Malate-aspartate shuttle
Encyclopedia
The malate-aspartate shuttle (sometimes also the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis
across the semipermeable inner membrane of the mitochondrion
for oxidative phosphorylation
in eukaryote
s. These electrons enter the electron transport chain
of the mitochondria via reduction equivalents
to generate ATP
. The shuttle system is required because the mitochondrial inner membrane
is impermeable to NADH, the primary reducing equivalent of the electron transport chain. To circumvent this, malate
carries the reducing equivalents across the membrane.
in the malate-aspartate shuttle is malate dehydrogenase
. Malate dehydrogenase is present in two forms in the shuttle system: mitchondrial malate dehydrogenase and cytosolic malate dehydrogenase. The two malate dehydrogenases are differentiated by their location and structure, and catalyze their reaction in opposite directions in this process.
First, in the cytosol, malate dehydogenase reacts with oxaloacetate and NADH to produce malate
and NAD+. In this process two hydrogen atoms generated from NADH and an accompanying H+ are attached to oxaloacetate to form malate.
Once malate is formed, the first antiporter (malate
-alpha-ketoglutarate) imports the malate from the cytosol into the mitochondrial matrix and also exports alpha-ketoglutarate from the matrix into the cytosol simultaneously. After malate reaches the mitochondrial matrix it is converted by mitochondrial malate dehydrogenase into oxaloacetate, during which NAD+ is reduced with two electrons to form NADH and an H+ is released. Oxaloacetate is then transformed into aspartate (since oxaloacetate cannot be transported into the cytosol) by mitochondrial aspartate aminotransferase. Since aspartate is an amino acid, an amino radical needs to be added to the oxaloacetate. This is supplied by glutamate, which in the process is transformed into alpha-ketoglutarate by the same enzyme.
The second antiporter (the glutamate-aspartate antiporter) imports glutamate from the cytosol into the matrix and exports aspartate from the matrix to the cytosol. Once in the cytosol, aspartate is converted by cytosolic aspartate aminotransferase to oxaloacetate.
The net effect of the malate-aspartate shuttle is purely redox
: NADH in the cytosol is oxidized to NAD+, and NAD+ in the matrix is reduced to NADH. The NAD+ in the cytosol can then be reduced again by another round of glycolysis, and the NADH in the matrix can be used to pass electrons to the electron transport chain so that ATP can be synthesized.
Since the malate-aspartate shuttle regenerates NADH inside the mitochondrial matrix, it is capable of maximizing the number of ATP produced in glycolysis (2.5/NADH), ultimately resulting in a net gain of 32 ATP molecules per molecule of glucose metabolized. Compare this to the glycerol 3-phosphate shuttle, which donates electrons to Complex II of the electron transport chain
(similar to FADH2), and is capable of generating only 1.5 ATP per NADH generated in glycolysis (ultimately resulting in a net gain of 30 ATP per glucose metabolized).
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
across the semipermeable inner membrane of the mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
for oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
in eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s. These electrons enter the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
of the mitochondria via reduction equivalents
Reducing equivalent
In biochemistry, the term reducing equivalent refers to any of a number of chemical species which transfer the equivalent of one electron in redox reactions...
to generate ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. The shuttle system is required because the mitochondrial inner membrane
Inner membrane
The inner membrane is the biological membrane of an organelle or Gram-negative bacteria that is within an outer membrane....
is impermeable to NADH, the primary reducing equivalent of the electron transport chain. To circumvent this, malate
Malic acid
Malic acid is an organic compound with the formula HO2CCH2CHOHCO2H. It is a dicarboxylic acid which is made by all living organisms, contributes to the pleasantly sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms , though only the L-isomer exists...
carries the reducing equivalents across the membrane.
Components
The shuttle consists of four protein parts:- malate dehydrogenaseMalate dehydrogenaseMalate dehydrogenase is an enzyme in the citric acid cycle that catalyzes the conversion of malate into oxaloacetate and vice versa...
in the mitochondrial matrix and intermembrane space. - aspartate aminotransferaseAspartate transaminaseAspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...
in the mitochondrial matrix and intermembrane space. - malateMalateMalate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
-alpha-ketoglutarate antiporterAntiporterAn antiporter is an integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in opposite directions.In secondary active transport, one species of solute moves along its electrochemical...
in the inner membrane. - glutamate-aspartate antiporterGlutamate aspartate transporterSolute carrier family 1 , member 3, also known as SLC1A3,is a protein that, in humans, is encoded by the SLC1A3 gene...
in the inner membrane.
Mechanism
The primary enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
in the malate-aspartate shuttle is malate dehydrogenase
Malate dehydrogenase
Malate dehydrogenase is an enzyme in the citric acid cycle that catalyzes the conversion of malate into oxaloacetate and vice versa...
. Malate dehydrogenase is present in two forms in the shuttle system: mitchondrial malate dehydrogenase and cytosolic malate dehydrogenase. The two malate dehydrogenases are differentiated by their location and structure, and catalyze their reaction in opposite directions in this process.
First, in the cytosol, malate dehydogenase reacts with oxaloacetate and NADH to produce malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
and NAD+. In this process two hydrogen atoms generated from NADH and an accompanying H+ are attached to oxaloacetate to form malate.
Once malate is formed, the first antiporter (malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
-alpha-ketoglutarate) imports the malate from the cytosol into the mitochondrial matrix and also exports alpha-ketoglutarate from the matrix into the cytosol simultaneously. After malate reaches the mitochondrial matrix it is converted by mitochondrial malate dehydrogenase into oxaloacetate, during which NAD+ is reduced with two electrons to form NADH and an H+ is released. Oxaloacetate is then transformed into aspartate (since oxaloacetate cannot be transported into the cytosol) by mitochondrial aspartate aminotransferase. Since aspartate is an amino acid, an amino radical needs to be added to the oxaloacetate. This is supplied by glutamate, which in the process is transformed into alpha-ketoglutarate by the same enzyme.
The second antiporter (the glutamate-aspartate antiporter) imports glutamate from the cytosol into the matrix and exports aspartate from the matrix to the cytosol. Once in the cytosol, aspartate is converted by cytosolic aspartate aminotransferase to oxaloacetate.
The net effect of the malate-aspartate shuttle is purely redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
: NADH in the cytosol is oxidized to NAD+, and NAD+ in the matrix is reduced to NADH. The NAD+ in the cytosol can then be reduced again by another round of glycolysis, and the NADH in the matrix can be used to pass electrons to the electron transport chain so that ATP can be synthesized.
Since the malate-aspartate shuttle regenerates NADH inside the mitochondrial matrix, it is capable of maximizing the number of ATP produced in glycolysis (2.5/NADH), ultimately resulting in a net gain of 32 ATP molecules per molecule of glucose metabolized. Compare this to the glycerol 3-phosphate shuttle, which donates electrons to Complex II of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
(similar to FADH2), and is capable of generating only 1.5 ATP per NADH generated in glycolysis (ultimately resulting in a net gain of 30 ATP per glucose metabolized).
See also
- Glycerol phosphate shuttleGlycerol phosphate shuttleThe glycerol-3-phosphate shuttle is a mechanism that regenerates NAD+ from NADH, a by-product of glycolysis. Its importance in transporting reducing equivalents is secondary to the malate-aspartate shuttle.-Reaction:...
- Mitochondrial shuttleMitochondrial shuttleThe mitochondrial shuttles are systems used to transport reducing agents across the inner mitochondrial membrane. NADH cannot cross the membrane, but it can reduce another molecule that can cross the membrane, so that its electrons can reach the electron transport chain.The two main systems in...