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vacotciC10

C10AcylCoAMAT = ∅

vacotciC12

C12AcylCoAMAT = ∅

vacotciC14

C14AcylCoAMAT = ∅

vacotciC16

C16AcylCoAMAT = ∅

vacotcsC10

C10AcylCoAMAT = ∅

vacotcsC12

C12AcylCoAMAT = ∅

vacotcsC14

C14AcylCoAMAT = ∅

vacotcsC16

C16AcylCoAMAT = ∅

vacotcsC4

C4AcylCoAMAT = ∅

vacotcsC6

C6AcylCoAMAT = ∅

vacotcsC8

C8AcylCoAMAT = ∅

vcactC10

C10AcylCarCYT = C10AcylCarMAT

vcactC12

C12AcylCarCYT = C12AcylCarMAT

vcactC14

C14AcylCarCYT = C14AcylCarMAT

vcactC16

C16AcylCarCYT = C16AcylCarMAT

vcactC4

C4AcylCarCYT = C4AcylCarMAT

vcactC6

C6AcylCarCYT = C6AcylCarMAT

vcactC8

C8AcylCarCYT = C8AcylCarMAT

vcpt1C10

C10AcylCoACYT = C10AcylCarCYT

vcpt1C12

C12AcylCoACYT = C12AcylCarCYT

vcpt1C14

C14AcylCoACYT = C14AcylCarCYT

vcpt1C16

∅ = C16AcylCarCYT

vcpt1C8

C8AcylCoACYT = C8AcylCarCYT

vcpt2C10

C10AcylCarMAT = C10AcylCoAMAT

vcpt2C12

C12AcylCarMAT = C12AcylCoAMAT

vcpt2C14

C14AcylCarMAT = C14AcylCoAMAT

vcpt2C16

C16AcylCarMAT = C16AcylCoAMAT

vcpt2C4

C4AcylCarMAT = C4AcylCoAMAT

vcpt2C6

C6AcylCarMAT = C6AcylCoAMAT

vcpt2C8

C8AcylCarMAT = C8AcylCoAMAT

vcratC10

C10AcylCoAMAT = C10AcylCarMAT

vcratC4

C4AcylCoAMAT = C4AcylCarMAT

vcratC6

C6AcylCoAMAT = C6AcylCarMAT

vcratC8

C8AcylCoAMAT = C8AcylCarMAT

vcrotC10

C10EnoylCoAMAT = C10HydroxyacylCoAMAT

vcrotC12

C12EnoylCoAMAT = C12HydroxyacylCoAMAT

vcrotC14

C14EnoylCoAMAT = C14HydroxyacylCoAMAT

vcrotC16

C16EnoylCoAMAT = C16HydroxyacylCoAMAT

vcrotC4

C4EnoylCoAMAT = C4HydroxyacylCoAMAT

vcrotC6

C6EnoylCoAMAT = C6HydroxyacylCoAMAT

vcrotC8

C8EnoylCoAMAT = C8HydroxyacylCoAMAT

vmcadC10

C10AcylCoAMAT = C10EnoylCoAMAT

vmcadC12

C12AcylCoAMAT = C12EnoylCoAMAT

vmcadC14

C14AcylCoAMAT = C14EnoylCoAMAT

vmcadC16

C16AcylCoAMAT = C16EnoylCoAMAT

vmcadC4

C4AcylCoAMAT = C4EnoylCoAMAT

vmcadC6

C6AcylCoAMAT = C6EnoylCoAMAT

vmcadC8

C8AcylCoAMAT = C8EnoylCoAMAT

vmckatC10

C10KetoacylCoAMAT = C8AcylCoAMAT

vmckatC12

C12KetoacylCoAMAT = C10AcylCoAMAT

vmckatC14

C14KetoacylCoAMAT = C12AcylCoAMAT

vmckatC16

C16KetoacylCoAMAT = C14AcylCoAMAT

vmckatC4

C4KetoacylCoAMAT = ∅

vmckatC6

C6KetoacylCoAMAT = C4AcylCoAMAT

vmckatC8

