Metabolism purine, regulation

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. 

Goordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs. 

This seventh edition includes discussions of neurotransmitters ranging from acetylcholine through other amines, amino acids, purines, peptides, steroids and lipids Whereas in most cases their metabolism and receptor interactions are known, much current research involves questions of identification of effector pathways, their regulation and control. 

For the regulation of metabolic pathways metabolites are often used which are a product of that pathway. The basic strategy for the regulation is exemplified in the mechanisms employed in the biosynthetic and degradation pathways of amino acids, purines, pyrimidines, as well as in glycolysis. In most cases a metabolite (or similar molecule) of the pathway is utilized as the effector for the activation or inhibition of enzymes in that pathway. 

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. 

The purine and pyrimidine bases play an important role in the metabolic processes of cells through their involvement in the regulation of protein synthesis. Thus, several synthetic analogues of these compounds are used to interrupt the cancer cell growth. One such example is an adenine mimic, 6-mercaptopurine, which is a well known anticancer drug. 

Kohl, D.H., Schubert, K.R., Carter, M.B., Hagedorn, C.H. Shearer, G. (1988). Proline metabolism in N2-fixing root nodules energy transfer and regulation of purine synthesis. Proceedings of the National Academy of Sciences (USA) 85, 2036-40. 

Fig. 4 Mechanisms involved in the extracellular inactivation of nucleotides (a, b and c) and adenosine (d) and their influence on purine concentration in the P2Y and PI receptor biophases, (a) NT-PDasel hydrolyses ATP and ADP very efficiently, thus preventing their action on P2Y receptors (b) NTPDase2 metabolizes ATP preferentially, allowing an accumulation of ADP and thus favouring activation of P2Yi, 12,13 receptors (c) NTPDase3 hydrolyses both ATP and ADP slowly, giving them time to activate both P2Y2,4 and P2Y 1,12,13 receptors. Formation of adenosine depends on the activity of ecto 5 -nucleotidase (CD73). Adenosine inactivation systems also influence adenosine concentration in the PI receptor biophase (d) the nucleoside transporters take up adenosine adenosine deaminase (ADA) regulates both the concentration of adenosine in the Ai receptor biophase and the functionality of Ai receptors.

Overproduction of uric acid can occur due to excessive de novo purine synthesis, excessive dietary purines, or the conversion of tissue nucleic acid to purine nucleotides. When these purines are metabolized, the by-products are converted to uric acid by the enzyme xanthine oxidase. Increased levels of uric acid result if the overproduction exceeds excretion. Underexcretion of uric acid can be due to defects in the renal tubular mechanisms that regulate uric acid levels in the body, causing decreased filtration, decreased secretion, or increased reabsorption. 

Feedback regulation of the de novo pathway of purine biosynthesis. Solid lines represent metabolic pathways, and broken lines represent sites of feedback regulation. , Stimulatory effect , inhibitory effect. Regulatory enzymes A, PRPP synthetase B, amidophosphoribosyltransferase C, adenylosuccinate synthetase D, IMP dehydrogenase. 

Compounds active in the regulation of oxypurine metabolism can influence the production of purines de novo and the interconversion or... 

Several enzyme systems regulate purine metabolism. Abnormalities in these regulatory systems can result in overproduction of uric acid. Uric acid also may be overproduced as a consequence of increased breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative disorders. Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination. 

Cydic purine nucleoside monophosphates (cAMP and cGMP) are important second messengers in metabolic regulation (i.e. they carry messages within the cell, triggered by extracellular hormones). 

Nucleotides are the building blocks of the nucleic acids. They also regulate metabolism and transfer energy. The purine and pyrimidine nucleotides are synthesized in both de novo and salvage pathways. 

Of all bacterial GDH s, only the one from Thiobacillus novellus is strongly affected by a purine nucleotide, AMP, but in a fashion which is distinct from that in which animal enzymes are regulated (S3). Since few regulatory features have been established for bacterial enzymes, it is unlikely that GDH constitutes a major point of control of nitrogen metabolism in these organisms. 

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