Urea cycle control

The enzyme carbamoyl phosphate synthase (CPS) is a control point in the process. Stage 3. The urea cycle (Figure 6.7)... 

Because of the importance of the urea cycle, the capacity to convert ornithine into arginine is obvious. Complete loss of the ability to produce ornithine (a catalyst or carrier in the urea cycle) would limit the organism s control over production of its nitrogen waste product. 

Mitochondria play a central role in a variety of biological processes, including ATP synthesis, steroid hormone synthesis, the urea cycle, lipid and amino acid metabolism, and cellular Ca2+ homeostasis. Ca2+ is an essential regulator of vital processes, such as secretion, motility, metabolic control, synaptic plasticity, proliferation, gene expression and apoptosis. Therefore, the location, amplitude,... 

Hyperammonemia occurs in biotin deficiency and the functional deficiency associated with lack of holocarboxylase synthetase (Section 11.2.2.1) and bio-tinidase (Section 11.2.3.1). In deficient rats, the activity of ornithine carbamyl-transferase is two - thirds of that in control animals, as a result of decreased gene expression, although the activities of other urea cycle enzymes are unaffected (Maeda etal., 1996). 

Bleeding is a welldmown complication of uraemia that is attributed to the suppression of platelet function by the disease process. Interestingly, L-arginine and some ofoer platelet-inhibitory metabolites of the urea cycle are accumulated in uraemia (Horowitz et al 1970) and this is associated witii an increase in TNF levels (Noris et al 1993). It has been shown that platelets obtained from luaemic patients generate more NO than controls so tiiat increased expression and/or activity of NOS may play a role in platelet dysfunction observed in uraemia (Noris et al 1993). 

To facilitate this process, enzymes of the urea cycle are controlled at the gene level. When dietary proteins increase significantly, enzyme concentrations rise. On return to a balanced diet, enzyme levels decline. Under conditions of starvation, enzyme levels rise as proteins are degraded and amino acid carbon skeletons are used to provide energy, thus increasing the quantity of nitrogen that must be excreted. 

The urea cycle enzymes are controlled in the short term by the concentrations of their substrates. Carbamoyl phosphate synthetase I is also allosterically activated by N-acetylglutamate. This latter molecule is a sensitive indicator of the cell s glutamate concentration. (Recall that a significant amount of NH4 is derived from glutamate.) N-acetylglutamate is produced from glutamate and acetyl-CoA in a reaction catalyzed by N-acetylglutamate synthase. 

The major emphasis in this chapter related to excretion is on ammonia and urea, particularly on the control of the latter as the normal excretion product. There are two major nitrogenous precursors of urea ammonia and aspartate. Before delving into the mechanism and control of urea synthesis, it would be wise to look at the different ways that these precursors can arise and the important tissues concerned with urea synthesis. In people, the predominant synthesis of urea occurs in the liver, with very small amounts of urea formed from arginine in other tissues. The complete synthesis of urea, from amino acids and other nitrogen sources, occurs via a process known as the urea cycle. 

The major control of the urea cycle, other than the availability of nitrogen, is exerted at the first potentially irreversible step of urea synthesis, that is, carbamoyl phosphate synthetase. Carbamoyl phosphate... 

Urea cycle and arginine synthesis. The general aspect and control of the urea synthesis and the role of the intestine and kidney in arginine synthesis are shown above. 

Aspartate is involved in the control point of pyrimidine biosynthesis (Reaction 1 below), in transamination reactions (Reaction 2 below), interconversions with asparagine (reactions 3 and 4), in the metabolic pathway leading to AMP (reaction 5 below), in the urea cycle (reactions 2 and 8 below), IMP de novo biosynthesis, and is a precursor to homoserine, threonine, isoleucine, and methionine (reaction 7 below). It is also involved in the malate aspartate shuttle. 

Two other types of regulation control the urea cycle allosteric activation of CPSI by 7V-acetylglutamate (NAG) and induction/repression of the synthesis of urea cycle enzymes. NAG is formed specifically to activate CPSI it has no other known function in mammals. The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine (Fig. 38.15). Thus, as arginine levels increase within the liver, two important reactions are stimulated. The first is the synthesis of NAG, which will increase the rate at which carbamoyl phosphate is produced. The second is to produce more ornithine (via the arginase reaction), such that the cycle can operate more rapidly. 

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