C8KetoacylCoAMAT = C6AcylCoAMAT

vmschadC10

C10HydroxyacylCoAMAT = C10KetoacylCoAMAT

vmschadC12

C12HydroxyacylCoAMAT = C12KetoacylCoAMAT

vmschadC14

C14HydroxyacylCoAMAT = C14KetoacylCoAMAT

vmschadC16

C16HydroxyacylCoAMAT = C16KetoacylCoAMAT

vmschadC4

C4HydroxyacylCoAMAT = C4KetoacylCoAMAT

vmschadC6

C6HydroxyacylCoAMAT = C6KetoacylCoAMAT

vmschadC8

C8HydroxyacylCoAMAT = C8KetoacylCoAMAT

vmtpC10

C10EnoylCoAMAT = C8AcylCoAMAT

vmtpC12

C12EnoylCoAMAT = C10AcylCoAMAT

vmtpC14

C14EnoylCoAMAT = C12AcylCoAMAT

vmtpC16

C16EnoylCoAMAT = C14AcylCoAMAT

vmtpC6

C6EnoylCoAMAT = ∅

vmtpC8

C8EnoylCoAMAT = C6AcylCoAMAT

vscadC4

C4AcylCoAMAT = C4EnoylCoAMAT

vscadC6

C6AcylCoAMAT = C6EnoylCoAMAT

vvlcadC10

C10AcylCoAMAT = C10EnoylCoAMAT

vvlcadC12

C12AcylCoAMAT = C12EnoylCoAMAT

vvlcadC14

C14AcylCoAMAT = C14EnoylCoAMAT

vvlcadC16

C16AcylCoAMAT = C16EnoylCoAMAT

vvlcadC8

C8AcylCoAMAT = C8EnoylCoAMAT

Parameters

Global parameters

C16AcylCoACYT*

C2AcylCarCYT*

C2AcylCarMAT*

C2AcylCoACYT*

C2AcylCoAMAT*

CarCYTt*

CarMATt*

CoACYTt*

CoAMATt*

CoASHseq*

ETFoxVSred*

KeqcactC10*

KeqcactC12*

KeqcactC14*

KeqcactC16*

KeqcactC4*

KeqcactC6*

KeqcactC8*

Keqcpt1C10*

Keqcpt1C12*

Keqcpt1C14*

Keqcpt1C16*

Keqcpt1C8*

Keqcpt2C10*

Keqcpt2C12*

Keqcpt2C14*

Keqcpt2C16*

Keqcpt2C4*

Keqcpt2C6*

Keqcpt2C8*

KeqcratC10*

KeqcratC4*

KeqcratC6*

KeqcratC8*

KeqcrotC10*

KeqcrotC12*

KeqcrotC14*

KeqcrotC16*

KeqcrotC4*

KeqcrotC6*

KeqcrotC8*

KeqmcadC10*

KeqmcadC12*

KeqmcadC14*

KeqmcadC16*

KeqmcadC4*

KeqmcadC6*

KeqmcadC8*

KeqmckatC10*

KeqmckatC12*

KeqmckatC14*

KeqmckatC16*

KeqmckatC4*

KeqmckatC6*

KeqmckatC8*

KeqmschadC10*

KeqmschadC12*

KeqmschadC14*

KeqmschadC16*

KeqmschadC4*

KeqmschadC6*

KeqmschadC8*

KeqmtpC10*

KeqmtpC12*

KeqmtpC14*

KeqmtpC16*

KeqmtpC6*

KeqmtpC8*

KeqscadC4*

KeqscadC6*

KeqvlcadC10*

KeqvlcadC12*

KeqvlcadC14*

KeqvlcadC16*

KeqvlcadC8*

Ki1cratC12AcylCoAMAT*

Ki1cratC14AcylCoAMAT*

Ki1cratC16AcylCoAMAT*

Ki2cratC10AcylCoAMAT*

Ki2cratC12AcylCoAMAT*

Ki2cratC14AcylCoAMAT*

Ki2cratC16AcylCoAMAT*

KiacotcsCoAMAT*

Kicpt1CarCYT*

Kicpt1MalCoACYT*

Kicpt2CarMAT*

KicrotC4KetoacylCoA*

KmacotciC10AcylCoAMAT*

