Malate gluconeogenesis

FIGURE 23.5 Pyruvate carboxyl compartmentalized reaction. Pyruva verted to oxaloacetate in the mitoci Because oxaloacetate cannot be trai across the mitochondrial membrant reduced to malate, transported to tl and then oxidized back to oxaloace gluconeogenesis can continue. 

In pigeon, chicken, and rabbit liver, phospho-enolpymvate carboxykinase is a mitochondrial enzyme, and phosphoenolpyruvate is transported into the cytosol for gluconeogenesis. In the rat and the mouse, the enzyme is cytosolic. Oxaloacetate does not cross the mitochondrial inner membrane it is converted to malate, which is transported into the cytosol, and convetted back to oxaloacetate by cytosolic malate dehydrogenase. In humans, the guinea pig, and the cow, the enzyme is equally disttibuted between mitochondria and cytosol. 

Gluconeogenesis from several amino acids uses the malate shuttle. 

Propionyl CoA is converted to sucdnyl CoA, a dtric add cyde intermediate, in the two-step propionic add pathway. Because this extra sucdnyl CoA can form malate and enter the cytoplasm and gluconeogenesis, odd-carbon fatty adds represent an exception to the rule that fatty... 

Figure 6-7. Conversion of mitochondrial pyruvate to cytosolic phosphoenolpyruvate to initiate gluconeogenesis. Oxaloacetate cannot pass across the inner mitochondrial membrane, so it is reduced to malate, which can do so.

To initiate gluconeogenesis, oxaloacetate is reduced to malate, which is then transported to the cytosol in the reverse of the malate shuttle. 

C. Oxaloacetate can also be converted to malate and transported to the cytoplasm for gluconeogenesis under fasting conditions (see Chapter 6). 

The standard free-energy change for this reaction is quite high, but under physiological conditions (including a very low concentration of oxaloacetate) AG 0 and the reaction is readily reversible. Mitochondrial malate dehydrogenase functions in both gluconeogenesis and the citric acid cycle, but the overall flow of metabolites in the two processes is in opposite directions. 

Tire glycerol-phosphate shuttle, because it depends upon a mitochondrial flavoprotein, provides 2 ATP per electron pair (P/O = 2), whereas the malate-aspartate shuttle may provide a higher yield of ATP. Tire glycerol-phosphate shuttle is essentially irreversible, but the reactions of the malate-aspartate shuttle can be reversed and utilized in gluconeogenesis (Chapter 17). 

The fumarate released in the urea cycle links the urea cycle with the TCA cycle. This fumarate is hydrated to malate, which is oxidized to oxaloacetate. The carbons of oxaloacetate can stay in the TCA cycle by condensation with acetyl-CoA to form citrate, or they can leave the TCA cycle either by gluconeogenesis to form glucose or by transamination to form aspartate as shown in figure 22.9. Because Krebs was involved in the discoveries of both the urea cycle and the TCA cycle, the interaction between the two cycles shown in figure 22.9 is sometimes referred to as the Krebs bicycle. 

Oxaloacetate, the product of the first step in gluconeogenesis, must leave the mitochondrion and enter the cytosol where the subsequent enzyme steps take place. Since the inner mitochondrial membrane is impermeable to oxaloacetate, it is converted to malate by mitochondrial malate dehydrogenase. This leaves the mitochondrion and is converted back to oxaloacetate in the cytosol by cytoplasmic malate dehydrogenase. 

Pyruvate carboxylase is a mitochondrial matrix enzyme whereas the other enzymes of gluconeogenesis are located outside the mitochondrion. Thus oxaloacetate, produced by pyruvate carboxylase, needs to exit the mitochondrion. However the inner mitochondrial membrane is not permeable to this compound. Thus oxaloacetate is converted to malate inside the mitochondrion... 

Figure 2.3(D). Uricogenesis during alanine catabolism and gluconeogenesis in avian liver. Some abbreviations are as in figure 2.3(C). 1 C refers to one-carbon units MDH, malate dehydrogenase XDH, xanthine dehydrogenase PRPP, phosphoribosylpyrophosphate IMP, inosoine monophosphate ino, inosine hyp, hypoxanthine xan, xanthine.

Citrate 2-Oxoglutarate Succinyl-CoA Malate Oxaloacetate Fatty acid biosynthesis Synthesis of glutamate Heme biosynthesis Gluconeogenesis Synthesis of aspartate... 

Pyruvate carboxylase is a mitochondrial enzyme, vhereas the other enzymes of gluconeogenesis are cytoplasmic. Oxaloacetate, the product of the pyruvate carboxylase reaction, is reduced to malate inside the mitochondrion for transport to the cytosol. The reduction is accomplished by an NADH-linked malate dehydrogenase. When malate has been transported across the mitochondrial membrane, it is reoxidized to oxaloacetate by an NAD+-linked malate dehydrogenase in the cytosol (Figure 16.28). 

Figure 16.28. Compartmental Cooperation. Oxaloacetate utilized in the cytosol for gluconeogenesis is formed in the mitochondrial matrix by carboxylation of pyruvate. Oxaloacetate leaves the mitochondrion by a specific transport system (not shovm) in the form of malate, -which is reoxidized to oxaloacetate in the cytosol.

Studies of the role of metabolic transporters in the control and modulation of metabolic fluxes have provided somewhat ambiguous results in the case of respiration and gluconeogenesis. The role of the glutamate transporter in the acute control of ammonia formation seems clear at this time, and a proposed role of the malate/a-ketoglutarate carrier in chronic acidosis is an intriguing possibility. 

The pyruvate produced at point (3) can be used to produce energy within the liver or for gluconeogenesis. Pyruvate produces energy when it is oxidized in the mitochondria by the Krebs cycle. It is used for gluconeogenesis when it is converted in the mitochondria to OAA, then to malate, which, after exit from the mitochondria, is converted to PEP and eventually to glucose. 

FIGURE 4.59 Enzymes of the Krebs Cycle and removal of malate for gluconeogenesis. The enzymes that catalyze each Step of the Krebs cycle are named all are mitochondria]. The section symbol ) indicates the two points in the Krebs cycle, and a gluconeogenesis step occurring in the cytoplasm, where carbon is lost as CO -... 

The introduction of each 2-carbon unit ties up one molecule of OAA, because the acetyl group condenses with OAA to form citric acid, which then travels through the cycle and becomes malate. Malate then leaves for the cytosol, and OAA is not regenerated. Consequently, continued use of acetyl groups for gluconeogenesis would lead to depletion of some of the intermediates of the Krebs cycle. This point introduces the concept that the intermediates in the Krebs cycle act in a catalytic manner in the conversion of eneigy fuels to C02. 

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