Glutamine degradation

Figure 3 Specific functions of glutamine and glutamine degradation products.

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

Joshi AB, Sawai M, Kearney WR, et al. Studies on the mechanism of aspartic acid cleavage and glutamine deamidation in the acidic degradation of glucagon. /. Pharm. Sci. 2005 94 1912-1927. 

Asparagine residues (and glutamine residues, see below) are sites of particular instability in peptides. As will be exemplified below, rates of degradation at asparagine residues are markedly faster (tenfold and even much more) than at aspartic acid residues. As reported, the tm values for the internal asparagine in a large number of pentapeptides ranged from 6 to 507 d under... 

The simplest degradation displayed by asparagine and glutamine is direct hydrolytic deamidation of the side-chain carboxamido group (Fig. 6.29, Pathway d). Such a reaction, however, is seen only at low pH values, and its biological significance appears negligible. Its product is the Asp peptide (6.62) whose further reactions have been presented in Fig. 6.27. 

The most important degradation mechanism of asparagine and glutamine residues is formation of an intermediate succinimidyl peptide (6.63) without direct backbone cleavage (Fig. 6.29, Pathway e). The reaction, which occurs only in neutral and alkaline media, begins with a nucleophilic attack of the C-neighboring N-atom at the carbonyl C-atom of the Asn side chain (slow step). The succinimide ring epimerizes easily and opens by hydrolysis (fast step), as shown in Fig. 6.27, to yield the iso-aspartyl peptide (6.64) and the aspartyl peptide (6.65) in a ratio of 3 1. 

As in the case of degradation at aspartic acid residues, the major structural factors that influence the reactivity of asparagine and glutamine residues... 

To illustrate some of the above points, the degradation of a few selected bioactive peptides containing asparagine and glutamine residues will be described. 

Hormones can modify the concentration of precursors, particularly the lipolytic hormones (growth hormone, glucagon, adrenaline) and cortisol. The lipolytic hormones stimulate lipolysis in adipose tissue so that they increase glycerol release and the glycerol is then available for gluconeogenesis. Cortisol increases protein degradation in muscle, which increases the release of amino acids (especially glutamine and alanine) from muscle (Chapter 18). 

Figure 8.12 Degradation of arginine, histidine, proline and glutamine. These amino acids are all converted to glutamate which can then be degraded to produce oxoglutarate and ammonia. For details, see Appendix 8.3.

The long tail of myosin contains a high proportion of the amino acids leucine, isoleucine, aspartate and glutamate. These are released upon the degradation of myosin by intracellular proteases and peptidases and they provide nitrogen for the synthesis of glutamine. It is then stored in muscle and is a very important fuel for immune cells (Chapter 17). 

Branched-chain amino acids are leucine, isoleucine and valine the increased concentrations are also consistent with an increased rate of degradation, as muscle protein contains a high proportion of these amino acids. The extent of the decrease in ATP concentration is even greater than in exaustive physical activity. Note the very large fall is glutamine concentration. 

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