KmacotciC12AcylCoAMAT*

KmacotciC14AcylCoAMAT*

KmacotciC16AcylCoAMAT*

KmacotcsC10AcylCoAMAT*

KmacotcsC12AcylCoAMAT*

KmacotcsC14AcylCoAMAT*

KmacotcsC16AcylCoAMAT*

KmacotcsC4AcylCoAMAT*

KmacotcsC6AcylCoAMAT*

KmacotcsC8AcylCoAMAT*

KmcactC10AcylCarCYT*

KmcactC10AcylCarMAT*

KmcactC12AcylCarCYT*

KmcactC12AcylCarMAT*

KmcactC14AcylCarCYT*

KmcactC14AcylCarMAT*

KmcactC16AcylCarCYT*

KmcactC16AcylCarMAT*

KmcactC2AcylCarCYT*

KmcactC2AcylCarMAT*

KmcactC4AcylCarCYT*

KmcactC4AcylCarMAT*

KmcactC6AcylCarCYT*

KmcactC6AcylCarMAT*

KmcactC8AcylCarCYT*

KmcactC8AcylCarMAT*

KmcactCarCYT*

KmcactCarMAT*

Kmcpt1C10AcylCarCYT*

Kmcpt1C10AcylCoACYT*

Kmcpt1C10CarCYT*

Kmcpt1C12AcylCarCYT*

Kmcpt1C12AcylCoACYT*

Kmcpt1C12CarCYT*

Kmcpt1C14AcylCarCYT*

Kmcpt1C14AcylCoACYT*

Kmcpt1C14CarCYT*

Kmcpt1C16AcylCarCYT*

Kmcpt1C16AcylCoACYT*

Kmcpt1C16CarCYT*

Kmcpt1C8AcylCarCYT*

Kmcpt1C8AcylCoACYT*

Kmcpt1C8CarCYT*

Kmcpt1CoACYT*

Kmcpt2C10AcylCarMAT*

Kmcpt2C10AcylCoAMAT*

Kmcpt2C10CarMAT*

Kmcpt2C12AcylCarMAT*

Kmcpt2C12AcylCoAMAT*

Kmcpt2C12CarMAT*

Kmcpt2C14AcylCarMAT*

Kmcpt2C14AcylCoAMAT*

Kmcpt2C14CarMAT*

Kmcpt2C16AcylCarMAT*

Kmcpt2C16AcylCoAMAT*

Kmcpt2C16CarMAT*

Kmcpt2C4AcylCarMAT*

Kmcpt2C4AcylCoAMAT*

Kmcpt2C4CarMAT*

Kmcpt2C6AcylCarMAT*

Kmcpt2C6AcylCoAMAT*

Kmcpt2C6CarMAT*

Kmcpt2C8AcylCarMAT*

Kmcpt2C8AcylCoAMAT*

Kmcpt2C8CarMAT*

Kmcpt2CoAMAT*

KmcratC10AcylCarMAT*

KmcratC10AcylCoAMAT*

KmcratC2AcylCarMAT*

KmcratC2AcylCoAMAT*

KmcratC4AcylCarMAT*

KmcratC4AcylCoAMAT*

KmcratC6AcylCarMAT*

KmcratC6AcylCoAMAT*

KmcratC8AcylCarMAT*

KmcratC8AcylCoAMAT*

KmcratCarMAT*

KmcratCoAMAT*

KmcrotC10EnoylCoAMAT*

KmcrotC10HydroxyacylCoAMAT*

KmcrotC12EnoylCoAMAT*

KmcrotC12HydroxyacylCoAMAT*

KmcrotC14EnoylCoAMAT*

KmcrotC14HydroxyacylCoAMAT*

KmcrotC16EnoylCoAMAT*

KmcrotC16HydroxyacylCoAMAT*

KmcrotC4EnoylCoAMAT*

KmcrotC4HydroxyacylCoAMAT*

KmcrotC6EnoylCoAMAT*

KmcrotC6HydroxyacylCoAMAT*

KmcrotC8EnoylCoAMAT*

KmcrotC8HydroxyacylCoAMAT*

KmmcadC10AcylCoAMAT*

KmmcadC10EnoylCoAMAT*

KmmcadC12AcylCoAMAT*

KmmcadC12EnoylCoAMAT*

KmmcadC14AcylCoAMAT*

KmmcadC14EnoylCoAMAT*

KmmcadC16AcylCoAMAT*

KmmcadC16EnoylCoAMAT*

KmmcadC4AcylCoAMAT*

KmmcadC4EnoylCoAMAT*

