Ornithine transcarbamoylase

L-Ornithine transcarbamoylase catalyzes transfer of the carbamoyl group of carbamoyl phosphate to ornithine, forming citrulline and orthophosphate (reaction 2, Figure 29-9). While the reaction occurs in the mitochondrial matrix, both the formation of ornithine and the subsequent metabolism of citmlline take place in the cytosol. Entry of ornithine into mitochondria... 

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Tuchman M et al The biochemical and molecular spectrum of ornithine transcarbamoylase deficiency. J Inherit Metab Dis 1998 21 40. 

Carbamoyl phosphate synthetase and ornithine transcarbamoylase are mitochondrial enzymes. 

The two conditions can be distinguished by an increase in orotic add and uracil, which occurs in ornithine transcarbamoylase deficiency, but not in the defldency of carbamoyl phosphate synthetase. Orotic acid and uracil are intermediates in pyrimidine synthrais (see Chapter 18). This pathway is stimulated by the accumulation of carbamoyl phosphate, the substrate for ornithine transcarbamoylase in the urea cycle and for aspartate transcarbamoylase in pyrimidine synthesis. 

Answer E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase. 

Condition Carbamoyl- phosphate synthetase Ornithine transcarbamoylase Argininosuccinate synthetase Argininosuccinate lyase Arginase... 

An increase in concentration of carbamoyl phosphate and/or an increase in the concentration of ornithine stimulates ornithine transcarbamoylase and increases flux through the cycle. 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

ORNITHINE TRANSCARBAMOYLASE NITRIC OXIDE SYNTHASE Citrulline phosphorylase,... 

ORNITHINE TRANSCARBAMOYLASE GLAISEN GONDENSATION Glass (A) metal ion,... 

ORNITHINE TRANSCARBAMOYLASE d-ORNITHINE 4,5-AMINOMUTASE ORNITHINE AMINOTRANSFERASE ORNITHINE DECARBOXYLASE Ornithine carbamoyltransferase,... 

ORNITHINE TRANSCARBAMOYLASE Ornithine ketoacid aminotransferase, ORNITHINE AMINOTRANSFERASE Ornithine oxo-acid aminotransferase, ORNITHINE AMINOTRANSFERASE ORNITHINE TRANSCARBAMOYLASE Orotate,... 

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. 

Supplementing the diet with arginine is useful in treating deficiencies of ornithine transcarbamoylase, argini-nosuccinate synthetase, and argininosuccinase. Many... 

It is not easy to mimic the shuffling of domains in vitro by manipulation of genes. For example, each catalytic polypeptide chain of the multimeric E. coli aspartate transcarbamoylase (ATCase) is composed of two globular domains connected by two interdomain helixes. The E. coli enzyme ornithine transcarbamoylase (OTCase) is 32% identical in sequence and thus of presumably similar structure (see section D8). None of the chimeras in which a domain from one enzyme was attached to the corresponding partner in the other is active. The specific intrachain and interchain side-chain interactions also have to evolve for the Correcting packing.32... 

Arginine Proline Proline oxidase Ornithine-glutamate transaminase Ornithine transcarbamoylase Argininosuccinate synthase Argininosuccinate lyase... 

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. 

The second reaction also occurs in the mitochondria and involves the transfer of the carbamoyl group from carbamoyl phosphate to ornithine by ornithine transcarbamoylase. This reaction forms another nonstandard amino acid citrulline which then has to be transported out of the mitochondrion into the cytosol where the remaining reactions of the cycle take place. 

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.

The entry of activated ammonia into the urea cycle occurs by the ornithine transcarbamoylase reaction where the carbamoyl group is transferred to the side chain amino group of the non-protein amino acid, ornithine. Ornithine has five carbons its carbon chain therefore has the same length as that of arginine. The product of the ornithine transcarbamoylase reaction is the amino acid citrulline. 

Ornithine transcarbamoylase OTC deficiency OTC Xp21.1 Liver Citrulline i Orotic acid TT... 

OSM, oncostatin M OTCase, ornithine transcarbamoylase Ox. phos., oxidative phosphorylation OX-R, oxytocin receptor... 

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.

B-9) Ornithine transcarbamoylase deficiency, another cause of hyperammonemia the most common of the urea cycle metabolic disorders. It is X-Iinked. 

The carbamoyl group of carbamoyl phosphate, which has a high transfer potential because of its anhydride bond, is transferred to ornithine to form citrulline, in a reaction catalyzed by ornithine transcarbamoylase. 

What about the other enzymes in the urea cycle Ornithine transcarbamoylase is homologous to aspartate transcarbamoylase and the structures of their catalytic subunits are quite similar (Figure 23.18). Thus, two consecutive steps in the pyrimidine biosynthetic pathway were adapted for urea synthesis. The next step in the urea cycle is the addition of aspartate to citrulline to form argininosuccinate, and the subsequent step is the removal of fumarate. These two steps together accomplish the net addition of an amino group to citrulline to form arginine. Remarkably, these steps are analogous to two consecutive steps in the purine biosynthetic pathway (Section 25.2 3). 

Figure 23.18. Homologous Enzymes. The structure of the catalytic subunit of ornithine transcarbamoylase (blue) is quite similar to that of the catalytic subunit of aspartate transcarbamoylase (red), indicating that these two enzymes are homologs. 

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