Purine nucleoside metabolism

The abnormal T- and B-cell functions in patients with SCID are the result of ADA dehciency. The ADA gene has been mapped to chromosome 20q.l3, and a number of point and deletion mutations have been identihed in SCID patients [5-7]. ADA catalyses the irreversible deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyi-nosine as a part of purine nucleoside metabolism. Adenosine and deoxyadeno-sine are suicide inachvators of S-adenosyl-homocysteine (SAH) hydrolase, and lead indirectly to intracellular accumulation of SAH, which is a potent inhibitor of methy-lation reactions. Cellular methylation function is essential for detoxihcation of adenosine and deoxyadenosine. As a result ADA dehciency leads to accumulation to... 

Purine nucleoside phosphorylase (PNP), which catalyzes the reversible phosphorolysis of ribonucleosides to ribose 1 -phosphate and the free base (Scheme 7), plays an important role in purine nucleoside metabolism and in T-ceU development (59, 60). PNP inhibitors have therapeutic utility for selective destruction of T cells in T-ceU leukemias and T-cell lymphomas as well as in the treatment of T-cell-mediated autoimmune diseases and for the suppression of the post-organ transplant T-ceU response (61). 

Jenuth, J.P. Mably, E.R. Snyder, F.F. Modeling of purine nucleoside metabolism during mouse embryonic development. Relative routes of adenosine, deoxyadenosine, and deoxyguanosine metabolism. Biochem. Cell Biol., 74, 219-225 (1996)... 

In addition to metabolizing some aldehydes, aldehyde oxidase also oxidizes a variety of azaheterocycles but not thia- or oxaheterocycles. Of the various purine nucleosides metabolized by aldehyde oxidase, the 2-hydroxy- and 2-amino derivatives are more efficiently metabolized, and for the N -substituents, the typical order of preference is the acyclic nucleosides is as follows 9-[(hydroxy-alkyloxy)methyl]-purines) > 2 -deoxyribofuranosyl > ribofuranosyl > arabinofuranosyl > H. The kinetic rate constants for purine analogues revealed that the pyrimidine portion of the purine ring system is more important for substrate affinity than the imidazole portion. Aldehyde oxidase is inhibited by potassium cyanide and menadione (synthetic vitamin K). 

PURINE NUCLEOSIDE METABOLISM IN ESCHERICHIA COLI Bjarne Jochimsen... 

This manuscript will mainly deal with purine nucleoside metabolism, and I would like to stress that the organism studied is the enteric bacterium Escherichia coll, with its natural habitat the human rectum. 

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. 

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. 

In addition to the enzymes that catalyse the formation of nucleotides and polynucleotides, a large number of catabolic systems exist which operate at all levels of the internucleotide pathways. The ribonucleases and deoxyribonucleases that degrade polynucleotides are probably not significantly involved in purine analogue metabolism, but the enzymes which dephosphorylate nucleoside 5 -monophosphates are known to attack analogue nucleotides and may be of some importance to their in vivo activity. Phosphatases of low specificity are abundant in many tissues [38], particularly the intestine [29]. Purified mammalian 5-nucleotidases hydrolyse only the nucleoside 5 monophosphates [28] and... 

Most biologically active purines or purine nucleosides must be anabolized to 5 -nucleotides to exert their effects. "The 5 -nucleotides are in some cases further phosphorylated to the di- and triphosphates and the number of potential sites of action of these compounds is obviously greater than the number of potential sites of action of compounds metabolized only to the monophosphate level. But even... 

A number of currently prescribed NRTIs are shown in Figure A.44. Compounds A.155 through A.158 are all analogues of pyrimidine nucleosides. Compounds A.159 and A.160 are both purine nucleoside analogues. Abacavir (Ziagen, A.160) is inactive until it is metabolized to carbovir (A.161) in vivo. The seven drugs in Figure A.44 were approved in the United States over a span of more than 25 years. Zidovudine reached the market first in 1987, and emtricitabine was the last to be approved in 2003. The steady release... 

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). 

Tenofovir is not metabolized to a significant extent by CYPs and is not known to inhibit or induce these enzymes. However, tenofovir has been associated with a few potentially important pharmacokinetic drug interactions. A 300-mg dose of tenofovir increased the didanosine AUC by 44 to 60% probably as a consequence of inhibition of the enzyme purine nucleoside phosphorylase by both tenofovir and tenofovir monophosphate. These two drugs probably should not be used together, or if this is essential, the dose of didanosine should be reduced from 400 to 250 mg/day. 

Konigk, E. (1978) Purine nucleotide metabolism in promastigotes of Leishmania tropica inhibitory effect on allopurinol and analogues of purine nucleosides. Tropenmed. Parasitol. 29 435-438. 

This drug is metabolized to 6-thioinosinic acid, which inhibits the purine nucleoside pathway. 

---