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Ethanol Metabolism: A Kinetics Simulation Using Vcell

Ethanol Metabolism: A Kinetics Simulation Using Vcell. A Project by: Ben Fowler Chemistry 324: Structural Bioinformatics Professor Sontum Middlebury College. http://www.patenthawk.com/blog_images/bud_girl2.jpg. Ethanol Consumption: Health Implications. -Fat synthesis -Liver disease

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Ethanol Metabolism: A Kinetics Simulation Using Vcell

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  1. Ethanol Metabolism: A Kinetics Simulation Using Vcell A Project by: Ben Fowler Chemistry 324: Structural Bioinformatics Professor Sontum Middlebury College http://www.patenthawk.com/blog_images/bud_girl2.jpg

  2. Ethanol Consumption: Health Implications -Fat synthesis -Liver disease -Stroke -Cancer -Impaired coordination and ability to operate machinery -General impaired judgment… http://www.chm.bris.ac.uk/motm/acetylcoa/homer1.gif http://www.bobiland.com/pictures/image/alcohol_2007.jpg

  3. Model Pathway for Ethanol Metabolism: A Simple System • Different metabolic routes, converging at acetaldehyde • Compartmentalization of reactions • Involvement of enzymes w/ unique Km values Ethanol----------->Acetaldehyde--->Acetate

  4. Kinetics Analysis Programs Vcell Gepasi VCell V.4.3 User Guide p. 41 http://www.gepasi.org/gep3time.png

  5. Plan of Action • 1. Obtain kinetics information (SWISSPROT/KEGG): Reaction rates; compartmentalization; membrane flux. • 2. Run simulation for each program. • 3. Export to Perl and parse data. http://www.shlomifish.org/philosophy/books-recommends/images/programming_perl.jpg

  6. Final output at time “t”: • [Acetaldehyde] at time “t” • Rate at time “t” for different enzymes • Analyze rate of reaction using different starting [ethanol] • Compare rate of reaction for different enzymes over time as ethanol is metabolized http://core.ecu.edu/phys/flurchickk/AtomicMolecularSystems/molecularStructures/images/acetaldehydeStructure.png

  7. 05/08/08: Project Presentation • A research project complete with: • Obstacles • Success

  8. Simplifying a Complicated System: Creating a BioModel with Vcell Too many metabolic factors involved. E.g. Many compartments involved in alcohol metabolism look at one aspect (cytoplasm) and simplify.

  9. Defining reactants • Use the KEGG database to define chemical species.

  10. Defining reactants: Limitations • KEGG is not a database complete with all chemical species information. •  Difficult to create an accurate physiological model. • Next: Obtain some meaningful result to parse with Perl.

  11. If not KEGG, … • HMDB

  12. Defining reactions Membrane Surface Reaction Cytoplasm Reaction

  13. Reaction Properties

  14. Defining Geometries • Define volume and surface area of compartments.

  15. Simulation parameters: Initial Conditions

  16. Overview of Simulation Parameters

  17. Edit Simulation parameters

  18. Simulation results Options for X&Y plot:

  19. Simulation Results: Export • Export over a specific time period • Export data for your choice of variables

  20. Read .csv file with Vim

  21. Perl program to parse Vcell output files # #File to search for time @ maximum acetaldehyde (and EtOH concentration) #Load file to read using argument $in_name= $ARGV[0] ; $out_name= $ARGV[1]; $col1= $ARGV[2]; if($col1 eq "") {$col1=3} print "first column ($col1) \n"; $col2= $ARGV[3]; if($col2 eq "") {$col2=4} print "second column ($col2) \n"; # open the file and associate a file handle open(infile,$in_name) || die " can not open $in_name \n"; # open an output file and associate a file handle open(outfile,">>$out_name") || die " can not create $out_name \n";

  22. Perl program, continued # # move to ethanol while (<infile>) { if(/Variable,/) {last} } print $_,"\n"; # # grab the values $max=0.0; while (<infile>) { chomp; @F=split(",",$_); $t=$F[1]; $eth=$F[$col1]; $acet=$F[$col2]; if($acet >= $max) { $tmax=$t; $ethmax=$eth; $acetmax=$acet; $max=$acet; } } # #Print t for maximum value of acetaldehyde print outfile "$tmax , $ethmax , $acetmax \n"; exit;

  23. Perl program: Output [EtOH] Max. [Acetaldehyde] Time Rxn 18 mM EtOH 18 mM EtOH+MEOS 42 mM EtOH 42 mM EtOH+MEOS (Files read one at a time; appended to the same outfile)

  24. Data Analysis: [Acetaldehyde] 42 mM EtOH + Upregulate MEOS 18 mM EtOH + Upregulate MEOS 42 mM EtOH 18 mM EtOH

  25. Conclusions/discussion • Complex systemNot possible to exactly simulate physiological conditions. • Lack of information allows for the possibility of inaccurate conclusions. • Best use for Vcell: Experimental data from laboratory…not just picking and choosing from different experiments.

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