O

(carbonyl) group of citrulline, forming argininosucci-nate (step (© in Fig. 18-10). This cytosolic reaction, catalyzed by argininosuccinate synthetase, requires ATP and proceeds through a citrullyl-AMP intermediate (Fig. 18-11b). The argininosuccinate is then cleaved by argininosuccinase (step ©in Fig. 18-10) to form free arginine and fumarate, the latter entering mitochondria to join the pool of citric acid cycle intermediates. This is the only reversible step in the urea cycle. In the last reaction of the urea cycle (step ©)), the cytosolic enzyme arginase cleaves arginine to yield urea and or-nithine. Ornithine is transported into the mitochondrion to initiate another round of the urea cycle.

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argini-nosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites.

The Citric Acid and Urea Cycles Can Be Linked

Because the fumarate produced in the argininosucci-nase reaction is also an intermediate of the citric acid cycle, the cycles are, in principle, interconnected—in a process dubbed the "Krebs bicycle" (Fig. 18-12). However, each cycle can operate independently and communication between them depends on the transport of key intermediates between the mitochondrion and cy-tosol. Several enzymes of the citric acid cycle, including fumarase (fumarate hydratase) and malate dehy-drogenase (p. 612), are also present as isozymes in the cytosol. The fumarate generated in cytosolic arginine synthesis can therefore be converted to malate in the cytosol, and these intermediates can be further metabolized in the cytosol or transported into mitochondria for use in the citric acid cycle. Aspartate formed in mitochondria by transamination between oxaloacetate and glutamate can be transported to the cytosol, where it serves as nitrogen donor in the urea cycle reaction catalyzed by argininosuccinate synthetase. These reactions, making up the aspartate-argininosuccinate shunt, provide metabolic links between the separate pathways by which the amino groups and carbon skeletons of amino acids are processed.

Aspartate-argininosuccinate shunt of citric acid cycle

Fumarate

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