Purines breakdown

Mammals other than primates further oxidize urate by a liver enzyme, urate oxidase. The product, allantoin, is excreted. Humans and other primates, as well as birds, lack urate oxidase and hence excrete uric acid as the final product of purine catabolism. In many animals other than mammals, allantoin is metabolized further to other products that are excreted Allantoic acid (some teleost fish), urea (most fishes, amphibians, some mollusks), and ammonia (some marine invertebrates, crustaceans, etc.). This pathway of further purine breakdown is shown in figure 23.22. 

Extra purines in the diet must be eliminated. In mammals, the product of purine breakdown is a weak acid, uric acid, which is a purine with oxygen at each of three carbons. 

In most studies no significant increase in serum uric acid values have been found (Al, T8, Wl), but in some an increase has been reported (B8, S24). The work of Eisen and Seegmiller (E3) is the only report concerned with the metabolic formation of uric acid using radioactive glycine. They did show an increase in the formation of uric acid in extensive psoriasis and a reduction to normal levels with treatment. In addition, the excretion of pseudouridine and uracil was increased in extensive psoriasis (E2) (Table 13). There was a direct correlation in the above studies between the serum uric acid level versus the extent of skin involvement, the excretion of pseudouridine versus the extent of skin involvement, and also the excretion of pseudouridine versus the uric acid excretion (E = 0.81). These findings imply increased nucleic acid synthesis and increased nucleic acid breakdown in the skin, access of the purine breakdown products to the blood stream and from there to the liver ( ) for transformation into uric acid and finally to the kidney for excretion. 

The existence of inhibitors in various tissues probably explains the discrepancies in the literature regarding the level of DNase in serum. Red blood cells contain a large amount of inhibitor of DNase that is easily released, and it has been postulated that the presence of this inhibitor in serum samples has led to the variations between published analytical results (G18). It is quite natural to speculate on the possible significance of the levels of these nucleic acid-destroying enzymes to the production of purine breakdown products from nucleic acids. 

Phosphodiesterases, phosphatases, 5 -nucleotidases, 3 -nucleotidases and phosphotransferases have been discussed in the section on purine breakdown. Some of these enzymes also act on pyrimidine nucleotides, yielding either the nucleoside or the free base. Cytosine deaminases have been found in yeast and E. coli. Cyti-dine and cytidylic acid deaminases are present in extract of most mammalian tissue. The properties of these enzymes are still poorly understood. 

The present work was undertaken in order to elucidate the mechanism of this direct stimulatory effect of ethanol on the hepatic production of purine catabolites Isolated preparations from rat liver were used, in which, due to the presence of uric-ase, allantoin constitutes the end-product of purine breakdown ... 

Uric acid represents the major catabolite of purine breakdown in humans. Therefore, it remains an important marker molecule for disorders associated with alterations of the plasma urea concentration such as hyperuricemia (gout), renal impairment, leukemia, ketoacidosis, Lesch-Nyhan syndrome and lactate excess. Uric acid may also act as an antioxidant in human body. Consequently its measurement for diagnosis and treatment of some disorders is routinely required. Zhang et developed a reagentless amperometric uric acid biosensor based on carboxyl modified, conductive zinc sulfide (ZnS) Qdots. The biosensor could detect uric acid without the presence of an electron mediator. The fabricated uricase/ZnS Qdot/l-cys biosensor exhibited higher amperometric response compared to the one without Qdots (uricase/l-cys biosensor). They were able to demonstrate a linear dependence on the uric acid concentration ranging from 5.0 x 10 to 2.0 x 10 mol with a detection limit of 2.0 x 10 mol at 3cr. 

Although uric acid is known to be the main nitrogenous excretion product in birds and in reptiles, the route by which it is formed from excess amino compounds is not well understood. Uric acid is also the end product of purine breakdown in man and is excreted as such, while in subprimate mammals, the purine ring is further oxidised to produce first, allantoin and, in some species, eventually urea. The interrelationship between these compounds is illustrated in Figure 42. 

