How might 12 (R) HETE cause the inhibition of Na,K-ATPase?
D R Whikehart1, H F Edelhauser, W D Woods
1Vision Science Research Center, School of Optometry, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. davwhik@vision.vsrc.uab.edu
Molecular Vision
|April 29, 1997
Summary
12 (R) hydroxy 5,8,10,14-eicosatetraenoic acid [12 (R) HETE] likely inhibits Na,K-ATPase by binding to plasma membrane lipids, especially when complexed with calcium. This binding may facilitate calcium transport, indirectly affecting the enzyme.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- 12 (R) hydroxy 5,8,10,14-eicosatetraenoic acid [12 (R) HETE] is identified as a potent inhibitor of the Na,K-ATPase enzyme.
- Understanding the precise mechanism of this inhibition is crucial for cellular physiology research.
Purpose of the Study:
- To investigate the molecular mechanisms by which 12 (R) HETE inhibits Na,K-ATPase using molecular modeling.
- To determine the binding interactions between 12 (R) HETE, its isomers, and related compounds with Na,K-ATPase components and membrane lipids.
Main Methods:
- Utilized HyperChem 2.0 for Windows to generate molecular models of 12 (R) HETE, 12 (S) HETE, and 8 (R) HHDTrE.
- Docking simulations were performed with phosphatidyl choline and the H3-H4 peptide of the Na,K-ATPase alpha-subunit.
- Modeled calcium complexes of 12 (R) HETE and related compounds to assess binding stability.
Main Results:
- 12 (R) HETE and 8 (R) HHDTrE exhibited optimal steric fitting and stabilization energies when bound to phosphatidyl choline.
- Calcium complexes of 12 (R) HETE demonstrated enhanced binding stability with phosphatidyl choline compared to non-complexed forms.
- The 12 (S) HETE isomer showed less favorable binding energies, irrespective of calcium complexation.
Conclusions:
- The study suggests that 12 (R) HETE and related compounds preferentially bind to plasma membrane lipids rather than directly to Na,K-ATPase.
- Calcium complexes of 12 (R) HETE and 8 (R) HHDTrE show a higher affinity for plasma membrane lipids.
- This lipid interaction may indirectly inhibit Na,K-ATPase by facilitating calcium transport into the cell, influencing the enzyme's sodium binding site.
More Related Videos
07:38Functional Characterization of Na+/H+ Exchangers of Intracellular Compartments Using Proton-killing Selection to Express Them at the Plasma Membrane
Published on: March 30, 2015
10:28A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
Published on: August 17, 2019
Related Concept Videos
01:27ATP Driven Pumps I: An Overview
ATP-driven pumps, also known as transport ATPases, are integral membrane proteins. They have binding sites for ATP located on the membrane's cytosolic side and the ion-conducting domain in the transmembrane region. These pumps use the free energy released from ATP hydrolysis to move the solutes across cell membranes against an electrochemical gradient.
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and are...
01:48ATP Synthase: Mechanism
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP...
01:18ATP Synthase: Structure
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
01:30ATP Driven Pumps III: V-type Pumps
V-type pumps are ATP-driven pumps found in the vacuolar membranes of plants, yeast, endosomal and lysosomal membranes of animal cells, plasma membranes of a few specialized eukaryotic cells, and some prokaryotes. They are also known as the V1Vo-ATPase, that couple ATP hydrolysis to transport protons against a concentration gradient.
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
The peripheral or cytosolic V1 domain with eight subunits is involved in ATP hydrolysis. The integral or transmembrane V0 domain containing at least five subunits...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...