Stages in Disruption of Nucleic Acid
As might be expected from the complex structure of the nucleic acid molecule, a number of ferments are concerned in its disruption. The gastric and pancreatic juices contain not a trace of any enzymes. Thus, when nucleo-protein is subjected to the gastric juice a moiety of protein is readily split off and hydrolysed to peptone and other products of proteolysis.
But the nuclein element remains unacted upon until it comes under the action of the pancreatic juice. Hydrolysis then ensues, and the ingested nuclein is broken down into nucleic acid and protein. The nucleic acid remains unaffected by the pancreatic juice, but, coming in contact with the succus entericus, it undergoes partial decomposition through the action of a ferment called nuclease or nucleic-acidase. Under its disruptive effect the nucleic acids or poly-nucleotides are further split up into groups known as nucleotides. The two pyrimidine nucleotides split off and undergo no further change. But, through the action of another ferment, nucleotidase, the purin nucleotides are further decomposed to yield nucleosides (substances of the glucoside class made up of a combination of a purin base with a carbohydrate group of the nucleic acid with which also phosphoric acid is linked).
No further stage in hydrolysis of nucleic acid occurs in the intestine, but the nucleosides are again in turn split up after reaching the tissues, particularly in the spleen, liver, and thymus. This, under the action of specific enzymes, nucleosidases, which succeed in breaking the nucleosides down into the so-called “building stones” of the nucleic acid molecule, phosphoric acid group, carbohydrate group, pyrimidine and purin bases, especially adenine and guanine. The adenine and guanine thus formed are, by the action of the ferments adenase and guanase, converted and, by the removal of their amino group, transformed, adenine into hypoxanthine, and guanine into xanthine, thus:—
By the action of oxidases also present in the tissues hypoxanthine is changed into xanthine and xanthine into uric acid (trioxy-purine), this by a specific ferment xanthine oxidase.
Scheme Illustrating the Probable Stages in the Passage of Purin through the Body (Walker Hall)
It will be seen that the disintegration of nucleic acid involves many stages, and its complexity is such that we make no apology for drawing upon the masterly monograph of Walter Jones for further elucidation of this intricate question. In relating the history of nucleic acid in the animal body Jones has found it convenient to introduce certain terms wherewith to designate the various elements of the nucleic acid molecule. Thus, the molecule in its entirety is termed a tetra-nucleotide. The cleavage of this complex is initiated by the action of two specific enzymes. Through their agency the tetra-nucleotide is first cloven into two di-nucleotides, which immediately divide up into four mono-nucleotides. These ferments are:—
(1) Phospho-nuclease (which splits off the phosphoric acid radicle, leaving a nucleoside, guanosine or adenosine).
(2) Purin-nuclease (which splits off the purin radicle, viz., separates out both phosphoric acid and carbohydrate groups, leaving free purin bases).
Now, in sequence to either of the foregoing cleavages by the phospho- or purin-nucleases another set of enzymes come into the field. Under their deaminising effect the amino group is abstracted, with the formation of either free oxy-purins or oxy-purins still bound in glucoside-like combination with sugar.
If the oxy-purins are free, the following is the reaction:—
Should, however, the guanine glucoside be present:—
In the latter instance a hydrolysing enzyme, xanthosine-hydrolase, by its action, splits off xanthine. We see, therefore, that by either route the end-product is the same. Following a like series of changes, the adenine radicle is transmuted into hypoxanthine. This either directly by the action of adenase:—
or indirectly through the agency of adenosine-deaminase, the hypoxanthine-glucoside (inosine) is formed, and subsequently the hypoxanthine is split off.
Xanthine and hypoxanthine are, therefore, now to hand, and given the presence of oxygen, their oxidation to uric acid ensues:—
Now, in man and the anthropoid apes, uric acid is the end-product of purin catabolism. In contrast therewith in most mammals only a minimal amount of the exogenous or endogenous purins escapes in the urine as uric acid. Most of it undergoes further oxidation into allantoin,[15] this change taking place in most mammals chiefly in the liver. According to Schittenhelm, if nucleic acid be given to dogs, pigs or rabbits, from 93-95 per cent. thereof appears in the urine as allantoin, and only 3-6 per cent. as uric acid, and 1-2 per cent. as purin bases.
Disruption of Nucleic Acid Molecule (Amberg and Jones).
In man, as in most mammals, uric acid is formed chiefly in the liver from purins, and in the preceding table Amberg and Walter Jones schematically represent the various steps by which disruption of the nucleic acid molecule is attained, and uric acid formed.