Purine enzymes

Kerstens, P. J., Stolk, J. N., De Abreu, R. A., Lambooy, L. H., van de Putte, L. B., and Boerbooms, A. A. (1995) Azathiopiine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis and Rheumatism. 38, 142-145. 

There appears to be a spectrum of severity in the immimological defect in ADA deficiency which correlates closely with amounts of residual ADA activity in the lymphocytes. e suggest that erythrocyte dATP levels also provide an accurate guide to the immunodeficiency. It seems that those patients with the most severe forms (such as ours) with a complete deficiency of the enzyme, show the poorest response to therapy, and indeed may not respond at all. Another discrepancy exists between the degree to which we were able to correct the biochemical defects (deoxynucleotide levels decreased to less than 10 of pretreatment values) and the immunological improvement obtained. The precise mechanism by which the immunodeficiency is related to the lack of the purine enzyme remains imexplained. The observation in S.Y. that T cells remained immature despite full biochemical restoration emphasises the complexity of the immimodeficiency. It has been... 

Hadacidin, bredinin and mycophenolic acid, each shown to effect specific purine enzymes in other types of cells acted predictably to disrupt purine nucleotide synthesis by PRBC. The lack of a detectable effect on adenylate synthesis by alanosine may be due to an inability to form the active metabolite, L-alanosyl-AICOR, which requires an active de novo purine pathway (10). 

Table 1. Comparison of purine enzyme values between normals and patients with infectious mononucleosis or patients with myeloid proliferation including 4 patients with acute myeloid leukemia.

Fig. 1. Purine enzyme activities of mononuclear cells from patients with infectious mononucleosis and from controls.

Kerstens PJ, Stolk IN, De Abreu RA, et al. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum 1995 38 142-145. 

This enzyme, sometimes also called the Schardinger enzyme, occurs in milk. It is capable of " oxidising" acetaldehyde to acetic acid, and also the purine bases xanthine and hypoxanthine to uric acid. The former reaction is not a simple direct oxidation and is assumed to take place as follows. The enzyme activates the hydrated form of the aldehyde so that it readily parts w ith two hydrogen atoms in the presence of a suitable hydrogen acceptor such as methylene-blue the latter being reduced to the colourless leuco-compound. The oxidation of certain substrates will not take place in the absence of such a hydrogen acceptor. 

Adenosine. Adenosine [58-61-7] (Ado), (29), a purine nucleoside, is an intracellular constituent acting as both an enzyme cofactor... 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

At the present time, the greatest importance of covalent hydration in biology seems to lie in the direction of understanding the action of enzymes. In this connection, the enzyme known as xanthine oxidase has been extensively investigated.This enzyme catalyzes the oxidation of aldehydes to acids, purines to hydroxypurines, and pteridines to hydroxypteridines. The only structural feature which these three substituents have in common is a secondary alcoholic group present in the covalently hydrated forms. Therefore it was logical to conceive of this group as the point of attack by the enzyme. 

A hypothesis for the oxidation of purines in the presence of this enzyme has been elaborated by Bergmann and his colleagues. It postulates that the purine, often in one of its less prevalent tautomeric forms, is adsorbed on the protein, or the riboflavin coenzyme, of the enzyme then hydration occurs under the influence of the electronic field of the enz5rme, and this must involve a group that is not sterically blocked by the enzyme but which is accessible to the electron-transport pathway of the riboflavin moiety. Finally, the secondary alcohol is assumed to be dehydrogenated in this pathway to give a doubly... 

The nucleic acids DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are biological polymers that act as chemical carriers of an organism s genetic information. Enzyme-catalyzed hydrolysis of nucleic acids yields nucleotides, the monomer units from which RNA and DNA are constructed. Further enzyme-catalyzed hydrolysis of the nucleotides yields nucleosides plus phosphate. Nucleosides, in turn, consist of a purine or pyrimidine base linked to Cl of an aldopentose sugar—ribose in RNA and 2-deoxyribose in DNA. The nucleotides are joined by phosphate links between the 5 phosphate of one nucleotide and the 3 hydroxyl on the sugar of another nucleotide. 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

Methotrexate belongs to the class of antimetabolites. As a derivative of folic acid it inhibits the enzyme dihydrofolate reductase resulting in a decreased production of thymidine and purine bases essential for RNA and DNA synthesis. This interruption of the cellular metabolism and mitosis leads to cell death. 

---