Arginase, urea cycle

We begin this overview of manganese biochemistry with a brief account of its role in the detoxification of free radicals, before considering the function of a dinuclear Mn(II) active site in the important eukaryotic urea cycle enzyme arginase. We then pass in review a few microbial Mn-containing enzymes involved in intermediary metabolism, and conclude with the very exciting recent results on the structure and function of the catalytic manganese cluster involved in the photosynthetic oxidation of water. 

Ammonia is highly toxic to animal tissues. In the urea cycle, ornithine combines with ammonia, in the form of carbamoyl phosphate, to form citrulline. A second amino group is transferred to citrulline from aspartate to form arginine—the immediate precursor of urea. Arginase catalyzes hydrolysis of arginine to urea and ornithine thus ornithine is regenerated in each turn of the cycle. 

Arginine is cleaved by arginase to produce ornithine. [Note This reaction occurs primarily in the liver as part of the urea cycle (9ee p. 253).] Ornithine is subsequently converted to a-ketoglutarate. 

The complete urea cycle as it occurs in the mammalian liver requires five enzymes Argininosuccinate synthase, arginase, and argininosuccinate lyase (which function in the cytosol), and ornithine transcarbamoylase, and carbamoyl phosphate synthase (which function in the mitochondria). Additional specific transport proteins are required for the mitochondrial uptake of L-ornithine, NH3, and HC03 and for the release of L-citrulline. 

Arginine and the urea cycle Argininemia and hyperammonemia Mental retardation Arginase... 

Fig. 1. The urea cycle. The enzymes involved in this cycle are (1) carbamoyl phosphate synthetase (2) ornithine transcarbamoylase (3) argininosuccinate synthetase (4) arginosuccinase and (5) arginase.

A number of inherited disorders of urea cycle metabolism are known. Hy per-ammonemia I and II are associated with CPS I and ornithine transcarbamylase deficiencies, respectively. Citrullinemia, arginosuccinic aciduria, and argininemia are associated with low levels of arginosuccinic acid synthetase, arginosuccinase, and arginase, respectively. All such disorders are associated with mental retardation, convulsions, and failure to thrive if not treated. Treatment involves the feeding of low-protein diets or, experimentally, the administration of a-keto analogs of essential amino acids instead of protein. 

The clinical syndrome of acute neonatal hyper-ammonemic encephalopathy described in the case report represents the classical presentation of a patient with a urea cycle disorder (UCD). It is important to note that this neonatal course represents only the most common and severe presentation of a UCD. This holds true for all the diseases listed in Table 18-1, with the exceptions of arginase (ARG-1) deficiency, which results in progressive spasticity of the lower limbs, and of the mitochondrial membrane transporters citrin and ornithine transporter 1 (ORNT-1). Deficiency of citrin results in adult-onset encephalopathy deficiency of... 

The final step of the urea cycle is the cleavage of arginine to release urea and regenerate ornithine. Ornithine then reenters the mitochondria via the ORNT-1 ornithine-citrulline antiporter. ARG-1 is a cytosolic homotrimeric enzyme of 35-kd monomers that is expressed in fiver and red blood cells. A second mitochondrial arginase (ARG-2) most likely plays a role in nitric oxide synthesis and is most abundant in brain, kidney, and prostate. ARG-1 deficiency is unique among the urea cycle deficiencies as patients do not present with hyperammonemia and encephalopathy but rather develop progressive spasticity of the lower limbs. Biochem-... 

Arginase. the last (fourth) enzyme in the urea cycle, catalyzes the hydrolytic cleavage of arginine to urea and ornithine. 

Figure 6.10 The urea cycle. The enzymes of the urea cycle include, 1 carbamoyl phosphate synthetase-I, 2 ornithine transcarbamoylase, 3 argininosuccinate synthetase, 4 argininosuc-cinase, 5 arginase.

The enzymes that catalyze these steps are homologous to argininosuccinate synthetase and argininosuccinase, respectively. Thus, four of the five enzymes in the urea cycle were adapted from enzymes taking part in nucleotide biosynthesis. The remaining enzyme, arginase, appears to be an ancient enzyme found in all domains of life. 

The clinical symptomatology, which is almost the same in all enzymatic disturbances of the urea cycle, is caused by hyperammonaemia. An arginase defect results in enhanced excretion of lysine, ornithine and cystine. Neurological symptoms such as hyperreactivity and athetosis followed by paresis and tetraplegia predominate. 

Arginine (arg) is hydrolyzed to ornithine by arginase from the urea cycle. 

Figure 24-2 The urea cycle pathway. CPS I, Carbamyl phosphate synthetase I N-acetyigiutamate as positive allosteric effector OTC, ornithine transcarbamyiase MS, argininosuccinate synthetase Ai, argininosuccinate iyase AR, arginase ADP, adenosine diphosphate, ATf adenosine triphosphate, P, inorganic phosphate.

In mammals, hepatic arginase is the terminal enzyme of the urea cycle, which represents the major end-product of nitrogen metabolism — the average adult human excretes some 10 kg of urea per year. The enzyme is not restricted to the liver, since ornithine is a precursor of the nonessential amino acid proUne, and a biosynthetic precursor of polyamines, required for rapidly dividing tissues. Arginine is also the precursor of the important messenger in many vertebrate signal-transduction pathways nitric oxide, NO (Scheme 16.1), of which more shortly. 

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