Nitrogenous bases present in the DNA can be grouped into two categories: purines (Adenine (A) and Guanine (G)), and pyrimidine (Cytosine (C) and Thymine (T)).

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From: Concepts and Techniques in Genomics and Proteomics, 2011

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Antonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017

Nucleotides

Nucleotides include: (1) a nitrogenous base, (2) a five-carbon monosaccharide (aldopentose), and (3) phosphoric acid.


Nitrogenous bases. Nucleotide hydrolysis produces two types of substances derived from the heterocyclic rings purine and pyrimidine known as the purine and pyrimidine bases. Fig. 6.1 shows their chemical structure and the numbering of the elements in the molecule. Purines are derived from pyrimidines by addition of an imidazole group. Both purines and pyrimidines have all their atoms on the same plane.



Figure 6.1. Numbering of pyrimidine elements is different to that of purine.

Only carbons 2 and 5 have the same number in both cycles.


Nucleic acids contain five different nucleotide bases. Three are pyrimidines and two purines. The pyrimidine bases are thymine (5-methyl-2,4-dioxipyrimidine), cytosine (2-oxo-4-aminopyrimidine), and uracil (2,4-dioxoypyrimidine) (Fig. 6.2).




Pyrimidine and guanine bases in Figs. 6.2 and 6.3 correspond to the ketone or lactam forms of these nucleotides, which predominate in natural products. There are isomers (tautomers) that produce the enol or lactim form of these nucleotides, which exist in much lower proportion. These isomers are produced by displacement of the hydrogen atom bound to the neighboring nitrogen toward the oxygen. Eventually, nucleic acids may contain a small amount of other bases that derive from the main ones, such as 5-methyl-cytosine.

Due to their aromatic nature, purine and pyrimidine bases absorb radiation in the ultraviolet (UV) region of the spectrum, with a maximum at a wavelength of 260 nm. This property allows to identify nucleic acids in a sample and to estimate their concentration by spectrophotometry.


Aldopentoses. The monosaccharide that forms nucleic acids can be d-ribose or d-2-deoxyribose. According to the pentose present, two kinds of nucleic acids can be distinguished: ribonucleic acids (RNAs) and deoxyribonucleic acids (DNAs). The aldopentoses in nucleic acids adopt the furanose form (Fig. 6.4) (carbons of the pentose are distinguished from those of the base by adding a quotation mark, 1′, 2′, etc.).



Figure 6.4. Aldoses present in nucleic acids.


Both ribose or deoxyribose, through their carbon 1′ are linked to nitrogen 9 of the purine or nitrogen 1 of the pyrimidine bases by a β-glycosidic bond, which allows their free rotation. The compound formed by a nitrogenous base, purine or pyrimidine and aldopentose is called nucleoside. The relative spatial arrangement of the nitrogenous base and the monosaccharide varies between the two main configurations shown in Fig. 6.5. These correspond to the syn and anti forms. The latter is thermodynamically more favorable (Fig. 6.6).



Figure 6.5. Adenosine (nucleoside).

(A) syn form; (B) anti form.


Figure 6.6. Thymidine (nucleoside).


A nucleotide is formed by esterification with phosphoric acid of the hydroxyl group in carbon 5′ of the ribose or deoxyribose that forms part of the nucleoside (Fig. 6.7).


Figure 6.7. Guanylic acid or guanosine monophosphate (nucleotide, anti form).


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Purine and Pyrimidine Metabolism


Antonio Blanco, Gustavo Blanco, in Medical Biochemistry, 2017

Summary


Humans produce nitrogenous bases endogenously and are not dependent on dietary intake of purines and pyrimidines.

Purine biosynthesis involves the formation of the purine ring from residues of different origins. C4, C5, and N7 are derived from glycine; N3 and N9 are derived from the amide group of glutamine; N1 is derived from aspartate; C2 and C8 come from formyl residues donated by formyl tetrahydrofolate; C6 is derived from CO2. The molecular assembly is performed with ribose-5-P bound to it. First, PRPP is formed through a reaction catalyzed by phosphoribosylpyrophosphate synthetase, an enzyme inhibited by the end products, AMP, GMP, IMP. Finally a nucleotide is obtained.

