Difference between revisions of "ATP-Binding Cassette Transporters"

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[[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]]
 
[[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]]
  
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The eicosanoids that are produced within the cell are immediately transported into the extracellular compartment, as they are cytotoxic \cite{Pompeia2002}. The transport systems relevant to each eicosanoid have not yet been fully characterised, therefore an ATP-binding cassette transporter has been assumed as the method of transportation across the cellular membrane for reactions 22-43. To model this we have used reversible the Michaelis Menten equation once more. The regeneration of ATP will be taken into account in the equilibrium constants. As there is no known data about the eicosanoid selectivity of the transporter, the Michaelis Menten constant (Km) and catalytic activity (kcat) are currently the same for each substrate.  
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At physiological pH, eicosanoids exist primarily as charged species and therefore exhibit poor membrane permeability <ref>Svensson, C. I., Yaksh, T. L., ''The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing'', Annu Rev Pharmacol Toxicol (2002), 42, 553-83.</ref>. Several studies have reported that eicosanoids are transported into the extracellular compartment via energy-dependant, active transport <ref>Kochel, T. J. Fulton, A. M., ''Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer'', Prostaglandins Other Lipid Mediat (2015), 116-117, 99-103.</ref><ref>Lin, Z. P. Zhu, Y. L. Johnson, D. R. Rice, K. P. Nottoli, T. Hains, B. C. McGrath, J. Waxman, S. G. Sartorelli, A. C. , ''Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response'', Mol Pharmacol (2008), 73, 243-51.</ref><ref>Chan, B. S. Satriano, J. A. Pucci, M. Schuster, V. L. , ''Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa Cells and Xenopus Oocytes expressing the prostaglandin transporter “PGT”'', J Biol Chem (1998), 273, 6689-6697.</ref>
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<ref>Schuster, V. L., ''Molecular mechanisms of prostaglandin transport'', Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.</ref><ref>Baroody, R. A. Bito, L. Z. , ''The impermeability of the basic cell membrane to thromboxane-B2' prostacyclin and 6-keto-PGF 1 alpha'', Prostaglandins (1981), 21, 133-42.</ref>.Responsible for this transport is an ATP-binding cassette (ABC) transporter, also known as a α-ketoglutarate organic anion exchanger and a prostaglandin specific organic anion transporter protein, OATP2A1 (PGT) <ref>Schuster, V. L., ''Molecular mechanisms of prostaglandin transport'', Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.</ref>. Both transporters are a channel/pump located in the phospholipid bilayer of a cell, which binds and hydrolyses ATP to drive translocation of eicosanoids against a concentration gradient <ref>Higgins, C. F., ''ABC transporters: from microorganisms to man'', Annu Rev Cell Biol (1992), 8, 67-113.</ref><ref>Dean, M. Allikmets, R., ''Evolution of ATP-binding cassette transporter genes'', Curr Opin Genet Dev (1995), 5, 779-85.</ref> <ref>Kanai, N. Lu, R. Satriano, J. A. Bao, Y. Wolkoff, A. W. Schuster, V. L. , ''Identification and characterization of a prostaglandin transporter
−
Lipids are reported to be exported out of cells via an ATP binding cassette transporter. This process occurs against a concentration gradient; therefore hydrolysis of ATP is required to overcome the thermodynamic barrier.
+
'', Science (1995), 268, 866-869.</ref>.
  
 +
The member of the ABC transporter family which is reported to transport eicosanoids is the multidrug resistance protein 4 (MRP4/ABCC4) <ref>Higgins, C. F., ''ABC transporters: from microorganisms to man'', Annu Rev Cell Biol (1992), 8, 67-113.</ref><ref>Dean, M. Allikmets, R., ''Evolution of ATP-binding cassette transporter genes'', Curr Opin Genet Dev (1995), 5, 779-85.</ref>. The eicosanoid specificity of  the ABC transporter has not been well explored beyond PGE2, but seems to be non-specific <ref>Schuster, V. L., ''Molecular mechanisms of prostaglandin transport'', Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.</ref>.
  
