Malate-aspartate shuttle

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The malate-aspartate shuttle (malate cycle) is a system for the indirect transfer of the reducing agent NADH from the cytosol into the matrix of the mitochondria .

functionality

Scheme of the malate-aspartate shuttle system. Please refer to the text for details. Abbreviations: ( 1 ) malate; ( 2 ) oxaloacetate; ( 3 ) aspartate; ( 4 ) glutamate; ( 5 ) α-ketoglutarate; cMDH cytosolic malate dehydrogenase; mMDH mitochondrial malate dehydrogenase; cAST cytosolic aspartate aminotransferase; MAST mitochondrial aspartate aminotransferase; OGC malate / α-ketoglutarate antiporter; AGC aspartate / glutamate antiporter; IMR intermembrane space; Cyt cytosol.

The shuttle system consists of a total of four different enzymes and two antiport carriers.

The working cycle begins with the NADH-dependent reduction of oxaloacetate to malate . As the enzyme it is the cytosolic malate dehydrogenase (CMDh) active, an isoenzyme of in the citric acid cycle involved mitochondrial malate dehydrogenase (mMDH). The malate formed is transported by the α-ketoglutarate malate carrier into the matrix of the mitochondrion, with α-ketoglutarate entering the cytosol in the antiport. α-Ketoglutarate is used in a later step of the cycle to regenerate the cytosolic oxaloacetate.

In the interior of the mitochondrion mitochondrial malate dehydrogenase oxidizes the imported again malate to oxaloacetate, wherein NAD + to NADH + H + is reduced. The actual transport function of the shuttle is already fulfilled, but further steps are necessary to maintain the cycle. The oxaloacetate in the mitochondrion is aminated to aspartate via a mitochondrial aspartate aminotransferase (MAST), depending on glutamate . Α-Ketoglutarate is formed from glutamate. The glutamate comes from the cytosol, whereby it is exchanged for the aspartate produced by the aspartate-glutamate carrier .

In the last step of the cycle, the aspartate in the cytosol is converted by a cytosolic aspartate aminotransferase (cAST) to oxaloacetate, the starting material for the first reaction. The α-ketoglutarate transported into the cytosol in exchange for malate is converted into glutamate. This can be transported back into the matrix space by the aspartate-glutamate carrier mentioned.

Biological importance

The shuttle system is necessary so that the u. a. NADH produced in glycolysis can be supplied to the respiratory chain located in the mitochondria in order to serve as an energy source for ATP synthesis. At the same time, NAD + is regenerated so that it can be used again in glycolysis. It occurs in mammals in both the mitochondria of the heart , liver, and kidneys . The transport process is not an active transport, so NADH gradients cannot be built up, only reduced. For a transport directed into the mitochondrion, a predominance of the cytosolic NADH concentration compared to the mitochondrial one is necessary.

In the rest of the tissue, especially in the muscles or the brain , cytosolic NADH is fed to the respiratory chain by a faster transport system, the so-called glycerol-3-phosphate shuttle .

The oxaloacetate transported into the cytosol by the shuttle system can also be used for gluconeogenesis .

Classification in the metabolic context

The malate-aspartate shuttle represents - next to the glycerine-3-phosphate shuttle - one of the main ways of transporting electrons / reduction equivalents from the cytosol to the mitochondria. In contrast to the glycerine-3-phosphate shuttle system, it is more energy-efficient because that NADH generated in the matrix can be fed directly into the respiratory complex I. In the glycerol-3-phosphate shuttle system, on the other hand, the energetically weaker flavin-adenine-dinucleotide FADH 2 is produced , whose electrons can only reach respiratory complex III via ubiquinone . A cytosolic NADH using the malate-aspartate shuttle delivers around 2.5 ATP in the respiratory chain, whereas it only generates around 1.5 ATP when transported by the glycerol-3-phosphate shuttle.

Individual evidence

  1. ↑ encoded by MDH1 in humans (HUGO Gene Nomenclature Committee HGNC)
  2. ↑ encoded by MDH2 in humans (HUGO Gene Nomenclature Committee HGNC)
  3. ↑ encoded by GOT2 in humans (HUGO Gene Nomenclature Committee HGNC)
  4. ↑ encoded by GOT1 in humans (HUGO Gene Nomenclature Committee HGNC)

literature

  • Jeremy M. Berg, Lubert Stryer, and John L. Tymoczko: Biochemistry . Spectrum Academic Publishing House; 6th edition 2007; ISBN 978-3827418005 ; P. 588f.
  • Fallert-Müller et al .: Lexicon of Biochemistry , Spektrum Akademischer Verlag, 2000

See also