Salvage pathway for purine synthesis requires the activity of APRT and hypoxanthine-guanine phosphoribosyl transferase.

Purine catabolism starts with the degradation of nucleic acids into nucleosides and nucleotides. Adenosine is deaminated (catalyzed by adenosine deaminase). Inosine formed is cleaved by phosphorylation (catalyzed by nucleoside phosphorylase) to produce hypoxanthine and ribose-P.

Then, hypoxanthine is oxidized to xanthine (catalyzed by xanthine oxidase). Guanosine is hydrolyzed to guanine and ribose. Guanine is deaminated to xanthine (catalyzed by guanase). Xanthine, formed from both adenine and guanine, is oxidized into uric acid (catalyzed by xanthine oxidase).

Uric acid is the end product of purine catabolism in humans. It is poorly soluble and is mainly excreted in the urine.

The concentration of uric acid in normal plasma is 4–6 mg/dL. In some pathological conditions this value increases.

Gout is a disease characterized by elevated levels of urate in the blood and urine. Urate precipitates causing arthritis and kidney stones.

Pyrimidine biosynthesis requires the binding of aspartate and carbamoyl phosphate. Carbamoyl phosphate is synthesized from the amide group of glutamine and CO2 (catalyzed by CPS 2). The reaction of carbamoyl-phosphate and aspartate forms carbamoylaspartate (catalyzed by aspartate transcarbamoylase), which is cyclized forming orotic acid. Aspartate transcarbamoylase is the main regulatory site of the pathway, it is inhibited by the end products (UTP, CTP).

Pyrimidine catabolism renders soluble compounds, which can be easily removed or used.

Degradation of cytosine produces β-alanine, CO2, and NH3. Thymine produces β-aminoisobutyrate, CO2, and NH3. β-Aminoisobutyrate is converted into succinyl-CoA.

Biosynthesis of nucleoside di-and triphosphate are obtained from nucleoside monophosphate by phosphoryl transfer from other nucleoside triphosphates (catalyzed by nucleoside kinase).

Deoxyribonucleotide biosynthesis is obtained by reduction of ribose already bound to the nucleotide by ribonucleotide reductase. NADPH and thioredoxin are required.


Many simple nitrogenous bases have been found to release histamine, and the simplest of all, ammonia, was found to be very potent (Garan, 1938; Schild, 1949). Alkaloids, such as atropine, strychnine and curare (or D-tubocurarine), were found to release histamine from various structures (Burstein and Parrot, 1949; Alam et al., 1939; Schild and Gregory, 1947). The release of histamine from the perfused dog's gastrocnemius by curare was demonstrated by Alam et al. (1939) and confirmed by 'Schild and Gregory (1947). Perfusion of the rat's hindlimbs through a cannula tied in the abdominal aorta showed release of histamine when D-tubocurarine was injected into the cannula (Rocha e Silva and Schild, 1949). In this type of experiment, repeated injections of curare caused a repeated liberation of histamine and very large quantities may be released in total. In each case a high molar ratio of curarine/histamine varying from 20 to 51 could be observed and amounts varying from 5 to 35.6μg could be released by 2-6 mg of D-tubocurarine. In order to have more accurate data on the quantities of histamine that are released by D-tubocurarine, Rocha e Silva and Schild (1949) developed the simple technique of using a piece of rat's diaphragm to study the histamine-releasing capacity of D-tubocurarine. The two lateral portions of the diaphragm were used as control pairs. After careful washing of the diaphragm, each half, weighing approximately 150 to 300 mg, was attached to platinum hooks fused into the tip of capillary glass tubes, transferred to warm oxygenated Tyrode solution and thence into the experimental solution containing d-tubocurarine. After a measured time the muscle was removed from the solution and transferred to a fresh solution of d-tubocurarine. The histamine appearing in the solution was assayed upon the isolated guinea pig gut. Figure 31 summarizes 106 individual measurements of histamine release by curarine.


