Hettling2011_CreatineKinase

  public model
Model Identifier
BIOMD0000000408
Short description

This model is from the article:
Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling.
Hettling H, van Beek JH PLoS Comput Biol.2011 Aug;7(8):e1002130. PMEDID,
Abstract:
In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The 'phosphocreatine shuttle' hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using 'sloppy modeling' ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.

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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V4)
Related Publication
  • Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling.
  • Hettling H, van Beek JH
  • PLoS computational biology , 8/ 2011 , Volume 7 , pages: e1002130 , PubMed ID: 21912519
  • Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam, The Netherlands. hettling@few.vu.nl
  • In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The 'phosphocreatine shuttle' hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using 'sloppy modeling' ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.
Contributors
Hannes Hettling

Metadata information

is
BioModels Database MODEL1201250000
BioModels Database BIOMD0000000408
isDerivedFrom
BioModels Database MODEL1006230027
BioModels Database BIOMD0000000041
isDescribedBy
PubMed 21912519
hasTaxon
isVersionOf

Curation status
Curated

Original model(s)
BIOMD0000000041

Tags
Name Description Size Actions

Model files

BIOMD0000000408_url.xml SBML L2V4 representation of Hettling2011_CreatineKinase 69.14 KB Preview | Download

Additional files

BIOMD0000000408.vcml Auto-generated VCML file 900.00 bytes Preview | Download
BIOMD0000000408-biopax3.owl Auto-generated BioPAX (Level 3) 35.94 KB Preview | Download
BIOMD0000000408.m Auto-generated Octave file 13.28 KB Preview | Download
BIOMD0000000408-biopax2.owl Auto-generated BioPAX (Level 2) 26.14 KB Preview | Download
BIOMD0000000408.pdf Auto-generated PDF file 217.14 KB Preview | Download
BIOMD0000000408.svg Auto-generated Reaction graph (SVG) 20.13 KB Preview | Download
BIOMD0000000408.png Auto-generated Reaction graph (PNG) 39.42 KB Preview | Download
BIOMD0000000408.sci Auto-generated Scilab file 67.00 bytes Preview | Download
BIOMD0000000408.xpp Auto-generated XPP file 9.45 KB Preview | Download
BIOMD0000000408_urn.xml Auto-generated SBML file with URNs 68.17 KB Preview | Download

  • Model originally submitted by : Hannes Hettling
  • Submitted: 25-Jan-2012 12:19:15
  • Last Modified: 25-Feb-2015 12:27:50
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 25-Feb-2015 12:27:50
    • Submitted by: Hannes Hettling
    • With comment: Current version of Hettling2011_CreatineKinase
  • Version: 1 public model Download this version
    • Submitted on: 25-Jan-2012 12:19:15
    • Submitted by: Hannes Hettling
    • With comment: Original import of Hettling_VanBeek_creatine_kinase_2011
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
ADPi

ADP ; ADP ; 3310; B01130
39.0 μmol
Cri

creatine ; Creatine ; 3594; B00084
9789.0 μmol
PCri

N-phosphocreatine ; Phosphocreatine ; 5359; B00422
5711.0 μmol
PCr

N-phosphocreatine ; Phosphocreatine ; B00422; 5359
5710.0 μmol
ADP

ADP ; ADP ; 3310; B01130
64.0 μmol
ATP

ATP ; ATP ; 3304; B01125
5601.0 μmol
Cr

creatine ; Creatine ; 3594; B00084
9789.0 μmol
P ii

inorganic phosphate
910.0 μmol
P i

inorganic phosphate
912.0 μmol
ATPi

ATP ; ATP ; 3304; B01125
5626.0 μmol
Reactions
Reactions Rate Parameters
(ATPi + Cri) => (PCri + ADPi)

([ATP; ATP; 3304; B01125] + [creatine; Creatine; 3594; B00084]) => ([N-phosphocreatine; Phosphocreatine; 5359; B00422] + [ADP; ADP; 3310; B01130])
j_ck_mi

j_ck_mi
[]
(Cr + ATP) => (PCr + ADP)

([creatine; Creatine; 3594; B00084] + [ATP; ATP; 3304; B01125]) => ([N-phosphocreatine; Phosphocreatine; B00422; 5359] + [ADP; ADP; 3310; B01130])
j_ck_mm

j_ck_mm
[]
(ADPi) => (ADP)

([ADP; ADP; 3310; B01130]) => ([ADP; ADP; 3310; B01130])
j_diff_adp

j_diff_adp
[]
(P_ii + ADPi) => (ATPi)

([inorganic phosphate] + [ADP; ADP; 3310; B01130]) => ([ATP; ATP; 3304; B01125])
Vmaxsyn*ADPi*P_ii/(Kadp*Kpi*(1+ADPi/Kadp+P_ii/Kpi+ADPi*P_ii/(Kadp*Kpi)))

Vmaxsyn*[[ADP; ADP; 3310; B01130]; [ADP; ADP; 3310; B01130]; 3310; B01130]*[inorganic phosphate]/(Kadp*Kpi*(1+[[ADP; ADP; 3310; B01130]; [ADP; ADP; 3310; B01130]; 3310; B01130]/Kadp+[inorganic phosphate]/Kpi+[[ADP; ADP; 3310; B01130]; [ADP; ADP; 3310; B01130]; 3310; B01130]*[inorganic phosphate]/(Kadp*Kpi)))
Kadp = 25.0 μmol*l^(-1); Vmaxsyn = 1503.74 μmol*l^(-1)*s^(-1); Kpi = 800.0 μmol*l^(-1)
(P_ii) => (P_i)

([inorganic phosphate]) => ([inorganic phosphate])
j_diff_pi

j_diff_pi
[]
(ATPi) => (ATP)

([ATP; ATP; 3304; B01125]) => ([ATP; ATP; 3304; B01125])
j_diff_atp

j_diff_atp
[]
(Cri) => (Cr)

([creatine; Creatine; 3594; B00084]) => ([creatine; Creatine; 3594; B00084])
j_diff_cr

j_diff_cr
[]
Curator's comment:
(added: 26 Jan 2012, 13:59:29, updated: 26 Jan 2012, 13:59:29)
Figure 8 of the reference publication has been reproduced using Copasi v4.7 (Build 34)