Glucose malate-aspartate shuttle

Because the 2 NADH formed in glycolysis are transported by the glycerol phosphate shuttle in this case, they each yield only 1.5 ATP, as already described. On the other hand, if these 2 NADH take part in the malate-aspartate shuttle, each yields 2.5 ATP, giving a total (in this case) of 32 ATP formed per glucose oxidized. Most of the ATP—26 out of 30 or 28 out of 32—is produced by oxidative phosphorylation only 4 ATP molecules result from direct synthesis during glycolysis and the TCA cycle. 

This transfer of reducing equivalents is essential for maintaining the favorable NAD+/NADH ratio required for the oxidative metabolism of glucose and synthesis of glutamate in brain (McKenna et al., 2006). The malate-aspartate shuttle is considered the most important shuttle in brain. It is particularly important in neurons. It has low activity in astrocytes. This shuttle system is fully reversible and linked to amino acid metabolism with the energy charge and citric acid cycle of neuronal cells. 

Answer NADH produced in the cytosol cannot cross the inner mitochondrial membrane, but must be oxidized if glycolysis is to continue. Reducing equivalents from NADH enter the mitochondrion by way of the malate-aspartate shuttle. NADH reduces oxaloacetate to form malate and NAD+, and the malate is transported into the mitochondrion. Cytosolic oxidation of glucose can continue, and the malate is converted back to oxaloacetate and NADH in the mitochondrion (see Fig. 19-29). 

Note The current value of 30 molecules of ATP per molecule of glucose supersedes the earlier one of 36 molecules of ATP. The stoichiometries of proton pumping, ATP synthesis, and metabolite transport should be regarded as estimates. About two more molecules of ATP are formed per molecule of glucose oxidized when the malate-aspartate shuttle rather than the glycerol 3-phosphate shuttle is used. 

A slight adjustment of the niunber 38 is required. The transport of electrons from the cytoplasm to the mitochondria requires a small amount of energy. This energy is used to drive the malate-aspartate shuttle. It is thought that 0.5 molecules of ATP are consumed with each ten of the malate-aspartate shuttle. Hence, transport of the electrons from the two NADHs generated by glycolysis into the mitochondria requires the input of 1 ATP. The sum of the ATPs (or ATP equivalents) produced by complete oxidation of glucose to CO2 is 37. 

Overall, when 1 mole of glucose is oxidized to C02 and H20, approximately 36 moles of ATP are produced if the glycerol phosphate shuttle is used, or 38 moles if the malate aspartate shuttle is used. 

Gluconeogenesis from pyruvate is not equal to the reverse process of glycolytic degradation of glucose to this 3-carbon intermediate. The glycolytic pathway and the gluconeogenetic pathway deviate at three steps. The conversion of pyruvate to PEP is not mediated by pyruvate kinase due to the irreversible nature of this metabolic step. Pyruvate, derived from either lactate or alanine, is converted to oxaloacetate in the mitochondrial matrix. This step is catalyzed by pyruvate carboxylase. Oxaloacetate per se cannot pass the mitochondrial inner membrane. However, with the use of the malate-aspartate shuttle, the 4-carbon skeleton of oxaloacetate can be transferred into the cytoplasmic compartment. Then oxaloacetate is converted to PEP by the action of PEP carboxykinase (Figure 1). 

A summary of the sources of ATP produced from one molecule of glucose is provided in Table 10.2. ATP production from fatty acids, the other important energy source, is discussed in Chapter 12. Several aspects of this summary require further discussion. Recall that two molecules of NADH are produced during glycolysis. When oxygen is available, the oxidation of this NADH by the ETC is preferable (in terms of energy production) to lactate formation. The inner mitochondrial membrane, however, is impermeable to NADH. Animal cells have evolved several shuttle mechanisms to transfer electrons from cytoplasmic NADH to the mitochrondrial ETC. The most prominent examples are the glycerol phosphate shuttle and the malate-aspartate shuttle. 

Aminooxyacetate, an inhibitor of glutamate— oxalacetate transaminase, inhibits the formation of aspartate. Soling Kleinicke (1976) observed that aminooxyacetate did not inhibit the formation of glucose from lactate and, therefore, concluded that the malate-aspartate shuttle was not essential for the lactate gluconeogenesis in avian liver. However, Ochs Harris (1980) found that aminooxyacetate did block lactate gluconeogenesis when lower concentrations of pyruvate were used and incubation was for longer than 15 min. They concluded that the malate-aspartate shuttle was required. 

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