 0 | 0 0 10 10000|0001 Metatool A program to do this for you: http://www2.bioinf.mdcberlin.de/metabolic/metatool/ Download the program and the example.dat file Try to compile with “gcc meta*.c” Fix the header Cogs What is COGS http://www.ncbi.nlm.nih.gov/COG/ Basically a method for finding orthologous proteins from fully sequenced genomes by using a cross species comparison. What does this have to do with pathways? Databases of enzymatic reactions http://www.genome.ad.jp/kegg/ is a good starting place EMP and http://www.expasy.ch/enzyme/ are other good places to look These can also be good places to look to get overviews of unfamilar pathways or reactions rather than a biochem textbook EC numbers EC Enzyme commision number 1.1.1.49 = Glucose-6-phosphate 1dehydrogenase Hierarchal assignment 1.x.x.x = Oxidoreductases 1.1.x.x = Acting on the CH-OH group of donors 1.1.1.x = With NAD or NADP as acceptor 1.1.1.49 = using glucose-6-phosphate as a donor Unifies and codifies enzyme nomenclature Http://www.chem.qmw.ac.uk/iubmb/enzyme/index. html