A number of substituted amines, containing the guanidine group or related radicals, were tested by MacIntosh and Paton (1949) for histamine-liberating capacity. Among the bases studied were diamines, diamidines, diguanidines, diisothioureas, diquaternaries and some benzamidine derivatives. Many of them produced a sudden fall of arterial pressure after a latency of 20–25 seconds, when given intravenously to cats and dogs. Many of such compounds—diamino-octane, diamidinodecane, diguanidinopentane, diisothioureas—produced wheals when injected in the human skin. The supposition that such compounds act by liberating histamine was confirmed for at least two of them, propamidine and 1,8-diamino-octane, by estimating and identifying histamine in the blood of cats and dogs given these simple compounds in a dose range of 5–15 mg/kg of body weight. Similar results were also obtained with the antibiotic polypeptide, licheniformin, extracted from Bacillus licheniformis by Callow et al. (1947). Injection of diamino-octane dihydrochloride (15 mg/kg) in the vein of a dog was followed by a sharp rise of blood histamine (up to 3μg/ml of plasma) and incoagulability of the blood which remained fluid for more than 24 hours. Addition of toluidine blue brought the clotting time back to normal indicating that heparin was the agent responsible for this increase in clotting time. The similarity between the effects of these simple bases and those produced by injected peptone suggests that they act by a common mechanism. This belief is further strengthened by the fact that a basic polypeptide like licheniformin is able to produce similar effects. The suggestion that peptone or the antigen in anaphylaxis might work by releasing simple bases like diamines and diamidines appears to be a more remote possibility.

Compound 48/80 obtained by condensation of p-methoxy-phenethylmethylamine with formaldehyde was found to be the most potent of all basic releasers (Paton, 1951; Mongar and Schild, 1952; Feldberg and Talesnik, 1953). It is interesting to note that this compound also releases heparin from dog's liver (MacIntosh, personal communication) but not from rat's organs (Mota et al., 1953) although it produces a rapid destruction of mast cells in the rat's skin. The possibility of a similar compound being one of the mediators in anaphylactic shock was postulated by Mongar and Schild (1952) who showed a correlation between the proportion of histamine set free from different tissues of the guinea pig when put into contact with compound 48/80 or with egg albumin. However striking this parallelism, certain peculiarities in the mode of action of each agent precludes any idea that in anaphylaxis the final mediator for the histamine release might be a comparable simple compound. For example a previous application of 48/80 to pieces of intestine increased considerably the output of histamine which followed contact with the egg albumin, while by reversing the order of addition, egg albumin had no effect upon the further release produced by 48/80. Furthermore, those compounds do not stimulate the smooth muscle of the guinea-pig gut and do not release in vivo histamine from the intestinal tract (Feldberg and Talesnik, 1953). It seems probable that those compounds work through some intermediary agent present in certain organs (rat's skin, for instance) but not in others.

More complete surveys of the basic agents which have been shown to release histamine can be found in Paton (1957) and Rothschild (1966).

The possibility of a simple displacement of histamine by basic compounds, in a way similar to that caused in a cationic exchange resin by stronger bases, was assumed by many to explain the release of histamine by 48/80, diamines, diamidines and so forth. This theory has been supported by some findings that histamine can be retained by heparin in solution, and since the mast cells are very rich in acid sulfated polysaccharides, these might constitute a natural site for histamine retention inside the mast-cells granules, prior to release. Some direct evidence of such histamine binding to heparin was presented by Lagunoff et al. (1964) and Uvnäs (1964), as we have seen above. But these experiments have only proved that a small part of histamine (no more than one-fifth) could be retained in the mast-cells granules by such salt linkage.

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It has always been difficult to understand why in the anaphylactic shock of the dog, histamine and heparin are both released from liver mast cells in a free form, and there is no evidence for the participation of any basic compound which could possibly combine with heparin in the places previously occupied by histamine. Furthermore, the mechanism of release of histamine by basic compounds (48/80) from rat mast cells appears to bear a strong similarity to the mechanism of release of histamine by anaphylaxis and anaphylatoxin, from the guinea-pig lung and rabbit platelets, structures upon which the basic compounds have a small effect or none at all. This point will be discussed in the next section where the mechanism of release will be described in relation to activation or inhibition of enzymes of the carbohydrate metabolism.