Urea cycle inhibition

Enzyme inhibition can be reversed by supplementation of arginine or citrulline.34 106 Pathovars of P. syringae were shown to inhibit Escherichia coli growth, an effect reversed by L-arginine, but not by L-citrulline or L-glutamine.121 This suggested that the site of action of the toxin produced is involved in the conversion of citrulline to arginine in the urea cycle. 

Inhibitor design. Compound A has been synthesized as a potential inhibitor of a urea-cycle enzyme. Which enzyme do you think compound A might inhibit ... 

With hepatic encephalopathy, there is often an increase in short-chain fatty acids such as propionate, butyrate, valerate and octa-noate in the serum and CSF. They are formed as a result of incomplete p-oxidation of long-chain fatty acids in the intestine. They are not - or only inadequately — metabolized in the damaged liver. The neuro toxic effect is based upon inhibition of various enzymes (including enzymes of the urea cycle) and competitive... 

Branched-chain amino acids apparently stimulate the urea cycle. Carbamoylphosphate synthetase, which channels ammonia into the urea cycle, is induced by ornithine and N-acetylglutamate as a cofactor of urea synthesis. Here, BCAA follow two modes of action (i.) they stimulate the synthesis of N-acetylglutamate via synthetase formed from glutamate and acetyl CoA, and (2.) they inhibit omithine-keto acid transferase, which is the enzyme responsible for ornithine degradation, leading to an increase in ornithine concentration. Ammonia detoxication is thus stimuiated by two regu-iatory mechanisms, (s. fig. 40.2)... 

Cynarine is the main active agent of artichoke extract. It is a cinnamic acid derivative the substitution pattern of its aromatic rings is similar to that of dopamine. Caffeic acid is also regarded as a major active substance. It has not yet been clarified to which constituents the known modes of action are attributable .) increase in choleresis, (2.) inhibition of cholesterol biosynthesis, (3.) hepatoprotection due to antioxidative effects, and (4.) activation of the urea cycle. 

In the first reaction, glutamine reacts with C02 and 2 ATP to form carbamoyl phosphate. This reaction is analogous to the first reaction of the urea cycle. However, for pyrimidine synthesis, glutamine provides the nitrogen and the reaction occurs in the cytosol, where it is catalyzed by carbamoyl phosphate synthetase II, which is inhibited by UTP. 

Since one of the most important, if not the most important, result of a defect of the biosynthesis of urea is an increased level of blood ammonia, it is essential to consider other conditions that might affect indirectly the urea cycle or in some other way raise the blood ammonia. For example, it has been suggested that since lysine can act as a competitive inhibitor of the conversion of arginine to ornithine and urea, an increased level of plasma lysine may therefore inhibit the urea cycle (B12). 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Valproate may contribute to hyperammonemia by inhibiting carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Phenobarbital may potentiate the toxic effect of valproate. The electroencephalogram in severe hyperammonemic encephalopathy exhibits continuous generalized slowing, a predominance of theta and delta waves, bursts of frontal intermittent rhythmic delta activity, and triphasic waves (Segura-Bruna et al., 2006). 

Other, more specific, transporter dysfunctions lead to distinct inborn errors of metabolism. Oxaluria and cystinuria, defects in oxalate and cysteine transport, respectively, manifest with renal stones. Cystinuria specifically presents with cysteine, ornithine, lysine, and arginine in the urine. The latter should not be confused with cystinosis. Lysinuric protein intolerance (LPI) is a defect in the dibasic amino acid transporter. This results in a specific amino aciduria pattern (ornithine, lysine, and arginine), which in turn results in secondary inhibition of the urea cycle. Individuals affected by LPI are at risk for hyperammonemia and also have a unique susceptibility to macrophage activation syndrome, an exaggerated systemic inflammatory response, and alveolar proteinosis. Renal damage... 

Propionyl-CoA Inhibits the urea cycle, citric acid cycle ai othe ... 

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. 

In one patient there was a possible synergistic interaction of valproic acid and topir-amate with respect to the emergence of hyperammonemic encephalopathy [316 ]. The authors speculated that inhibition of carbonic anhydrase by topiramate might be the basis of this, since HCO is used in the sjmthesis of carbamoylphosphate in the urea cycle. 

Vinblastine suppresses cell growth during metaphase, affects amino acid metabolism, in particular at the level of including glutamine acid into the citric acid cycle and preventing it from transformation into urea, and it also inhibits protein and nucleic acid synthesis. 

---