Malate-aspartate shuttle

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"Diagram Illustrating the Malate-Asparate Shuttle Pathway"

The malate-aspartate shuttle (sometimes also the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis (TCA/Krebs Cycle) across the impermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes. This allows the hydrogen ions (reduction equivalents) of the cofactor NADH produced in the cytosol to reach the electron transport chain in the mitochondria and generate ATP. The shuttle system is required because the inner membrane is impermeable to NADH and its oxidized form NAD⁺ It is important to note that NAD+/NADH does not actually cross the membrane, only ions (attached to malate) cross membrane.

1 Components
2 Mechanism
3 References
4 See also

[edit] Components

It consists of four protein parts:

malate dehydrogenase in the mitochondrial matrix and intermembrane space.
aspartate aminotransferase in the mitochondrial matrix and intermembrane space.
Malate-alpha-Ketoglutarate antiporter in the inner membrane.
Glutamate-Aspartate antiporter in the inner membrane.

[edit] Mechanism

The primary enzyme in the malate-aspartate shuttle is malate dehydrogenase. Malate dehydrogenase is present in two forms in the shuttle system: mitchondrial malate dehydrogenase and cytosolic dehydrogenase. The function of both malate dehydrogenases are identical; they are differentiated solely for clarity in regards to their location.

First, in the cytosol, malate dehydogenase reacts with oxaloacetate and NADH to produce malate and NAD⁺. In this process two hydrogen ions are moved from NADH and the accompanying H+, and 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 is in the mitochrondial matrix it gets converted by mitochrondrial malate dehydrogenase into oxaloacetate, during which NAD+ is reduced to form NADH with an accompanying hydrogen ion. Oxaloacetate is then transformed into asparate (since oxaloacetate cannot be transported into the cytosol) by mitochrondrial asparate aminotransferase. The same enzyme also converts glutamate (exported from the second antiporter, glutamate-aspartate transporter) to alpha-ketoglutarate.

The second antiporter (glutamate-asparate antiporter) imports glutamate from the cytosol into the matrix and exports asparate from the matrix to the cytosol. Once in the cytosol, asparate is converted by cytosolic asparate 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 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 only capable of generating 1.5 ATP per NADH generated in glycolysis (ultimately resulting in a net gain of 30 ATP per glucose metabolized).

[edit] References

Monty Krieger; Matthew P Scott; Matsudaira, Paul T.; Lodish, Harvey F.; Darnell, James E.; Lawrence Zipursky; Kaiser, Chris; Arnold Berk. Molecular Cell Biology, Fifth Edition. San Francisco: W. H. Freeman. ISBN 0716743663.