Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast

  public model
Model Identifier
BIOMD0000000547
Short description
Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast
The model implements arsenite (AsIII) transport regulation, its distribution within main cellular AsIII pools and detoxification. The intracellular As pools considered are free AsIII (AsIIIin), protein-bound AsIII (AsIIIprot), glutathione conjugated AsIII (AsGS3) and vacuolar sequestered AsIII (vAsGS3).

This model is described in the article:

Talemi SR, Jacobson T, Garla V, Navarrete C, Wagner A, Tamás MJ, Schaber J.
Mol. Microbiol. 2014 Jun; 92(6): 1343-1356

Abstract:

Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein-bound during short-term (acute) exposure, whereas glutathione-conjugated arsenic dominates during long-term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1-dependent and Hog1-independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast.
  • Talemi SR, Jacobson T, Garla V, Navarrete C, Wagner A, Tamás MJ, Schaber J
  • Molecular microbiology , 6/ 2014 , Volume 92 , pages: 1343-1356 , PubMed ID: 24798644
  • Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
  • Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein-bound during short-term (acute) exposure, whereas glutathione-conjugated arsenic dominates during long-term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1-dependent and Hog1-independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy.
Contributors
Soheil Rastgou Talemi

Metadata information

is
BioModels Database MODEL1403280000
BioModels Database BIOMD0000000547
isDescribedBy
PubMed 24798644
hasTaxon
isVersionOf

Curation status
Curated

Original model(s)
Rastgou2014_Arsenic_Kinetic_Yeast

Tags
Name Description Size Actions

Model files

BIOMD0000000547_url.xml SBML L2V4 representation of Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast 109.45 KB Preview | Download

Additional files

BIOMD0000000547.xpp Auto-generated XPP file 11.54 KB Preview | Download
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BIOMD0000000547_urn.xml Auto-generated SBML file with URNs 109.04 KB Preview | Download
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BIOMD0000000547.png Auto-generated Reaction graph (PNG) 219.03 KB Preview | Download
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BIOMD0000000547.sci Auto-generated Scilab file 968.00 bytes Preview | Download

  • Model originally submitted by : Soheil Rastgou Talemi
  • Submitted: Mar 28, 2014 10:34:27 AM
  • Last Modified: Sep 10, 2014 3:43:15 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Sep 10, 2014 3:43:15 PM
    • Submitted by: Soheil Rastgou Talemi
    • With comment: Current version of Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast
  • Version: 1 public model Download this version
    • Submitted on: Mar 28, 2014 10:34:27 AM
    • Submitted by: Soheil Rastgou Talemi
    • With comment: Original import of AsIII

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
species 3

arsenite(1-)
2.08447005232452E-11 ��mol
species 1

arsenite(1-) ; intracellular
3.94647E-13 ��mol
species 2

arsenite(1-) ; protein
5.29105658389632E-12 ��mol
species 6

arsenite(1-) ; extracellular region
5.0E-9 ��mol
species 10

Mitogen-activated protein kinase HOG1 ; phosphorylated
5.12422021489774E-17 ��mol
species 9

Mitogen-activated protein kinase HOG1
8.29875779785102E-15 ��mol
species 11

Glycerol uptake/efflux facilitator protein
8.44139912229068E-17 ��mol
species 4

arsenite(1-) ; vacuolar part
3.31525035810391E-12 ��mol
Reactions
Reactions Rate Parameters
parameter_40*species_3

parameter_40*species_3
parameter_40 = 6.1432
(36*pi)^(1/3)*compartment_1^(2/3)*parameter_37*species_4/compartment_1

(36*pi)^(1/3)*compartment_1^(2/3)*parameter_37*species_4/compartment_1
parameter_37 = 1.92773E-7
(36*pi)^(1/3)*compartment_3^(2/3)*species_11/compartment_3*parameter_33*(species_6/compartment_2-species_1/compartment_4)

(36*pi)^(1/3)*compartment_3^(2/3)*species_11/compartment_3*parameter_33*(species_6/compartment_2-species_1/compartment_4)
parameter_33 = 0.00215551
parameter_41*species_1

parameter_41*species_1
parameter_41 = 0.00880734
parameter_42*species_2

parameter_42*species_2
parameter_42 = 6.56918E-4
compartment_4*parameter_39*parameter_22*species_1/compartment_4*species_7/compartment_4

compartment_4*parameter_39*parameter_22*species_1/compartment_4*species_7/compartment_4
parameter_39 = 0.202797; parameter_22 = 1.0
(36*pi)^(1/3)*compartment_3^(2/3)*species_14/compartment_3*parameter_34*species_1/compartment_4/(parameter_35+species_1/compartment_4)

(36*pi)^(1/3)*compartment_3^(2/3)*species_14/compartment_3*parameter_34*species_1/compartment_4/(parameter_35+species_1/compartment_4)
parameter_35 = 5.16159E-6; parameter_34 = 1.0
parameter_38*species_5/compartment_3*parameter_36*(36*pi)^(1/3)*compartment_1^(2/3)*species_3/compartment_4

parameter_38*species_5/compartment_3*parameter_36*(36*pi)^(1/3)*compartment_1^(2/3)*species_3/compartment_4
parameter_38 = 1.0; parameter_36 = 3.49703E-6
compartment_3*parameter_26*parameter_28*species_1/compartment_4*species_9/compartment_3

compartment_3*parameter_26*parameter_28*species_1/compartment_4*species_9/compartment_3
parameter_28 = 1.0; parameter_26 = 0.0757274
parameter_32*species_15

parameter_32*species_15
parameter_32 = 0.0719168
Curator's comment:
(added: 10 Sep 2014, 16:38:42, updated: 10 Sep 2014, 16:38:42)
Figure 4 of the reference publication is reproduced using SimulationCore Solver in CellDesigner. To reproduce the figure set the "ko-8" to zero. The plot was generated using gnuplot. This parameter, ko-8, is inducing the GSH knockdown situation. In this situation the cellular GSH level is about 0.2 of its level in the wild type cells exposed to 0.1mM of arsenite for 24 hours. For more details see TableS5 (Supplementary Materials of the reference publication, Page29). The model has to be simulated for 12000 secs (=200 mins).