Biosynthesis and Degradation of Nucleotides:- Degradation of Purines and Pyrimidines Produces Uric Acid and Urea, Respectively
Purine nucleotides are degraded by a pathway in which they lose their phosphate through the action of 5-nucleotidase (Fig. 1). Adenylate yields adenosine, which is deaminated to inosine by adenosine deaminase, and inosine is hydrolyzed to hypoxanthine (its purine base) and D-ribose. Hypoxanthine is oxidized successively to xanthine and then uric acid by xanthine oxidase, a flavoenzyme with an atom of molybdenum and four iron-sulfur centers in its prosthetic group. Molecular oxygen is the electron acceptor in this complex reaction.
FIGURE 1 Catabolism of purine nucleotides. Note that primates excrete much more nitrogen as urea via the urea cycle (Chapter 18) thanas uric acid from purine degradation. Similarly, fish excrete much more nitrogen as NH+4 than as urea produced by the pathway shown here.
GMP catabolism also yields uric acid as end prod uct. GMP is first hydrolyzed to guanosine, which is then cleaved to free guanine. Guanine undergoes hydrolytic removal of its amino group to yield xanthine, which is converted to uric acid by xanthine oxidase (Fig. 1). Uric acid is the excreted end product of purine catabolism in primates, birds, and some other animals. A healthy adult human excretes uric acid at a rate of about 0.6 g/24 h; the excreted product arises in part from ingested purines and in part from turnover of the purine nucleotides of nucleic acids. In most mammals and many other vertebrates, uric acid is further degraded to allantoin by the action of urate oxidase. In other or ganisms the pathway is further extended, as shown in Figure 1.
The pathways for degradation of pyrimidines generally lead to NH+4 production and thus to urea syn thesis. Thymine, for example, is degraded to methyl malonyl semialdehyde (Fig. 2), an intermediate of valine catabolism. It is further degraded through propionyl-CoA and methylmalonyl-CoA to succinyl CoA . Genetic aberrations in human purine metabolism have been found, some with serious consequences. For example, adenosine deaminase (ADA) deficiency leads to severe immunodeficiency disease in which T lymphocytes and B lymphocytes do not develop properly. Lack of ADA leads to a 100-fold increase in the cellular concentration of dATP, a strong inhibitor of ribonucleotide reductase . High levels of dATP produce a general deficiency of other dNTPs in T lymphocytes. The basis for B-lymphocyte toxicity is less clear. Individuals with ADA deficiency lack an effective immune system and do not survive unless isolated in a sterile “bubble” environment. ADA deficiency is one of the first targets of human gene therapy trials .
FIGURE 2 Catabolism of a pyrimidine. Shown here is the path way for thymine. The methylmalonylsemialdehyde is further degraded to succinyl-CoA.
