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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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.  
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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
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'', Science (1995), 268, 866-869.</ref>.
  
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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.  
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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>.
  
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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 ==
 
== Reaction ==

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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