KmmcadC6AcylCoAMAT*

KmmcadC6EnoylCoAMAT*

KmmcadC8AcylCoAMAT*

KmmcadC8EnoylCoAMAT*

KmmcadETFox*

KmmcadETFred*

KmmckatAcetylCoAMAT*

KmmckatC10AcylCoAMAT*

KmmckatC10CoAMAT*

KmmckatC10KetoacylCoAMAT*

KmmckatC12AcylCoAMAT*

KmmckatC12CoAMAT*

KmmckatC12KetoacylCoAMAT*

KmmckatC14AcylCoAMAT*

KmmckatC14CoAMAT*

KmmckatC14KetoacylCoAMAT*

KmmckatC16CoAMAT*

KmmckatC16KetoacylCoAMAT*

KmmckatC2AcylCoAMAT*

KmmckatC4AcylCoAMAT*

KmmckatC4CoAMAT*

KmmckatC4KetoacylCoAMAT*

KmmckatC6AcylCoAMAT*

KmmckatC6CoAMAT*

KmmckatC6KetoacylCoAMAT*

KmmckatC8AcylCoAMAT*

KmmckatC8CoAMAT*

KmmckatC8KetoacylCoAMAT*

KmmschadC10HydroxyacylCoAMAT*

KmmschadC10KetoacylCoAMAT*

KmmschadC12HydroxyacylCoAMAT*

KmmschadC12KetoacylCoAMAT*

KmmschadC14HydroxyacylCoAMAT*

KmmschadC14KetoacylCoAMAT*

KmmschadC16HydroxyacylCoAMAT*

KmmschadC16KetoacylCoAMAT*

KmmschadC4HydroxyacylCoAMAT*

KmmschadC4KetoacylCoAMAT*

KmmschadC6HydroxyacylCoAMAT*

KmmschadC6KetoacylCoAMAT*

KmmschadC8HydroxyacylCoAMAT*

KmmschadC8KetoacylCoAMAT*

KmmschadNADHMAT*

KmmschadNADMAT*

KmmtpAcetylCoAMAT*

KmmtpC10AcylCoAMAT*

KmmtpC10CoAMAT*

KmmtpC10EnoylCoAMAT*

KmmtpC12AcylCoAMAT*

KmmtpC12CoAMAT*

KmmtpC12EnoylCoAMAT*

KmmtpC14AcylCoAMAT*

KmmtpC14CoAMAT*

KmmtpC14EnoylCoAMAT*

KmmtpC16CoAMAT*

KmmtpC16EnoylCoAMAT*

KmmtpC4AcylCoAMAT*

KmmtpC6AcylCoAMAT*

KmmtpC6CoAMAT*

KmmtpC6EnoylCoAMAT*

KmmtpC8AcylCoAMAT*

KmmtpC8CoAMAT*

KmmtpC8EnoylCoAMAT*

KmmtpNADHMAT*

KmmtpNADMAT*

KmscadC4AcylCoAMAT*

KmscadC4EnoylCoAMAT*

KmscadC6AcylCoAMAT*

KmscadC6EnoylCoAMAT*

KmscadETFox*

KmscadETFred*

KmvlcadC10AcylCoAMAT*

KmvlcadC10EnoylCoAMAT*

KmvlcadC12AcylCoAMAT*

KmvlcadC12EnoylCoAMAT*

KmvlcadC14AcylCoAMAT*

KmvlcadC14EnoylCoAMAT*

KmvlcadC16AcylCoAMAT*

KmvlcadC16EnoylCoAMAT*

KmvlcadC8AcylCoAMAT*

KmvlcadC8EnoylCoAMAT*

KmvlcadETFox*

KmvlcadETFred*

MalCoACYT*

NADoxVSred*

NADtMAT*

Vfcact*

Vrcact*

contactSiteCPT*

expressionacotci*

expressionacotcs*

expressioncpt1*

expressioncpt2*

expressioncrat*

expressioncrot*

expressionetf*

expressionmcad*

expressionmckat*

expressionmschad*

expressionmtp*

expressionscad*

expressionvlcad*

pfC10AcylCar*

pfC10AcylCoA*

pfC10EnoylCoA*

pfC10HydroxyacylCoA*