  
 
== Reaction ==
 
== Reaction ==
  
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+
{|width ="80%"
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==Chemical equation==
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|
−
 
+
* [[Transformation of PGF2a to exPGF2a |Transformation of PGF<sub>2a</sub> to exPGF<sub>2a</sub> (R22)]]
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<center><math> Intracellular Lipid + 2ATP + 2H2O \rightleftharpoons Extracellular Lipid + 2ADP + 2Pi + 2H(+) </math></center>
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* [[Transformation of TXB2 to exTXB2 |Transformation of TXB<sub>2</sub> to exTXB<sub>2</sub> (R23)]]
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* [[Transformation of K6PGF2a to exK6PGF2a  |Transformation of 6-keto-PGF<sub>1a</sub> to ex6-keto-PGF<sub>1a</sub> (R24)]]
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== Rate equation ==
+
* [[Transformation of PGE2 to exPGE2 |Transformation of PGE<sub>2</sub> to exPGE<sub>2</sub> (R25)]]
−
 
+
* [[Transformation of D15PGJ2 to exD15PGJ2 |Transformation of 15-deoxy-PGJ<sub>2</sub> to ex15-deoxy-PGJ<sub>2</sub> (R26) ]]
−
 
+
* [[Transformation of 5-Oxo-ETE to ex5-Oxo-ETE |Transformation of 5-Oxo-ETE to ex5-Oxo-ETE (R27)]]
−
== Parameters ==
+
* [[Transformation of 15-HETE to ex15-HETE |Transformation of 15-HETE to ex15-HETE (R28)]]
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{|class="wikitable sortable"
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* [[Transformation of LTB4 to exLTB4 |Transformation of LTB<sub>4</sub> to exLTB<sub>4</sub> (R29)]]
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|+  style="text-align: left;" | Michaelis-Menten Constants
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* [[Transformation of LTC4 to exLTC4 |Transformation of LTC<sub>4</sub> to exLTC<sub>4</sub> (R30)]]
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|-
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* [[Transformation of 12-HETE to ex12-HETE |Transformation of 12-HETE to ex12-HETE (R31)]]
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! Value
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* [[Transformation of TXA2 to exTXA2 |Transformation of TXA<sub>2</sub> to exTXA<sub>2</sub> (R32)]]
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! Units
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* [[Transformation of PGI2 to exPGI2 |Transformation of PGI<sub>2</sub> to exPGI<sub>2</sub> (R33)]]
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! Species
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* [[Transformation of PGH2 to exPGH2 |Transformation of PGH<sub>2</sub> to exPGH<sub>2</sub> (R34) ]]
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! Notes
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* [[Transformation of PGD2 to exPGD2 |Transformation of PGD<sub>2</sub> to exPGD<sub>2</sub> (R35)]]
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! Reference
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* [[Transformation of PGJ2 to exPGJ2 |Transformation of PGJ<sub>2</sub> to exPGJ<sub>2</sub> (R36)]]
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|-
+
* [[Transformation of 12-HPETE to ex12-HPETE |Transformation of 12-HPETE to ex12-HPETE (R37) ]]
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|0.0109 ± 0.00391
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* [[Transformation of 15-HPETE to ex15-HPETE |Transformation of 15-HPETE to ex15-HPETE (R38)]]
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|mM
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* [[Transformation of 5-HPETE to ex5-HPETE |Transformation of 5-HPETE to ex5-HPETE (R39)]]
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|Human
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* [[Transformation of 5-HETE to ex5-HETE |Transformation of 5-HETE to ex5-HETE (R40) ]]
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|Substrate: LTC4
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* [[Transformation of LTA4 to exLTA4 |Transformation of LTA<sub>4</sub> to exLTA<sub>4</sub> (R41)]]
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pH 7.0, 37°C, recombinant MRP2, using 4mM MgATP and 5g of isolated membranes.
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* [[Transformation of AA to exAA|Transformation of AA to exAA (R42)]]
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|<ref name="Yas2007"> [http://ac.els-cdn.com/S0928098708003618/1-s2.0-S0928098708003618-main.pdf?_tid=a147bd90-1dc8-11e6-9405-00000aab0f26&acdnat=1463666001_5a08a971497da36ce8a604f84caadfc2 Yasunaga M. "Molecular cloning and functional characterization of cynomolgus monkey multidrug resistance-associated protein 2 (MRP2)''  Eur. J. Pharm. Sci. 35, 326-334 (2008)]</ref>
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* [[Transformation of 15-Keto-PGE2 to ex15-Keto-PGE2  |Transformation of 15-Keto-PGE<sub>2</sub> to ex15-Keto-PGE<sub>2</sub> (R67)]]
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|-
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* [[Transformation of 3,4-Dihydro-15-Keto-PGE2  to ex3,4-Dihydro-15-Keto-PGE2  |Transformation of 13,14-Dihydro-15-Keto-PGE2  to ex13,14-Dihydro-15-Keto-PGE<sub>2</sub> (R70) ]]  
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|0.0000366 ± 0.0000038
 
