chemistry

Malate–aspartate shuttle

Malate–aspartate shuttle is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Malate–aspartate shuttle rather than just read about it. In short: The malate–aspartate shuttle (sometimes simply 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 eukaryotes. These electrons enter the electron transport chain of the mitochondria via reduction equivalents to generate ATP.

Key takeaways

Malate–aspartate shuttle belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Malate–aspartate shuttle to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Malate–aspartate shuttle from memory before moving on to harder problems.

Reference excerpt

The malate–aspartate shuttle (sometimes simply 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 eukaryotes. 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.

Components The shuttle consists of four protein parts:

Malate dehydrogenase in the mitochondrial matrix and intermembrane space. Aspartate aminotransferase in the mitochondrial matrix and intermembrane space. Malate–α-ketoglutarate antiporter in the inner membrane. Glutamate–aspartate antiporter in the inner membrane.

Mechanism The primary enzyme in the malate–aspartate shuttle is malate dehydrogenase. Malate dehydrogenase is present in two forms in the shuttle system: mitochondrial malate dehydrogenase and cytosolic malate dehydrogenase. The two malate dehydrogenases are differentiated by their location and structure, and catalyze their reactions in opposite directions in this process. First, in the cytosol, malate dehydrogenase catalyses the reaction of oxaloacetate and NADH to produce malate and NAD+. In this process, two electrons generated from NADH, and an accompanying H+, are attached to oxaloacetate to form malate. Once malate is formed, the first antiporter (malate–α-ketoglutarate) imports the malate from the cytosol into the mitochondrial matrix and also exports α-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. 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 α-ketoglutarate by the same enzyme. The second antiporter (AGC1 or AGC2) 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 ATP can be synthesized. Since the malate–aspartate shuttle regenerates NADH inside the mitochondrial matrix, it is capable of maximizing the number of ATPs produced in glycolysis (3/NADH), ultimately resulting in a net gain of 38 ATP molecules per molecule of glucose metabolized. Compare this to the glycerol 3-phosphate shuttle, which reduces FAD+ to produce FADH2, donates electrons to the quinone pool in the electron transport chain, and is capable of generating only 2 ATPs per NADH generated in glycolysis (ultimately resulting in a net gain of 36 ATPs per glucose metabolized). (These ATP numbers are prechemiosmotic, and should be reduced in light of the work of Mitchell and many others. Each NADH produces only 2.5 ATPs, and each FADH2 produces only 1.5 ATPs. Hence, the ATPs per glucose should be reduced to 32 from 38 and 30 from 36. The extra H+ required to bring in the inorganic phosphate during oxidative-phosphorylation contributes to the 30 and 32 numbers as well).

Regulation The activity of malate–aspartate shuttle is modulated by arginine methylation of malate dehydrogenase 1 (MDH1). Protein arginine N-methyltransferase CARM1 methylates and inhibits MDH1 by disrupting its dimerization, which represses malate–aspartate shuttle and inhibits mitochondria respiration of pancreatic cancer cells.

Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles.

See also Glycerol phosphate shuttle Mitochondrial shuttle

References

Monty Krieger; Matthew P Scott; Matsudaira, Paul T.; Lodish, Harvey F.; Darnell, James E.; Lawrence Zipursky; Kaiser, Chris; Arnold Berk (2003). Molecular Cell Biology, Fifth Edition. San Francisco: W. H. Freeman. ISBN 0-7167-4366-3.

Illustrations

Worked examples

Example 1 — a first encounter with Malate–aspartate shuttle

Start with the simplest possible case. Write down what Malate–aspartate shuttle claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Malate–aspartate shuttle before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Malate–aspartate shuttle ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Malate–aspartate shuttle

In research: Malate–aspartate shuttle appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Malate–aspartate shuttle in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Malate–aspartate shuttle is common in secondary-school and first-year university syllabi. It links to neighbouring topics Biochemical reactions, Cellular respiration, so understanding it makes those chapters shorter.
In everyday life: Look for Malate–aspartate shuttle outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Malate–aspartate shuttle in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Malate–aspartate shuttle means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Malate–aspartate shuttle out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Malate–aspartate shuttle in simple terms?

Why does Malate–aspartate shuttle matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Malate–aspartate shuttle?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Malate–aspartate shuttle.