Nucleotides interconversion

The de novo synthesis of inosinic acid The salvage pathways Purine nucleotide interconversions Other enzymes... 

The elucidation of the steps by which cells synthesize inosinic acid de novo for purine nucleotide interconversions is largely due to the brilliant work of Buchanan and his co-workers [65]. The biosynthetic scheme as it is currently envisioned is shown in Figure 2.4. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

P. falciparum Adenylate Kinase (PfAK). PfAK helps the parasite meet the high demand for adenine nucleotide interconversion and energy homeostasis within the infected RBC. One study investigated the ATP concentrations in infected erythrocytes and found that ATP levels are kept constant throughout the host and parasite compartments and that this equalization of ATP concentration is accomplished in part by host and parasite adenylate kinase activities... 

All the required enzymes occur in the cytosol. This is also true for enzymes of salvage pathways, nucleotide interconversion, and degradation. 

Thioguanine has multiple metabolic effects. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis inhibition of purine nucleotide interconversions or incorporation into DNA and RNA. The net conseqnence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 

The role of soluble, cytoplasmic enzymes in saccharide assembly seems chiefly to be in the phosphorylation of sugars and the interconversion of sugar phosphates. The enzymes of sugar nucleotide interconversion are generally membrane-associated and must, in most cases, be firmly membrane-bound. They are, therefore, likely to be integral membrane proteins and must, for the most part, be constituents of the endoplasmic reticulum. 

I. Pathways of Sugar Nucleotide Interconversion Further Reading... 

Swama Latha Y, Yathindra N (1992) Stereochemical studies on nucleic acid analogs. I. Conformations of a-nucleosides and a-nucleotides interconversion of sugar puckers via 04 -exo. Biopolymers 32 249-269... 

Since the two isozymes of adenylosuccinate synthetase differ so markedly, changes in the relative amounts of the two could drastically affect the regulation of the reaction they catalyze, and therefore the direction of purine nucleotide metabolism. Determination of this ratio could be a useful indicator of the relative importance of the biosynthetic and the cyclic aspects of the adenine nucleotide interconversion pathway in different tissues or under different metabolic conditions. 

The dual role of adenylosuccinate synthetase in purine nucleotide interconversions and in de novo AMP biosynthesis complicates studies of its regulation. There is evidence suggesting that in wild-type cells, both the de novo and the salvage pathways play an active role in the maintenance of appropriate ATP/GTP ratios (78). 

Guanylate reductase, which deaminates this nucleotide, catalyzes a reductive, rather than hydrolytic, deamination and has been discussed in Chapter 9. Like adenylate deaminase, it has a catabolic role and also functions in purine nucleotide interconversion. A guanosine deaminase has recently been identified in a pseudomonad (13), but it is not known to occur in animal cells. 

Inosinic acid is an intermediate for the biosynthesis of both adenylic and guanylic acids. These nucleotide interconversions are complex reactions, and their... 

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