Shuttle Systems In Metabolism

Shuttle Systems In Metabolism

Introduction

Shuttle systems play a critical role in metabolism by facilitating the transfer of electrons from NADH to the electron transport chain. This process is essential for oxidative phosphorylation, particularly during glycolysis, since the inner mitochondrial membrane is impermeable to NADH.

Types of Shuttle Systems

1. Malate-Aspartate Shuttle System

2. Glycerol 3-Phosphate Shuttle System

- Shuttle systems are essential during glycolysis for transporting NADH (electrons) from the cytoplasm to the mitochondrial matrix.

- The electrons enter the electron transport chain to generate ATP.

- The net ATP gain during glycolysis depends on the specific shuttle system used.

Malate-Aspartate Shuttle System

The malate-aspartate (M-A) shuttle is a vital mechanism for regulating glycolysis and lactate metabolism, particularly in the heart. It transfers reducing equivalents from the cytosol into the mitochondria and is the principal method for moving NADH from the cytoplasm to the mitochondrial matrix.

Mechanism

- Enzyme Involved

Malate dehydrogenase, which exists in two forms:

Mitochondrial malate dehydrogenase

Cytosolic malate dehydrogenase.

- Reaction in Cytosol:

Malate dehydrogenase catalyzes the reaction of oxaloacetate and NADH to produce malate and NAD+. Two electrons and a proton (H+) are transferred to oxaloacetate, forming malate.

- Transport Proteins:

The inner mitochondrial membrane contains two antiporter proteins:

- Glutamate-Aspartate Transporter (Transporter I)

- Malate-α-Ketoglutarate Transporter (Transporter II)

Process

1. Malate Formation:

In the cytosol, malate is formed and transported into the mitochondrial matrix by the malate-α-ketoglutarate transporter, which simultaneously exports alpha-ketoglutarate to the cytosol.

2. Conversion in Mitochondria:

In the mitochondrial matrix, malate is converted back to oxaloacetate by mitochondrial malate dehydrogenase, reducing NAD+ to NADH.

3. Aspartate Formation:

Oxaloacetate is then transformed into aspartate by mitochondrial aspartate aminotransferase. Glutamate provides the necessary amino group, converting into alpha-ketoglutarate.

4. Transport Back to Cytosol:

The glutamate-aspartate antiporter imports glutamate into the matrix and exports aspartate to the cytosol.

5. Cycle Completion:

In the cytosol, aspartate is converted back to oxaloacetate by cytosolic aspartate aminotransferase.

Energy Yield

The malate-aspartate shuttle system regenerates NADH inside the mitochondrial matrix, maximizing ATP production. This results in a net gain of approximately 38 ATP molecules per glucose molecule metabolized during glycolysis.

Steps of Malate-aspartate shuttle:

1. NADH in the cytosol enters the intermembrane space through openings in the outer membrane (porins), then passes two reducing equivalents to oxaloacetate, producing malate .

2. Malate crosses the inner membrane via the malate–α-ketoglutarate transporter.

3. In the matrix, malate passes two reducing equivalents to NAD+, and the resulting NADH is oxidized by the respiratory chain; the oxaloacetate formed from malate cannot pass directly into the cytosol.

4. Oxaloacetate is first transaminated to aspartate, and 5. Aspartate can leave via the glutamate-aspartate transporter.

6. Oxaloacetate is regenerated in the cytosol, completing the cycle, and glutamate produced in the same reaction enters the matrix via the glutamate-aspartate transporter.

 When body utilises α-glycero-P-shuttle, net ATP produced by glycolysis—TCA cycle per molecule glucose oxidised will be 36 ATP (2 ATP less) and NOT 38 ATP.

 Use of Malate shuttle will form 38 ATP

Shuttle pathways and tissues

Liver, kidney, and heart utilize malate-aspartate shuttle, and yield 3 ATP per mole of NADH.

Skeletal muscle and the brain utilize glycerol-phosphate shuttle and liberate 2 ATP from NADH.

Glycerol-phosphate shuttle

-Cytosolic glycerol 3-phosphate dehydrogenase oxidizes NADH to NAD+.

-The reducing equivalents are transported through glycerol 3-phosphate into the mitochondria.

-Glycerol 3-phosphate dehydrogenase—present on outer surface of inner mitochondrial membrane— reduces FAD to FADH2.

-Dihydroxyacetone phosphate escapes into the cytosol and the shuttling continues as depicted.

-FADH2 gets oxidized via ETC to generate 2 ATP.

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