Mitochondria urea cycle reactions

The carbamoyl phosphate, which functions as an activated carbamoyl group donor, now enters the urea cycle. The cycle has four enzymatic steps. First, carbamoyl phosphate donates its carbamoyl group to ornithine to form citrulline, with the release of Pj (Fig. 18-10, step ). Ornithine plays a role resembling that of oxaloacetate in the citric acid cycle, accepting material at each turn of the cycle. The reaction is catalyzed by ornithine transcarbamoylase, and the citrulline passes from the mitochondrion to the cytosol. 

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 argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

The other part of the urea cycle that has occurred is the conversion of the carbons of aspartate to fumarate. The fumarate is recycled back to oxaloacetate through TCA cycle reactions in the mitochondrion. Transamination with glutamate regenerates aspartate. The glutamate comes from the glutamate dehydrogenase reaction. 

The urea cycle converts ammonium ions into urea, which is less toxic. The sources of the atoms are shown in color and the intracellular locations of the reactions are indicated. Citrulline, formed in the reaction between ornithine and carbamoyl phosphate, is transported out of the mitochondrion and into the cytoplasm. Ornithine, a substrate for the formation of citrulline, is transported from the cytoplasm into the mitochondrion. 

Reactions of the urea cycle occur in both the mitochondria and cytosol of liver cells. Glutamate dehydrogenase, the citric acid cycle enzymes, carbamoyl phosphate synthetase I, and ornithine transcarbamoylase are localized in the mitochondrion, whereas the rest of the cycle occurs in the cytosol. This means that ornithine must be transported into mitochondria, and citrulline must be exported to the cytosol, in order for the cycle to proceed. 

Urea is synthesized in the liver by a series of reactions known collectively as the urea cycle (Fig. 14.37). One nitrogen is derived from ammoniiun, the second from aspartate the carbon is derived from COj. The synthesis of urea requires the formation of carbamoyl phosphate and the four enzymic reactions of the urea cycle. These take place partly in the mitochondrion and partly in the cytoplasm. The enzymes involved in the synthesis of urea are discussed next. 

Figure 16.S illustrates the reactions and the com-partmentalization of the enzymes of the urea cycle. The first reaction in urea biosynthesis is the mitochondrial formation of carbamoyl phosphate, the substrate of the urea cycle. The reaction utilizes an ammonium (NH4 ) ion, delivered into the mitochondrion as glutamate by the action of both the glutamate-aspartate (Section 11.3) and the glutamate-hydroxyl ion antiport carriers. Oxidative deamination of glutamate by glutamate dehydrogenase releases an NH4 ion.

Finally, arginine is hydrolyzed to generate urea and ornithine in a reaction catalyzed by arginase. Ornithine is then transported back into the mitochondrion to begin another cycle. The urea is excreted. Indeed, human beings excrete about 10 kg (22 pounds) of urea per year. 

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