pfC10KetoacylCoA*

pfC12AcylCar*

pfC12AcylCoA*

pfC12EnoylCoA*

pfC12HydroxyacylCoA*

pfC12KetoacylCoA*

pfC14AcylCar*

pfC14AcylCoA*

pfC14EnoylCoA*

pfC14HydroxyacylCoA*

pfC14KetoacylCoA*

pfC16AcylCar*

pfC16AcylCoA*

pfC16EnoylCoA*

pfC16HydroxyacylCoA*

pfC16KetoacylCoA*

pfC2AcylCar*

pfC2AcylCoA*

pfC4AcylCar*

pfC4AcylCoA*

pfC4EnoylCoA*

pfC4HydroxyacylCoA*

pfC4KetoacylCoA*

pfC6AcylCar*

pfC6AcylCoA*

pfC6EnoylCoA*

pfC6HydroxyacylCoA*

pfC6KetoacylCoA*

pfC8AcylCar*

pfC8AcylCoA*

pfC8EnoylCoA*

pfC8HydroxyacylCoA*

pfC8KetoacylCoA*

sfacotciC10*

sfacotciC12*

sfacotciC14*

sfacotciC16*

sfacotcsC10*

sfacotcsC12*

sfacotcsC14*

sfacotcsC16*

sfacotcsC4*

sfacotcsC6*

sfacotcsC8*

sfcactC10*

sfcactC12*

sfcactC14*

sfcactC16*

sfcactC4*

sfcactC6*

sfcactC8*

sfcpt1C10*

sfcpt1C12*

sfcpt1C14*

sfcpt1C16*

sfcpt1C8*

sfcpt2C10*

sfcpt2C12*

sfcpt2C14*

sfcpt2C16*

sfcpt2C4*

sfcpt2C6*

sfcpt2C8*

sfcratC10*

sfcratC4*

sfcratC6*

sfcratC8*

sfcrotC10*

sfcrotC12*

sfcrotC14*

sfcrotC16*

sfcrotC4*

sfcrotC6*

sfcrotC8*

sfmcadC10*

sfmcadC12*

sfmcadC14*

sfmcadC16*

sfmcadC4*

sfmcadC6*

sfmcadC8*

sfmckatC10*

sfmckatC12*

sfmckatC14*

sfmckatC16*

sfmckatC4*

sfmckatC6*

sfmckatC8*

sfmschadC10*

sfmschadC12*

sfmschadC14*

sfmschadC16*

sfmschadC4*

sfmschadC6*

sfmschadC8*

sfmtpC10*

sfmtpC12*

sfmtpC14*

sfmtpC16*

sfmtpC6*

sfmtpC8*

sfscadC4*

sfscadC6*

sfvlcadC10*

sfvlcadC12*

sfvlcadC14*

sfvlcadC16*

sfvlcadC8*

VCYT*

VMAT*

default*

Initial values

C10AcylCarCYT*

C10AcylCarMAT*

C10AcylCoACYT*

C10AcylCoAMAT*

C10EnoylCoAMAT*

C10HydroxyacylCoAMAT*

C10KetoacylCoAMAT*

C12AcylCarCYT*

C12AcylCarMAT*

C12AcylCoACYT*

C12AcylCoAMAT*

C12EnoylCoAMAT*

C12HydroxyacylCoAMAT*

C12KetoacylCoAMAT*

C14AcylCarCYT*

C14AcylCarMAT*

C14AcylCoACYT*

C14AcylCoAMAT*

C14EnoylCoAMAT*

C14HydroxyacylCoAMAT*

C14KetoacylCoAMAT*

C16AcylCarCYT*

C16AcylCarMAT*

C16AcylCoAMAT*

C16EnoylCoAMAT*

C16HydroxyacylCoAMAT*

C16KetoacylCoAMAT*

C4AcylCarCYT*

C4AcylCarMAT*

C4AcylCoAMAT*

C4EnoylCoAMAT*

C4HydroxyacylCoAMAT*

C4KetoacylCoAMAT*

C6AcylCarCYT*

C6AcylCarMAT*

C6AcylCoAMAT*

C6EnoylCoAMAT*

C6HydroxyacylCoAMAT*

