Urea enzyme deficiency

CH 10 METABOLISM OF AMMONIA AND NUCLEIC ACIDS Table 10.5 Changes in the concentration of various intermediates of the urea cycle or their metabolites in plasma or urine in various enzyme deficiency diseases in humans ... 

In the urea cycle, two molecules of ammonia combine with a molecule of carbon dioxide to produce a molecule of urea and water. The overall cycle involves a series of biochemical reactions dependent on enzymes and carrier molecules. During the urea cycle the amino acid ornithine (C5H12N202) is produced, so the urea cycle is also called the ornithine cycle. A number of urea cycle disorders exist. These are genetic disorders that result in deficiencies in enzymes needed in one of the steps in the urea cycle. When a urea cycle deficiency occurs, ammonia cannot be eliminated from the body and death ensues. 

Christmann R. Valproate-induced coma in a patient with urea cycle enzyme deficiency. Epilepsia 1990 31 228. 

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-... 

Second, modified microorganisms could correct errors of metabolism resulting from either gastric or intestinal enzyme deficiencies (e.g., lipase or lactase) [11] or organ failure (by removing urea in the case of kidney failure or ammonia in the case of liver failure) [12,13]. This could constitute an alternative to current therapy such as renal dialysis, which is time consuming and uncomfortable for the patient. 

The expression hepatic encephalopathy (HE) is a collective term covering five clinical forms of disease (H.O. Conn, 1989) (7.) Reyc s syndrome, (2.) enzyme deficiency of the urea cycle, (i.) pseudoportosystemic encephalopathy, (4.) fulminant liver failure, and (J.) portosystemic encephalopathy. It is not known whether the pathogenic mechanisms of these various clinical forms are identical, (s. tab. 15.3)... 

As a congenital disorder, an enzyme deficiency in the urea cycle relates to carbamoylphosphate synthetase or N-ace-tyl-glutamate synthetase (= hyperammonaemia type I) and ornithine carbamoyltransferase (= hyperammonaemia type II) (D.B. Flannery et al., 1982). (27) (s. p. 594) This condition mainly affects the channelling of ammonium into the mitochondria and the conversion of ornithine into citrulline. (s. fig. 3.12) Similar acquired enzymopathies can be expected in Reye s syndrome and in cases of zinc deficiency. Such a hyperammonaemia syndrome can also produce the clinical picture of HE. 

Todo, S., Starzl, T.E., Tzakis, A., Benkov, K.J., Kalousek, F., Saheki, T., Tanikawa, K., Fenton, W.A. Orthotopic liver transplantation for urea cycle enzyme deficiency. Hepatology 1992 15 419—422... 

However, not all the results in glycogen storage disease can be dismissed as resulting from imperfect laboratory technique. Enzyme deficiencies could occur if the mutation was in an operator gene controlling more than one adjacent gene (Jl), and it is not impossible that such a situation exists in the hereditary metabolic errors of urea formation. 

Valproic add, a common anticonvulsant, can accumulate and induce a hyperammonemic encephalopathy, presenting as acutely impaired consciousness, focal neurologic symptoms, and increased seizure frequency. Moreover, valproate-induced hyperammonemic encephalopathy can occur more readily in the child (or adult) with carnitine deficiency or with congenital urea cycle enzymatic defects. In fact, the occult presence of a urea cycle enzymatic defect is occasionally uncovered by the development of valproate-induced encephalopathy an occult enzyme deficiency can even make its first presentation, in the absence of valproate, in the generically stressed critical care patient, young or old (Verrotti et al., 2002 Thakur et al., 2006 Summar et al., 2005). 