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|mM
 
−
|Human
 
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|Substrate LTC4, 37 °C, 4 mM ATP,
 
−
|<ref name="Mao2000"> [http://www.jbc.org/content/275/44/34166.full.pdf Zeng H. "Transport of amphipathic anions by human multidrug resistance protein 3''  J. Biol. Chem. 275, 34166-34172 (2000)]</ref>
 
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|-
 
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|5.3E-3 ± 2.6E-3
 
−
|mM
 
−
|Human
 
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|4 mM ATP, 37°C, 5–10 ml of membrane vesicle suspension (30
 
−
mg protein).
 
−
|<ref name="Zeng2000"> [http://cancerres.aacrjournals.org/content/60/17/4779.full.pdf "Functional reconstitution of substrate transport by purified multidrug resistance protein MRP1 (ABCC1) in phospholipid vesicles''  Cancer Res. 60, 4779-4784 (2000)]</ref>
 
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|-
 
−
|}
 
−
 
 
−
{|class="wikitable sortable"
 
−
|+  style="text-align: left;" | Turnover Number
 
−
|-
 
−
! Value
 
−
! Units
 
−
! Species
 
−
! Notes
 
−
! Reference
 
−
|-
 
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|11.34
 
−
|per minute
 
−
|Human
 
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|Substrate: ATP
 
−
|<ref name="Yas2007"> [http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2009.07072.x/abstract;jsessionid=C62D36B7C02D54530D521224C3C52976.f01t03 Sato, T "Functional role of the linker region in purified human P-glycoprotein''  FEBS J. 276, 3504-3516 (2009))]</ref>
 
−
|-
 
 
|}
 
|}
  
−
{|class="wikitable sortable"
+
== Rate Law ==
−
|+  style="text-align: left;" | 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.
 
−
|<ref name="Yas2007"> [http://ac.els-cdn.com/S0928098708003618/1-s2.0-S0928098708003618-main.pdf?_tid=a147bd90-1dc8-11e6-9405-00000aab0f26&acdnat=1463666001_5a08a971497da36ce8a604f84caadfc2 Yasunaga M. "Molecular cloning and functional characterization of cynomolgus monkey multidrug resistance-associated protein 2 (MRP2)''  Eur. J. Pharm. Sci. 35, 326-334 (2008)]</ref> 
 
−
|-
 
−
|1.25e-7 ± 1.2e-8
 
−
|mmol/min/mg
 
−
|Human
 
−
|Substrate LTC4, 37 °C, 4 mM ATP,
 
−
|<ref name="Mao2000"> [http://www.jbc.org/content/275/44/34166.full.pdf Mao Q. "Functional reconstitution of substrate transport by purified multidrug resistance protein MRP1 (ABCC1) in phospholipid vesicles''  J. Biol. Chem. 275, 34166-34172 (2000)]</ref>
 
−
|-
 
−
|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).
 
