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BIOMD0000000495 - Sen2013 - Phospholipid Synthesis in P.knowlesi

 

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Reference Publication
Publication ID: 24209716
Sen P, Vial HJ, Radulescu O.
Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways.
BMC Syst Biol 2013; 7: 123
Dynamique des Interactions Membranaires Normales et Pathologiques, UMR 5235 CNRS, UM1, UM2, CP 107, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France. partho.phd@gmail.com.  [more]
Model
Original Model: Phospholipid synthetic pat...
Submitter: Ovidiu Radulescu
Submission ID: MODEL1310130000
Submission Date: 13 Oct 2013 21:12:28 UTC
Last Modification Date: 28 Feb 2014 11:50:12 UTC
Creation Date: 25 Nov 2013 12:12:47 UTC
Encoders:  Vijayalakshmi Chelliah
   Partho Sen
set #1
bqbiol:occursIn Taxonomy Plasmodium knowlesi
bqbiol:isVersionOf Gene Ontology phospholipid biosynthetic process
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
Notes
Sen2013 - Phospholipid Synthesis in P.knowlesi

The model describes the multiple phospholipid synthetic pathways in Plasmodium knowlesi.

This model is described in the article:

Sen P, Vial HJ, Radulescu O.
BMC Syst Biol 2013 Nov; 7(1): 123

Abstract:

BACKGROUND: Plasmodium is the causal parasite of malaria, infectious disease responsible for the death of up to one million people each year. Glycerophospholipid and consequently membrane biosynthesis are essential for the survival of the parasite and are targeted by a new class of antimalarial drugs developed in our lab. In order to understand the highly redundant phospholipid synthethic pathways and eventual mechanism of resistance to various drugs, an organism specific kinetic model of these metabolic pathways need to be developed in Plasmodium species. RESULTS: Fluxomic data were used to build a quantitative kinetic model of glycerophospholipid pathways in Plasmodium knowlesi. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters (maximum rates and Michaelis constants) has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimization method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors.The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine (PC) is the CDP-choline Kennedy pathway.In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase (PMT) and phosphatidylethanolamine-N-methyltransferase (PEMT) for PC synthesis.The flux values indicate that, major part of serine derived phosphatidylethanolamine (PE) is formed via serine decarboxylation, whereas major part of phosphatidylserine (PS) is formed by base-exchange reactions.Sensitivity analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest sensitivity coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step. CONCLUSION: We provide a fully parametrized kinetic model for the multiple phospholipid synthetic pathways in P. knowlesi. This model has been used to clarify the relative importance of the various reactions in these metabolic pathways. Future work extensions of this modelling strategy will serve to elucidate the regulatory mechanisms governing the development of Plasmodium during its blood stages, as well as the mechanisms of action of drugs on membrane biosynthetic pathways and eventual mechanisms of resistance.

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.

Model
Publication ID: 24209716 Submission Date: 13 Oct 2013 21:12:28 UTC Last Modification Date: 28 Feb 2014 11:50:12 UTC Creation Date: 25 Nov 2013 12:12:47 UTC
Mathematical expressions
Reactions
R1 R2 R3 R4
R5 R6 R7 R8
R9 R10 R11 R12
R13 R14 R15 R16
R17      
Physical entities
Compartments Species
unnamed SerE Ser PS
Etn PEtn PCho
PE PC ChoE
Cho EtnE  
Global parameters
Vm1 km1 Vm2 km2
Vm3 km3 Vm4 km4
Vm5 km5 Vm6 km6
Vm7 km7 Vm8 km8
Vm9 km9 Vm10 km10
Vm11 km11 Vm12 km12
Vm13 km13 Vm14 km14
Vm15 km15 Vm16 km16
kf17 kb17    
Reactions (17)
 
 R1 [SerE] → [Ser];   {SerE} , {SerE}
 
 R2 [Ser] → [PS];   {Ser} , {Ser}
 
 R3 [Ser] → [Etn];   {Ser} , {Ser}
 
 R4 [Etn] → [PEtn];   {Etn} , {Etn}
 
 R5 [PEtn] → [PCho];   {PEtn} , {PEtn}
 
 R6 [PS] → [PE];   {PS} , {PS}
 
 R7 [PEtn] → [PE];   {PEtn} , {PEtn}
 
 R8 [PCho] → [PC];   {PCho} , {PCho}
 
 R9 [PE] → [PC];   {PE} , {PE}
 
 R10 [PC] → [PS];   {PC} , {PC}
 
 R11 [PE] → [PS];   {PE} , {PE}
 
 R12 [PC] → ;   {PC} , {PC}
 
 R13 [PS] → ;   {PS} , {PS}
 
 R14 [PE] → ;   {PS} , {PS}
 
 R15 [ChoE] → [Cho];   {ChoE} , {ChoE}
 
 R16 [Cho] → [PCho];   {Cho} , {Cho}
 
 R17 [EtnE] ↔ [Etn];   {EtnE} , {Etn} , {EtnE} , {Etn}
 
 unnamed Spatial dimensions: 3.0  Compartment size: 1.0  (Units: liter)
 