The inherited enzyme deficiencies listed in Table 11.2 lead to the accumulation of substrates and deficiencies of products. For correct interpretation of laboratory results, one need be aware that substrate accumulation can affect the prior enzyme in the pathway (e.g. increased carbamyl phosphate inhibits CPS). A deficiency of urea cycle intermediates (transport or enzyme products or dietary substances) e.g. arginine or ornithine, is often rate limiting. It can initiate a vicious cycle, which worsens the urea synthetic capacity in the cytosol (e.g. by limiting protein synthesis), or in the mitochondria (deficient stimulation of NAGS and of substrate for OTC). Measured plasma values reflect cytosolic metabolite concentrations, not those of mitochondria. Protein catabolism contributes to the plasma amino acid values. Thus, the interpretation of results for plasma arginine, proline and lysine must be done within the context of the pattern found for all of the amino acids. Urea concentrations depend upon the arginine in the cytosol originating from protein catabolism, urea cycle synthesis, and therapeutic applications. 

Sucrase-isomaltase deficiency Urea cycle enzyme deficiencies Phenylketonuria... 

Deficiency of a Urea Cycle Enzyme Results in Excretion of Pyrimidine Precursors... 

Cows and calves fed low-zinc diets of 25 mg Zn/kg ration showed a decrease in plasma zinc from 1.02 mg/L at start to 0.66 mg/L at day 90 cows fed 65 mg Zn/kg diet had a significantly elevated (1.5 mg Zn/L) plasma zinc level and increased blood urea and plasma proteins (Ram-achandra and Prasad 1989). Biomarkers used to identify zinc deficiency in bovines include zinc concentrations in plasma, unsaturated zinc-binding capacity, ratio of copper to zinc in plasma, and zinc concentrations in other blood factors indirect biomarkers include enzyme activities, red cell uptake, and metallothionein content in plasma and liver (Binnerts 1989). 

The toxicity of ammonia was dramatically demonstrated by experiments carried out as early as 1931 injection of the enzyme urease, which catalyses the conversion of urea to ammonia, into rabbits rapidly caused their death. The normal concentration of ammonia in blood is about 0.02 mmol/L toxicity becomes apparent at a concentration of abont 0.2 mmol/L or above (see Table 10.1). Ammonia toxicity in very young children is usually associated with vomiting and eventually coma. It is almost invariably due to the deficiency of an enzyme of the urea cycle (see below). In adults, ammonia accnmulation, and hence toxicity, usually results from damage to the liver caused by poisons, alcohol or viral infection. 

Figure 10.10 The use of benzoate and phenylacetate to lower the concentration of ammonia in patients with a deficiency of a urea cycle enzyme.

Deficiencies ofseverai key enzymes in the pathways for handiing ammonia and synthesizing urea (Figure 9-2) are responsibie for the foiiowing ... 

The answer is B. All the findings are consistent with a diagnosis of hyperammonemia. A clue to its hereditary etiology is provided by the family history suggesting that the patient s sibling may have died of a similar condition. It is likely that the patient is suffering from a deficiency of one of the enzymes of the urea cycle the most common... 

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

FIGURE 18-14 Treatment for deficiencies in urea cycle enzymes. The aromatic acids benzoate and phenylbutyrate, administered in the diet, are metabolized and combine with glycine and glutamine, respectively. The products are excreted in the urine. Subsequent synthesis of glycine and glutamine to replenish the pool of these intermediates removes ammonia from the bloodstream. 

Metabolism of nitrogen in a patient with a deficiency in the urea cycle enzyme carbamoyl phosphate synthetase I. Treatment with phenylbutyrate converts nitrogenous waste to a form that can be excreted. 

Symptoms include tremors, slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision. All inherited deficiencies of urea cycle enzymes cause mental retardation. 

Nickel has long been suspected to be an essential trace element for living organisms, but the identification of its functions in molecular terms is relatively recent. The first nickel protein to be identified was urease (urea ammonia hydrolase) (i). This was demonstrated 49 years after the original isolation and crystallization of the enzyme by Sumner (2). This enzyme is of widespread occurrence, and the specific requirement for nickel explains many of the effects of nickel deficiency in plants (3, 4). 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

The accumulation of any of these amino acids could be due to reduced activity of their respective enzymes in the urea cycle (Sec. 15.5), resulting in decreased overall activity of the cycle. Inborn errors of metabolism are known for deficiencies in these enzymes. Decreased activity of the urea cycle results in elevated levels of ammonia in the blood, a condition known as hyperammonemia that causes nausea, vomiting and even coma. 

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