C6KetoacylCoAMAT*

C8AcylCarCYT*

C8AcylCarMAT*

C8AcylCoACYT*

C8AcylCoAMAT*

C8EnoylCoAMAT*

C8HydroxyacylCoAMAT*

C8KetoacylCoAMAT*

Functions and Rules

Assignment rules

Vcpt1 = 0.872 * expressioncpt1

Vscad = 0.01668 * expressionscad

ETFtMAT = 46.0 * expressionetf

Vacotcs = 0.002 * expressionacotcs

CoACYT = -C16AcylCoACYT - C2AcylCoACYT + CoACYTt - MalCoACYT - C10AcylCoACYT - C12AcylCoACYT - C14AcylCoACYT - C8AcylCoACYT

Vcpt2 = 0.28 * expressioncpt2

Vvlcad = 0.076 * expressionvlcad

Vmschad = 2.31 * expressionmschad

Vmtp = 0.1656 * expressionmtp

Vmcad = 0.038 * expressionmcad

CarCYT = -C2AcylCarCYT + CarCYTt - C10AcylCarCYT - C12AcylCarCYT - C14AcylCarCYT - C16AcylCarCYT - C4AcylCarCYT - C6AcylCarCYT - C8AcylCarCYT

Vcrat = 0.06 * expressioncrat

CarMAT = -C2AcylCarMAT + CarMATt - C10AcylCarMAT - C12AcylCarMAT - C14AcylCarMAT - C16AcylCarMAT - C4AcylCarMAT - C6AcylCarMAT - C8AcylCarMAT

Vmckat = 2.98 * expressionmckat

Vcrot = 10.0 * expressioncrot

Vacotci = 0.001 * expressionacotci

CoAMAT = -C2AcylCoAMAT + CoAMATt - CoASHseq - C10AcylCoAMAT - C10EnoylCoAMAT - C10HydroxyacylCoAMAT - C10KetoacylCoAMAT - C12AcylCoAMAT - C12EnoylCoAMAT - C12HydroxyacylCoAMAT - C12KetoacylCoAMAT - C14AcylCoAMAT - C14EnoylCoAMAT - C14HydroxyacylCoAMAT - C14KetoacylCoAMAT - C16AcylCoAMAT - C16EnoylCoAMAT - C16HydroxyacylCoAMAT - C16KetoacylCoAMAT - C4AcylCoAMAT - C4EnoylCoAMAT - C4HydroxyacylCoAMAT - C4KetoacylCoAMAT - C6AcylCoAMAT - C6EnoylCoAMAT - C6HydroxyacylCoAMAT - C6KetoacylCoAMAT - C8AcylCoAMAT - C8EnoylCoAMAT - C8HydroxyacylCoAMAT - C8KetoacylCoAMAT

Function definitions

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.

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Show compartments*

Gravity*

Repulsion*

Pool threshold*

Species:

Reactions:

Middle-click: pin/unpin nodes
Shift-click: pool/unpool species
Right-click: context menu

Apply alternate model layout to overlapping elements in current model:

Model schema*

Start time*

End time*

log scales

y-axis min/max

x-axis min/max

Species

Rates

Assignment rules

Parameter*

Start*

End*

Steps*

Species

Rates

Assignment rules

Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.