 SerE
Compartment: unnamed
Initial concentration: 1.0E-4  (Units: mole)
 
 Ser
Compartment: unnamed
Initial amount: 0.0
 
 PS
Compartment: unnamed
Initial amount: 0.0
 
 Etn
Compartment: unnamed
Initial amount: 0.0
 
 PEtn
Compartment: unnamed
Initial amount: 0.0
 
 PCho
Compartment: unnamed
Initial amount: 0.0
 
 PE
Compartment: unnamed
Initial amount: 0.0
 
 PC
Compartment: unnamed
Initial amount: 0.0
 
 ChoE
Compartment: unnamed
Initial concentration: 5.0E-5  (Units: mole)
 
 Cho
Compartment: unnamed
Initial amount: 0.0
 
 EtnE
Compartment: unnamed
Initial amount: 0.0
 
Global Parameters (34)
 
   Vm1
Value: 3.40936490738966E-6   (Units: mole/liter/minute)
Constant
 
   km1
Value: 3.62894258752347E-4   (Units: mole/liter)
Constant
 
   Vm2
Value: 1.30568052867489E-6   (Units: mole/liter/minute)
Constant
 
   km2
Value: 7.96722533770371E-4   (Units: mole/liter)
Constant
 
   Vm3
Value: 2.620389955953E-6   (Units: mole/liter/minute)
Constant
 
   km3
Value: 2.39591245105385E-5   (Units: mole/liter)
Constant
 
   Vm4
Value: 8.62083015294042E-6   (Units: mole/liter/minute)
Constant
 
   km4
Value: 1.08608492867695E-4   (Units: mole/liter)
Constant
 
   Vm5
Value: 1.0780611108133E-6   (Units: mole/liter/minute)
Constant
 
   km5
Value: 1.22223738254533E-4   (Units: mole/liter)
Constant
 
   Vm6
Value: 2.24518521682572E-6   (Units: mole/liter/minute)
Constant
 
   km6
Value: 2.03868171233541E-4   (Units: mole/liter)
Constant
 
   Vm7
Value: 5.61352652271706E-6   (Units: mole/liter/minute)
Constant
 
   km7
Value: 2.27368268903121E-4   (Units: mole/liter)
Constant
 
   Vm8
Value: 4.12788404046025E-7   (Units: mole/liter/minute)
Constant
 
   km8
Value: 3.10498877738431E-5   (Units: mole/liter)
Constant
 
   Vm9
Value: 0.00141678261342411   (Units: mole/liter/minute)
Constant
 
   km9
Value: 0.321125432799976   (Units: mole/liter)
Constant
 
   Vm10
Value: 6.97333029651601E-7   (Units: mole/liter/minute)
Constant
 
   km10
Value: 3.76085190209901E-6   (Units: mole/liter)
Constant
 
   Vm11
Value: 8.99054709659885E-5   (Units: mole/liter/minute)
Constant
 
   km11
Value: 0.171122974053956   (Units: mole/liter)
Constant
 
   Vm12
Value: 1.5662833197895E-6   (Units: mole/liter/minute)
Constant
 
   km12
Value: 2.41308392167819E-5   (Units: mole/liter)
Constant
 
   Vm13
Value: 1.53754224136353E-6   (Units: mole/liter/minute)
Constant
 
   km13
Value: 2.03777063277265E-4   (Units: mole/liter)
Constant
 
   Vm14
Value: 7.7375270429582E-4   (Units: mole/liter/minute)
Constant
 
   km14
Value: 0.155164586398126   (Units: mole/liter)
Constant
 
   Vm15
Value: 2.32432741134546E-7   (Units: mole/liter/minute)
Constant
 
   km15
Value: 1.02326862282225E-4   (Units: mole/liter)
Constant
 
   Vm16
Value: 5.55658410000431E-7   (Units: mole/liter/minute)
Constant
 
   km16
Value: 3.04072645117622E-5   (Units: mole/liter)
Constant
 
   kf17
Value: 5.0E-4   (Units: 1/minute)
Constant
 
   kb17
Value: 1.32810241970949E-4   (Units: 1/minute)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000495

Curator's comment: (updated: 25 Nov 2013 12:12:04 GMT)

Figure 4d (SerE = 0.0001microM) of the reference publication, which lists the distribution of reaction fluxes are reproduced here using Copasi v4.11 (build 64).

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