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Table 2 Parameter values of the model (except for FOXO part)

From: Computational modelling of the regulation of Insulin signalling by oxidative stress

Module

Reaction

Name

Parameter

Value

Order

Comments & Ref

All

 

Volume

extracellular

8.3 × 10-12 l

 

0.5 × cytoplasm

  

Volume

cell surface

6.4 × 10-14 l

 

assumes thickness of 20 nm

  

Volume

cytoplasm

1.65 × 10-11 l

 

typical of many cells

  

Volume

nucleus

5 × 10-13 l

  
  

Volume

DNA-bound

1 × 10-13 l

  

Receptor binding

R1f

 

k1

2.0 × 10-5

2

[36] Figure 1

m8b2_recep.6mod

R1r

 

kminus1

12072

1

[36]

 

R2

 

k3

2500

1

[36]

 

R3f

 

k2

1.2 × 10-5

2

[36]

 

R3r

 

kminus2

9 × 104

1

> > kminus1

 

R4

 

kminus3

2 × 10-6

2 (cat)

 
 

R5f

 

k4

0.0333

1

forward/reverse ratio 10, much faster than [26]

 

R5r

 

kminus4

0.3

1

see R5f

 

R6f

 

k4’

0.0021

1

unchanged from [26]

 

R6r

 

kminus4’

2.1 × 10-4

1

[26]

 

R7f

 

k4’

0.0021

1

[26]

 

R7r

 

kminus4’

2.1 × 10-4

1

[26]

 

R10

 

k6

4.61 × 10-6

2 (cat)

[26] corrected for mol number of PTP1B

 

R11

 

k6

4.61 × 10-6

2 (cat)

see R10

IRS

R12f

 

k7

5.8

2 (cat)

fitted to IRSYp

m8b2_irs.6.mod

R12r

 

kminus7a

8.75 × 10-5

2 (cat)

as R12f

 

R12_a_f

IRS-SerP by PKC_P

kpsp2

2.2 × 10-4

2

changed to simple MA; [27] used for fitting

 

R12_a_r

 

kminus7b

0.28 × 10-5

2 (cat)

as R12_a_f

 

R12_b_(f,r)

 

as R12_a_(f,r)

   
 

R13f

 

k8

2.6 × 10-6

2

[36] Figure 3

 

R13r

 

kminus8

1.55

1

as R13f

 

R50f

IRS basal synth

k_irs1_basal_syn

260

0

increased to keep IRS1 const

 

R50r1

IRS degrade

k_irs_basal_degr

10-3

1

Lifetime of ~2 days

 

R50r2

IRS-Yp degr

k_irs_basal_degr

10-3

1

as R50r2

 

R50r3

IRS1-Sp degr

k_irs_polyserp_degr

10-2

1

10 × faster than r50r2 [43]

 

R51

IRS-SerP by IKK_P

kcat51

0.87

 

consistent with [43] and IKK/JNK activation

  

IRS-SerP by IKK_P

Km51

100

 

as above

 

R52

IRS-SerP by JNK_P

kcat52

6.95

 

as R51

  

IRS-SerP by JNK_P

Km52

100

 

as above

Phosphatases

R30f

oxidation of PTP1B

k30f

0.08

2

[18, 19]

m8b2_phosph.6.mod

R30r

reduction of PTP1B by GSH

k30r

5 × 10-3

2

[18–20]

 

R31f

oxidation of PTEN

k31f

2.7 × 10-4

2

slower than R30f

 

R31r

reduction of PTEN by GSH

k31r

2 × 10-3

2

similar to R30r

 

R34f

Activation of NOX

k34f

2 × 10-5

2

consistent with R35

 

R34r1

NOX deactivation

k34r1

10-3

2

consistent with R35

 

R34r2

NOX inactivation(1)

k34r2

0.25

1

consistent with R35

 

R34r3

NOX deact- > inact

k34r3

10-3

2

consistent with R35

 

R35f

ROS production by NOX

k35f

450

1

fitted to get desired ROS level (30/5) and PTP1B inhibition [18]

 

R35r

ROS elimination by SOD2

k35r

0.12

2

lifetime < 0.01 s

 

R36f

ROS production by Mitoch

k36f

180

1

 
 

R37f, R37r

ROS transport across plasma membrane

ros_perm

7.8 × 108 (thousands cm-2min-1)

1

[35]

   

membrane_area

6.5 × 10-9 cm2

 

from volume

   

k_ros_perm

4.8 thousands min-1

 

product of above

 

R38f

Glutathione oxidation

k38f

0.05

2

see R38f

 

R38r

Glutathione reduction

k38r

2

1

(auto-reduction)

Akt

R14f

PI(3,4,5)P3 generation, basal

k9_basal

0.13145

1

[26]

m8b2_akt.6.mod

 

By PI3K complex

k9

0.055

2 (cat)

derived from [26]

 

R14r

PIP3 breakdown, basal

kminus9_basal

2.7

1

[26]

  

by PTEN

kminus9

0.0014

2 (cat)

 
 

R16f

Akt activation

k11

2.5 × 10-5

2

modified mass action, effect similar to express in [26]

   

pip3_basal

200

2 (cat)

offset

 

R16r

Akt deactivation by PP2A

kminus11

1.188 × 10-6

2 (cat)

[26]

 

R17f

PKC activation

k12

3.5 × 10-5

2 (cat)

as R16f

 

R17r

PKC deactivation

kminus12

1.25 × 10-6

2 (cat)

as R16r

 

R16a

AS160 activation by AKT

kr16a

3.33 × 10-4

2 (cat)

see methods; [26, 36]

 

R16r

AS160 deactivation

kminusr16a

1 × 10-6

2 (cat)

see R16a

 

R20f

GLUT4 translocation to cell surface; basal

k13_basal

0.015

1

see R16a

  

and by AS160

k13

7.5 × 10-6

2 (cat)

see R16a

 

R20r

GLUT4 translocation to cytoplasm

kminus13

0.167

1

see R16a

JNK

R32f

DUSP oxidation

k32f

6 × 10-4

2 (cat)

consistent with [16, 35, 44]

m8b2_jnk.6.mod

R32r

DUSP reduction by GSH

k32r

4 × 10-4

2 (cat)

as R32f

 

R42f

JNK activation by ROS

k42fa

2.5 × 10-4

2 (cat)

as R32f

 

R42r

JNK deactivation by DUSP

k42r

0.5 × 10-6

2 (cat)

as R32f

 

R43f

IKK activation by ROS

k43f

0.5 × 10-4

2 (cat)

as R32f

 

R43r

IKK deactivation

k43r

0.5 × 10-6

2 (cat)

as R32f

  1. a k42f expressed as α × k42f’ where α = 5 and k42f’ = 0.5 × 10-4.
  2. (phosphatases, Akt, JNK, FOXO).
  3. Kinetic parameters of the model, except for the FOXO components. Units of rate constants are min-1 for first order or (number)-1 min-1 for second order.