ATP-Binding Cassette Transporters

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When a cell produces eicosanoids they are immediately transported into the extracellular compartment, as they are cytotoxic \cite{Pompeia2002}. An ATP-binding cassette (ABC) transporter has been assumed as the method of transportation across the cellular membrane for reactions 22-43.

An ABC transporter was assumed as the export transporter of lipids because it is widely reported as transporting organic molecules (ref). Due to the increased amount of free energy provided by the ATP hydrolysis reaction, the transporter is able to relocate molecules against a concentration gradient. The model only contains an inward facing transporter, although in reality there is also an outward facing variant.

In the literature a prostaglandin transporter is reported (Schuster2015), but due to the lack of kinetic analysis of the transporter, the ABC transporter was modelled. We assume that rate of transportation across the membrane may be similar between transporters, however once specific transporter kinetics become available, the model will be updated.

The rate law was designed to encompass the basic principles of an ATP transporter, e.g. the consumption of the internal lipid is directly proportional to amount of transporters. The ratio of substrate and product describes how the gradient would affect the rate of transportation, for example if the concentration of the external lipid equalled that of the internal, transportation would cease. The final term in the equation is the driving force for the transportation, calculated using Gibbs free energy of ATP hydrolysis, the gas constant, temperature and the concentrations of ATP and ADP. As the reformation of ATP is considerably faster than the lipid transporter the ratio was assumed to remain constant.

Reaction

Transformation of PGF2a to exPGF2a Transformation of TXB2 to exTXB2 Transformation of K6PGF2a to exK6PGF2a Transformation of PGE2 to exPGE2 Transformation of D15PGJ2 to exD15PGJ2 Transformation of 5-Oxo-ETE to ex5-Oxo-ETE Transformation of 15-HETE to ex15-HETE Transformation of LTB4 to exLTB4 Transformation of LTC4 to exLTC4 Transformation of 12-HETE to ex12-HETE Transformation of TXA2 to exTXA2 Transformation of PGI2 to exPGI2 Transformation of PGH2 to exPGH2 Transformation of PGD2 to exPGD2 Transformation of PGJ2 to exPGJ2 Transformation of 12-HPETE to ex12-HPETE Transformation of 15-HPETE to ex15-HPETE Transformation of 5-HPETE to ex5-HPETE Transformation of 5-HETE to ex5-HETE Transformation of LTA4 to exLTA4 Transformation of AA to exAA Transformation of 15-Keto-PGE2 to ex15-Keto-PGE2 Transformation of 3,4-Dihydro-15-Keto-PGE2 to ex3,4-Dihydro-15-Keto-PGE2

Chemical equation

$Intracellular Lipid + 2ATP + 2H2O \rightleftharpoons Extracellular Lipid + 2ADP + 2Pi + 2H(+)$

Parameters

Michaelis-Menten Constants

Value	Units	Species	Notes	Reference
0.0109 ± 0.0041	mM	Human	Substrate: LTC4 pH 7.0, 37°C, recombinant MRP2, using 4mM MgATP and 5g of isolated membranes.
0.0000366 ± 0.0000038	mM	Human	Substrate LTC4, 37 °C, 4 mM ATP,
5.3E-3 ± 2.6E-3	mM	Human	4 mM ATP, 37°C, 5–10 ml of membrane vesicle suspension (30 mg protein).
0.1954 ± 0.0612	mM	Human	pH 7.0, 37°C, recombinant MRP2, Substrate: 17beta-estradiol 17-(beta-D-glucuronide)
0.1097 ± 0.0391	mM	Human	pH 7.0, 37°C, recombinant MRP2, Substrate: Estrone glucuronide
0.0207	mM	Human	pH 7.4, 37°C, Substrate: Progesterone, Expression vector: Human HepG2 hepatoma

No data available on the turnover of ABCC4 transporter therefore based upon estimates made by http://book.bionumbers.org/what-are-the-rates-of-membrane-transporters/

Turnover Number

Value	Units	Transporter	Notes	Reference
3.5	min-1	Glucose transporter ptsI	Organism: Bacteria Escherichia coli Back of the envelope calculation by BioNumbers: http://bionumbers.hms.harvard.edu/bionumber.aspx?&id=102931
0.33 - 0.83	min-1	Rate of transport of H+/Lactose transporter	Organism: Bacteria Escherichia coli Back of the envelop calculation on bionumbers http://bionumbers.hms.harvard.edu/bionumber.aspx?&id=103159
3.28	min-1	Catalytic Rate of transporter HXT7	Organism: Budding yeast Saccharomyces cerevisiae Back of the envelope calculation http://bionumbers.hms.harvard.edu/bionumber.aspx?&id=101737

Vmax ***

Value	Units	Species	Notes	Reference
0.00019 ± 1.96e-5	mmol/min/mg protein	Human	Substrate: LTC4 pH 7.0, 37°C, recombinant MRP2, using 4mM MgATP and 5g of isolated membranes.
1.25e-7 ± 1.2e-8	mmol/min/mg	Human	Substrate LTC4, 37 °C, 4 mM ATP,
2.02e-8 ± 5.9e-9	mmol/mg/min	Human	4 mM ATP, 37°C, 5–10 ml of membrane vesicle suspension (30 mg protein).

Abundance

Value	Units	Species	Notes	Reference
5.15	ppm	Human	Expression Vector: Stomach Enzyme: ABCC4 pH: 7.5 Temperature: 37 °C
5.94	ppm	Human	Expression Vector: Lung Enzyme: ABCC4 pH: 7.5 Temperature: 37 °C
2.66	ppm	Human	Expression Vector: Gut Enzyme: ABCC4 pH: 7.5 Temperature: 37 °C

Related Reactions

• Transformation of AA to PGH2
• Transformation of PGD2 to PGJ2