Deficiency purine metabolism

S.K. Wadman, P.K. de Bree, A.H. van Gennip, J.W. Stoop, B.J.M. Zegers and G.E.J. Staal, Urinary purines in a patient with a severely defective T cell immunity and a purine nucleoside phos-phorylase deficiency, "Purine Metabolism in Man-II regulation of pathways and enzyme defects", M.M. Muller, E. Kaiser and J.E. Seegmiller, Plenum Publishing Corporation, New York (1977) pp 471-477. 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited disorder of purine metabolism and is inherited in an autosomal recessive manner (K18, V7). This enzyme deficiency results in an inability to salvage the purine base adenine, which is oxidized via the 8-hydroxy intermediate by xanthine oxidase to 2,8-di-hydroxyadenine (2,8-DHA). This produces crystalluria and the possible formation of kidney stones due to the excretion of excessive amounts of this insoluble purine. Type I, with virtually undetectable enzyme activity, found predominantly in Caucasians, is found in homozygotes or compound heterozygotes for null alleles. Type II, with significant APRT activity, found only in Japan, is related to a missense mu-... 

H4. Hershfield, M. S., and Mitchell, B. S., Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Metabolic and Molecular Bases of Inherited Disease, 7th ed. (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds.), pp. 1725-1768. McGraw-Hill, New York, 1995. 

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Adenosine deaminase replacesthe C6 amino group with a hydroxyl group, an important step in purine metabolism, A genetic deficiency of the enzyme causes a severe immunodeficiency, called "baby in a bubble syndrome," because the child must live in a sterile environment. 

Adenosine deaminase (ADA EC 3.5.4.4) is the enzyme of the purine metabolism that deaminates adenosine and l deoxyadenosme to inosine and 2 -deoxymosine, respectively. ADA deficiency, which leads to severe combined immunodeficiency disease (SCID), is associated with a decrease in RBC adenosine deaminase activity, without hemolysis. ADA deficiency will not be discussed here. 

Several disorders affect purine metabolism. They are gout and the syndromes associated with deficiency of HPRT, APRT, adenosine deaminase, nucleoside phosphorylase, myoadenylate deaminase, and xanthine oxidase. 

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 (Fig. 22-42). High levels... 

This enzyme is of considerable biological, medicinal and commercial interest. It plays a fundamental role in purine metabolism, it degrades anticancer drugs being targeted to specific cancers and its absence is associated with severe T-cell deficiency. Crystals of the enzyme on a conventional source diffractometer did not diffract beyond 4 A resolution, a resolution which is not adequate to study the structural interactions with various substrates and inhibitors. With intense synchrotron X-radiation at Daresbury, data could be collected to between 3.2 A and 2.8 A resolution the data to 3.2 A (table 10.3) were sufficient to solve the structure. This is another example of time-dependent radiation damage. Very fast data collection methods at the SRS involved collection of 100 reflections per second, where one crystal was used for four minutes of exposure time. The structure has been described in Ealick et al (1990) (figures 10.5 and 2.1). 

E4. Emmerson, B. T., and Wyngaarden, J. B., Purine metabolism in heterozygous carriers of hypoxanthine-guanine phosphoribosyltransferase deficiency. Science 166, 1533-1535 (1969). 

Simmonds, H.A., Sahota, A., Potter, C.F., Cameron, J.S. Purine metabolism and immunodeficiency urinary purine excretion as a diagnostic screening test in adenosine deaminase and purine nucleoside phosphorylase deficiency. Clin. Sci. and Molec. Med. 54 579-584 (1978). 

In 1974 Cartier (3) was the first to describe a complete deficiency of APRT. Since that time 9 children have been described, 4 in London, 3 in Paris, and 2 in Innsbruck (4, 5,6). As a consequence of the complete deficiency of APRT the following abnormalities in purine metabolism can be found (Fig. 1). In the absence of APRT, adenine cannot be reutilized. 2,8-dihydroxyadenine (DOA) ist formed, because adenine now becomes available for oxidation by xanthine oxidase. High levels of adenine and DOA are found in the urine. The clinical consequence of homozygocity for this enzyme defect is presented in two case reports. 

The quantitative importance of the salvage pathway in purine metabolism is difficult to estimate [156]. Comparison between uric acid production in normal children and in children affected with a deficiency in hypoxanthine guanine phosphoribosyl transferase has, however, permitted researchers to approximate how much the salvage pathway contributes to purine metabolism. Thus, whereas in normal children uric acid excretion in the urine (per 24 hours and per kilogram of body weight) is of the order of 10 mg, in children affected with the Lesch-Nyhan syndrome, uric acid excretion is around 47 mg. The difference between enzyme-deficient and normal children is believed to reflect the amount of uric acid normally used in the salvage pathway. 

Lesch-Nyhan disease is an X-linked recessive disorder characterized by hyperuricemia, physical and mental retardation, choreo-athetosis, and compulsive self-mutilation. The disease is associated with absence of activity of an enzyme involved in purine metabolism, namely hypoxanthlne guanine phosphoribosyl transferase (HGPRT), and is believed to affect male only. We present here, however, an unusual case of a girl with the Lesch-Nyhan syndrome, whose mother is not heterozygous for a deficiency of the enzyme. 

K.C.Rich,E.Mejians,I.H.Fox. Purine nucleoside phosphorylase deficiency improved metabolic and immunological function with erythrocyte transfusion. N.Eng.J.Med.303 973 (1980). 

The number of inherited defects of the pyrimidine metabolism described so far is small, compared to that of the purine metabolism. Combined deficiency of orotate phosphoribosyltransferase (OPRT) (EC 2.4.2.10) and orotidine 5 -monophosphate decarboxylase (ODC) (EC 4.1.1.23), designated as type I hereditary orotic aciduria, presents with characteristic clinical features such as hypochromic anemia with a megaloblastic bone marrow and crystalluria. Only six patients have been described and, as far as we know, new cases have not been discovered recently. ODC deficiency with similar clinical phenomena and leading to increased urinary excretion of orotate and orotidine has been detected in only one patient (1). A third defect, a deficiency of pyrimidine 5 -nucleotidase (Py-5NX (EC 3.1.3.5.) in erythrocytes, is associated with chronic hemolytic anemia and prominent basophylic stippling of the erythrocytes due to accumulated pyrimidine nucleotides. An increasing number of patients have been reported, their detection being facilitated by the typical phenomena. We do not know whether the urinary pyrimidine profile in this condition is abnormal. 

Evidence that purine metabolism is important in the immune response has been obtained from the observation that markedly reduced or absent adenosine deaminase (ADA) activity in man has been casually associated with an autosomal recessive form of severe combined immunodeficiency disease (3). Recently, ADA levels in lymphocytes from patients with untreated chronic lymphatic leukemia have been found to be consistently lower than in lymphocytes from normal subjects (4). Children with ADA deficiency and immunodeficiency have been shown to have increased levels in plasma, urine, lymphocytes and erythrocytes of adenosine, adenine, deoxy-adenosine, adenine nucleotides, and deoxyadenine (5, 6). Although the exact biochemical mechanism(s) is unknown, elevated levels of adenosine, and/or deoxyadenosine and their metabolites are thought to be selective inhibitors of both differentiation and effector function of lymphocytes (7, 8). Adenosine was known to inhibit the PHA-induced blastogenesis of human peripheral blood lymphocytes (9) even before the discovery of the first ADA-deficient child. In addition, elevated levels of cyclic AMP (cAMP) were known to be inhibitory for lymphocyte-mediated cytotoxicity (7). Since... 

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