JWS Online

sen1

sen1

 Detail
 Download

Reactions

mw106407fc_e33f_45aa_b5ae_258bd4790633

R11

mwf166ad55_4ff0_49fb_95d2_b657ad7653d5 > mwfcfaf604_14d4_47a6_b021_226d1fb5497c

mw155447fb_ce5b_4ba2_bd74_434951481a78

R2

mw15abaa48_d7d0_4845_ae04_c573d289d495 > mwfcfaf604_14d4_47a6_b021_226d1fb5497c

mw15bb92b6_4cff_4a41_b815_c1d904618e57

R10

mwee54b5b4_b8c0_41df_8dda_5b160c5e10a5 > mwfcfaf604_14d4_47a6_b021_226d1fb5497c

mw185e644d_6f10_499f_a3a6_5a47d7ba2eef

R16

mw812f63db_4cb0_40ad_b92b_9874be969dfe > mwcb834e43_dc57_45ae_9452_f4c10955caf1

mw307551ca_91cc_4634_bba5_0e3ecd38cfdd

R9

mwf166ad55_4ff0_49fb_95d2_b657ad7653d5 > mwee54b5b4_b8c0_41df_8dda_5b160c5e10a5

mw4c9aa283_577e_4b6c_ae5a_c96f62dbbb08

R3

mw15abaa48_d7d0_4845_ae04_c573d289d495 > mw8796c919_9251_4970_8f87_0bca9ecfeb5c

mw4f62d07e_217b_4602_b6fe_548af112eec8

R8

mwcb834e43_dc57_45ae_9452_f4c10955caf1 > mwee54b5b4_b8c0_41df_8dda_5b160c5e10a5

mw5194cffd_f75a_4c61_b60e_23d5b0fea120

R17

mw08818dfe_fb12_45cc_8c1d_d965f142d0ce = mw8796c919_9251_4970_8f87_0bca9ecfeb5c

mw55fba323_0865_4254_a6e9_09acd2b4a10f

R4

mw8796c919_9251_4970_8f87_0bca9ecfeb5c > mw849ed3fd_87d9_44d2_9f3e_4d631b900d41

mw79830677_2d7e_4f49_9d0b_f05fe026749f

R1

mw73259e20_240e_4f3a_b2e0_9ca248658898 > mw15abaa48_d7d0_4845_ae04_c573d289d495

mwa25d1a3d_bbd9_41b8_8274_236f9d67bb60

R15

mw919f8a86_e702_4b24_9cd7_adad694fcf9b > mw812f63db_4cb0_40ad_b92b_9874be969dfe

mwb47b4c45_fac9_49e6_a6a4_87b9050ddfbb

R7

mw849ed3fd_87d9_44d2_9f3e_4d631b900d41 > mwf166ad55_4ff0_49fb_95d2_b657ad7653d5

mwb8420f59_69c3_4707_918c_2e06bedff243

R5

mw849ed3fd_87d9_44d2_9f3e_4d631b900d41 > mwcb834e43_dc57_45ae_9452_f4c10955caf1

mwc9170c21_608b_4bd7_b2d0_f359d045da17

R6

mwfcfaf604_14d4_47a6_b021_226d1fb5497c > mwf166ad55_4ff0_49fb_95d2_b657ad7653d5

mwd71cb6c2_6420_46b9_ab17_eedc7b0fd8dc

R13

mwfcfaf604_14d4_47a6_b021_226d1fb5497c > ∅

mwdd7079dc_8d70_41b7_a369_3334522cdd13

R14

mwf166ad55_4ff0_49fb_95d2_b657ad7653d5 > ∅

mwfb854977_51ea_4daa_b84e_3bcb2fcccd39

R12

mwee54b5b4_b8c0_41df_8dda_5b160c5e10a5 > ∅

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

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.


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:

log scales

y-axis min/max

x-axis min/max

Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways.

  • Partho Sen
  • Henri J Vial
  • Ovidiu Radulescu
BMC Syst Biol 2013; 7 : 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.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000495) Biomodels notes: 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). JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.