title: Optimality in the zonation of ammonia detoxification in rodent liver.
abstract: The rodent liver eliminates toxic ammonia. In mammals, three enzymes (or enzyme systems) are involved in this process: glutaminase, glutamine synthetase and the urea cycle enzymes, represented by carbamoyl phosphate synthetase. The distribution of these enzymes for optimal ammonia detoxification was determined by numerical optimization. This in silico approach predicted that the enzymes have to be zonated in order to achieve maximal removal of toxic ammonia and minimal changes in glutamine concentration. Using 13 compartments, representing hepatocytes, the following predictions were generated: glutamine synthetase is active only within a narrow pericentral zone. Glutaminase and carbamoyl phosphate synthetase are located in the periportal zone in a non-homogeneous distribution. This correlates well with the paradoxical observation that in a first step glutamine-bound ammonia is released (by glutaminase) although one of the functions of the liver is detoxification by ammonia fixation. The in silico approach correctly predicted the in vivo enzyme distributions also for non-physiological conditions (e.g. starvation) and during regeneration after tetrachloromethane (CCl4) intoxication. Metabolite concentrations of glutamine, ammonia and urea in each compartment, representing individual hepatocytes, were predicted. Finally, a sensitivity analysis showed a striking robustness of the results. These bioinformatics predictions were validated experimentally by immunohistochemistry and are supported by the literature. In summary, optimization approaches like the one applied can provide valuable explanations and high-quality predictions for in vivo enzyme and metabolite distributions in tissues and can reveal unknown metabolic functions.
authors.affiliation: Research Group Theoretical Systems Biology, Friedrich Schiller University Jena, Leutragraben 1, 07743, Jena, Germany. martin.bartl@uni-jena.de.|BioControl Jena GmbH, Wildenbruchstr. 15, 07745, Jena, Germany. martin.bartl@uni-jena.de.|Department of Simulation and Optimal Processes, Ilmenau University of Technology, Helmholtzplatz 5, 98693, Ilmenau, Germany. martin.bartl@uni-jena.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Bartl
authors.affiliation: BioControl Jena GmbH, Wildenbruchstr. 15, 07745, Jena, Germany. michael.pfaff@fh-jena.de.|Department of Medical Engineering and Biotechnology, University of Applied Sciences Jena, 07745, Jena, Germany. michael.pfaff@fh-jena.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Pfaff
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Ardeystr. 67, 44139, Dortmund, Germany. ghallab@ifado.de.|Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt. ghallab@ifado.de.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ghallab
authors.affiliation: BioControl Jena GmbH, Wildenbruchstr. 15, 07745, Jena, Germany. dominik.driesch@biocontrol-jena.com.
authors.forename: Dominik
authors.initials: D
authors.lastname: Driesch
authors.affiliation: BioControl Jena GmbH, Wildenbruchstr. 15, 07745, Jena, Germany. sebastian.henkel@biocontrol-jena.com.
authors.forename: Sebastian G
authors.initials: SG
authors.lastname: Henkel
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Ardeystr. 67, 44139, Dortmund, Germany. hengstler@ifado.de.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of Bioinformatics, Friedrich Schiller University Jena, Ernst-Abbe-Platz 2, 07743, Jena, Germany. stefan.schu@uni-jena.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schuster
authors.affiliation: Research Group Theoretical Systems Biology, Friedrich Schiller University Jena, Leutragraben 1, 07743, Jena, Germany. c.kaleta@iem.uni-kiel.de.|Research Group Medical Systems Biology, Institute for Experimental Medicine, Christian-Albrechts-University Kiel, Brunswiker Str. 10, 24105, Kiel, Germany. c.kaleta@iem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaleta
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany. rolf.gebhardt@medizin.uni-leipzig.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Johannisallee 30, 04103, Leipzig, Germany. sebastian.zellmer@bfr.bund.de.|Department of Chemicals and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany. sebastian.zellmer@bfr.bund.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zellmer
authors.affiliation: Department of Simulation and Optimal Processes, Ilmenau University of Technology, Helmholtzplatz 5, 98693, Ilmenau, Germany. pu.li@tu-ilmenau.de.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000378:metabolism; D003198:Computer Simulation; D005974:Glutamate-Ammonia Ligase; D005972:Glutaminase; D005973:Glutamine / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008658:Inactivation, Metabolic / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014508:Urea / Q000378:metabolism
chemical_list: D005973:Glutamine; D000641:Ammonia; D014508:Urea; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: Ammonia metabolism; Glutamine synthetase; Liver zonation; Optimization; Systems biology