Most Insects only carry uricolysis to the stage of uric acid. The form of the uricolytic system in Insects compared to the most primitive form of the Crustaceans, is characterized by the disappearance of urease, allan-toicase, allantoinase and uricase. The enzyme system for purine breakdown consists of uricase, allantoinase and allantoicase in the Batracians, it consists of only uricase in the Mammals, with the exception of the Primates who have lost the complete system of enzymes as likewise have the terrestrial Reptiles and Birds. 

The purine-containing nucleotides are degraded stepwise to uric acid. Not all of the enzymes concerned with purine breakdown have been studied extensively. Those that have been investigated were found in many tissues of higher animals, in especially high concentrations in cell nuclei... 

The following two experimental approaches are cited because they have helped to clarify some aspects of the pathways of purine breakdown (67, 215). It would seem that additional experimentation along the.se lines is needed. 

Gout is caused by an abnormality in uric acid metabolism. Uric acid is a waste product of the breakdown of purines contained in the DNA of degraded body cells and dietary protein. Uric acid is water soluble and excreted primarily by the kidneys, although some is broken down by colonic bacteria and excreted via the gastrointestinal tract. 

Such enzymes catalyse the condensation of specific compounds, accompanied by the breakdown of a pyrophosphate bond in adenosine triphosphate (10.64). Adenosine is the condensation product of a pentose (D-ribofuranose) and a purine (adenine). Scheme 10.15 shows the action of glutamine synthetase on a mixture of L-glutamic acid (10.65) and... 

Nucleic acids are broken down into their components by nucleases from the pancreas and small intestine (ribonucleases and deoxyribonucleases). Further breakdown yields the nucleobases (purine and pyrimidine derivatives), pentoses (ribose and deoxyribose). 

If photosynthetic and respiratory changes cannot account for the increases in adenylate concentration, which system is responsible It has been reported that ADP and ATP concentrations of Ehrlich ascites tirnior cells increase in the presence of adenine (15), Whether this wo ild hold true for plant cells is not known, but it seems plausible that equilibrium shifts would initiate similar responses. An increase in adenine concentrations could occur if there was any breakdown of nucleic acids. There is one report that the number of ribosomes in the chloroplast does decrease in response to ozone (16). An increase in synthesis of purines is also possible but there is no evidence to either support or refute this hypothesis. 

Adenosine deaminase (ADA) is a ubiquitous enzyme that is essential for the breakdown of the purine base adenosine, from both food intake and the turnover of nucleic acids. ADA hydrolyzes adenosine and deoxyadenosine into inosine and deoxyinosine, respectively, via the removal of an amino group. Deficiency of the ADA enzyme results in the build-up of deoxyadenosine and deoxyATP (adenosine triphosphate), both of which inhibit the normal maturation and survival of lymphocytes. Most importantly, these metabolites affect the ability of T-cells to differentiate into mature T-cells [656430], [666686]. ADA deficiency results in a form of severe combined immunodeficiency (SCID), known as ADA-SCID [467343]. 

The determination of purine and pyrimidines derivatives and their breakdown products can give useful information about the degree of food spoilage or food degradation undertaken in treatments such as storing and heating. 

In addition to the pathways for synthesis de novo, mammalian cells and microorganisms can readily form mononucleotides from purine bases and their nucleosides and to a lesser extent from pyrimidine bases and their nucleosides. In this way bases and nucleosides formed by constant breakdown of mRNA and other nucleic acids can be reconverted (or salvaged ) to useful nucleotides, and the energy expended by the cell in synthesizing the bases is retained. 

Salvage pathway. A family of reactions that permits nucleosides or purine and pyrimidine bases resulting from the partial breakdown of nucleic acids, to be reutilized in nucleic acid synthesis. 

Uric acid, the major nitrogenous waste product of uricotelic organisms, is also formed in other organisms from the breakdown of purine bases. Gout is caused by the deposition of excess uric acid crystals in the joints. 

Uric acid (Fig. 6) is the main nitrogenous waste product of uricotelic organisms (reptiles, birds and insects), but is also formed in ureotelic organisms from the breakdown of the purine bases from DNA and RNA (see Topics FI and Gl). Some individuals have a high serum level of sodium urate (the predominant form of uric acid at neutral pH) which can lead to crystals of this compound being deposited in the joints and kidneys, a condition known as gout, a type of arthritis characterized by extremely painful joints. 

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