Christoff Odendaal
Emmalie A Jager
Anne-Claire M F Martines
Marcel A Vieira-Lara
Nicolette C A Huijkman
Ligia A Kiyuna
Albert Gerding
Justina C Wolters
Rebecca Heiner-Fokkema
Karen van Eunen
Terry G J Derks
Barbara M Bakker

BMC Biol 2023; 21 (1): 184

PubMed: 37667308
PubMed Central: PMC10478272
DOI: 10.1186/s12915-023-01652-9
ISSN: 1741-7007
URL: https://ncbi.nlm.nih.gov/pubmed/37667308

Abstract

BACKGROUND: Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients.
RESULTS: We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients.
CONCLUSIONS: We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.

Model adapted from odendaal1 to emulate the experimental conditions of HepG2 cells in an respirometry experiment. Vmax values are under assignments as they are dependent on expression terms and includes an expression term for each enzyme except the transporter CACT, as well as for the total ETF (ETFtMAT)

JWS Online documentation

C10AcylCarCYT
C10AcylCarMAT
C10AcylCoACYT
C10AcylCoAMAT
C10EnoylCoAMAT
C10HydroxyacylCoAMAT
C10KetoacylCoAMAT
C12AcylCarCYT
C12AcylCarMAT
C12AcylCoACYT
C12AcylCoAMAT
C12EnoylCoAMAT
C12HydroxyacylCoAMAT
C12KetoacylCoAMAT
C14AcylCarCYT
C14AcylCarMAT
C14AcylCoACYT
C14AcylCoAMAT
C14EnoylCoAMAT
C14HydroxyacylCoAMAT
C14KetoacylCoAMAT
C16AcylCarCYT
C16AcylCarMAT
C16AcylCoAMAT
C16EnoylCoAMAT
C16HydroxyacylCoAMAT
C16KetoacylCoAMAT
C4AcylCarCYT
C4AcylCarMAT
C4AcylCoAMAT
C4EnoylCoAMAT
C4HydroxyacylCoAMAT
C4KetoacylCoAMAT
C6AcylCarCYT
C6AcylCarMAT
C6AcylCoAMAT
C6EnoylCoAMAT
C6HydroxyacylCoAMAT
C6KetoacylCoAMAT
C8AcylCarCYT
C8AcylCarMAT
C8AcylCoACYT
C8AcylCoAMAT
C8EnoylCoAMAT
C8HydroxyacylCoAMAT
C8KetoacylCoAMAT

vacotciC10
vacotciC12
vacotciC14
vacotciC16
vacotcsC10
vacotcsC12
vacotcsC14
vacotcsC16
vacotcsC4
vacotcsC6
vacotcsC8
vcactC10
vcactC12
vcactC14
vcactC16
vcactC4
vcactC6
vcactC8
vcpt1C10
vcpt1C12
vcpt1C14
vcpt1C16
vcpt1C8
vcpt2C10
vcpt2C12
vcpt2C14
vcpt2C16
vcpt2C4
vcpt2C6
vcpt2C8
vcratC10
vcratC4
vcratC6
vcratC8
vcrotC10
vcrotC12
vcrotC14
vcrotC16
vcrotC4
vcrotC6
vcrotC8
vmcadC10
vmcadC12
vmcadC14
vmcadC16
vmcadC4
vmcadC6
vmcadC8
vmckatC10
vmckatC12
vmckatC14
vmckatC16
vmckatC4
vmckatC6
vmckatC8
vmschadC10
vmschadC12
vmschadC14
vmschadC16
vmschadC4
vmschadC6
vmschadC8
vmtpC10
vmtpC12
vmtpC14
vmtpC16
vmtpC6
vmtpC8
vscadC4
vscadC6
vvlcadC10
vvlcadC12
vvlcadC14
vvlcadC16
vvlcadC8