−
|<ref name="Zeng2000"> [http://cancerres.aacrjournals.org/content/60/17/4779.full.pdf "Functional reconstitution of substrate transport by purified multidrug resistance protein MRP1 (ABCC1) in phospholipid vesicles''  Cancer Res. 60, 4779-4784 (2000)]</ref>
 
−
|-
 
−
|}
 
  
−
== References ==
+
[[File:ABC_CI.PNG]]
−
<references/>
 
  
 
== Related Reactions ==
 
== Related Reactions ==
 
* [[Transformation of AA to PGH2 |Transformation of AA to PGH2]]
 
* [[Transformation of AA to PGH2 |Transformation of AA to PGH2]]
 
* [[Transformation of PGD2 to PGJ2 |Transformation of PGD2 to PGJ2]]
 
* [[Transformation of PGD2 to PGJ2 |Transformation of PGD2 to PGJ2]]

Latest revision as of 13:53, 26 August 2019

Return to overview

At physiological pH, eicosanoids exist primarily as charged species and therefore exhibit poor membrane permeability [1]. Several studies have reported that eicosanoids are transported into the extracellular compartment via energy-dependant, active transport [2][3][4] [5][6].Responsible for this transport is an ATP-binding cassette (ABC) transporter, also known as a α-ketoglutarate organic anion exchanger and a prostaglandin specific organic anion transporter protein, OATP2A1 (PGT) [7]. Both transporters are a channel/pump located in the phospholipid bilayer of a cell, which binds and hydrolyses ATP to drive translocation of eicosanoids against a concentration gradient [8][9] [10].

The member of the ABC transporter family which is reported to transport eicosanoids is the multidrug resistance protein 4 (MRP4/ABCC4) [11][12]. The eicosanoid specificity of the ABC transporter has not been well explored beyond PGE2, but seems to be non-specific [13].


Reaction

Rate Law

ABC CI.PNG

Related Reactions

  • ↑ Svensson, C. I., Yaksh, T. L., The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing, Annu Rev Pharmacol Toxicol (2002), 42, 553-83.
  • ↑ Kochel, T. J. Fulton, A. M., Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer, Prostaglandins Other Lipid Mediat (2015), 116-117, 99-103.
  • ↑ Lin, Z. P. Zhu, Y. L. Johnson, D. R. Rice, K. P. Nottoli, T. Hains, B. C. McGrath, J. Waxman, S. G. Sartorelli, A. C. , Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response, Mol Pharmacol (2008), 73, 243-51.
  • ↑ Chan, B. S. Satriano, J. A. Pucci, M. Schuster, V. L. , Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa Cells and Xenopus Oocytes expressing the prostaglandin transporter “PGT”, J Biol Chem (1998), 273, 6689-6697.
  • ↑ Schuster, V. L., Molecular mechanisms of prostaglandin transport, Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.
  • ↑ Baroody, R. A. Bito, L. Z. , The impermeability of the basic cell membrane to thromboxane-B2' prostacyclin and 6-keto-PGF 1 alpha, Prostaglandins (1981), 21, 133-42.
  • ↑ Schuster, V. L., Molecular mechanisms of prostaglandin transport, Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.
  • ↑ Higgins, C. F., ABC transporters: from microorganisms to man, Annu Rev Cell Biol (1992), 8, 67-113.
  • ↑ Dean, M. Allikmets, R., Evolution of ATP-binding cassette transporter genes, Curr Opin Genet Dev (1995), 5, 779-85.
  • ↑ Kanai, N. Lu, R. Satriano, J. A. Bao, Y. Wolkoff, A. W. Schuster, V. L. , Identification and characterization of a prostaglandin transporter , Science (1995), 268, 866-869.
  • ↑ Higgins, C. F., ABC transporters: from microorganisms to man, Annu Rev Cell Biol (1992), 8, 67-113.
  • ↑ Dean, M. Allikmets, R., Evolution of ATP-binding cassette transporter genes, Curr Opin Genet Dev (1995), 5, 779-85.
  • ↑ Schuster, V. L., Molecular mechanisms of prostaglandin transport, Prostaglandins Other Lipid Mediat (2002), 68-69, 633-47.
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