Hypoxanthine is a purine envriate and is found in bound form as a nucleobase and in free form, such as in urine. It is equally present in glands and bone marrow. As a deamination product of adenine, hypoxanthine is oxidized to uric acid and xanthine. Less commonly, it forms a backbone of nucleic acids.
What is hypoxanthine-guanine phosphoribosyltransferase?
Hypoxanthine and guanine give rise to the tetrameric enzyme hypoxanthine-guanine phosphoribosyltransferase. In this context, tetramers are macromolecules consisting of four similar building blocks, or more precisely monomers. The enzyme is one of the most important in the purine metabolism of eukaryotes, reacts sensitively to gene changes and in humans can cause deviations through gene mutation, which are expressed in certain metabolic diseases. Such are, for example, Lesch-Nyhan and Kelley-Seegmiller syndromes.
Function, effects, and roles
The enzyme hypoxanthine-guanine phosphoribosyltransferase increases purine metabolism and its energetic potency. This is based on purine bases, which are nucleic acids structurally derived from purine. Such are xanthine, hypoxanthine, adenine and guanine, which attach to other bases by hydrogen bonds. Such bonds have a major influence on DNA double helix and replication and play a role in protein biosynthesis. Purine bases can be recycled by two enzymes. In addition to hypoxanthine-guanine phosphoribosyltransferase, this is adenine phosphoribosyltransferase. Both form a nucleotide through a phosphoribosyl residue, which in turn is a basic building block of nucleic acids in both DNA and RNA. The molecule consists of sugar, base and phosphate and regulates vital functions in cells. During assembly, ATP is saved and uric acid formation is reduced. When purine bases are recycled, it is referred to as the salvage pathway. This is a general term for metabolic pathways in which biomolecule synthesis results from degradation products. Here, the organism performs endogenous recycling, with about ninety percent of the purine bases being recycled and ten percent actually excreted. This demonstrates the efficiency of purine base recycling and the importance of hypoxanthine-guanine phosphoribosyltransferase.
Formation, occurrence, properties, and optimal levels
If mutations now occur at the HPRT gene, the size and amino acids may change. This can be the insertion of additional DNA sequences or nucleotides, which in turn leads to incorrect production of the gene product encoded on the gene in question, or even deletion of the entire sequence. For example, if the amino acid sequence is altered, diseases such as gout will result. Metabolic diseases such as Lesch-Nyhan syndrome are particularly serious as a result of a gene defect. This is inherited in an x-linked recessive manner, which means that it mainly affects males who have only one X chromosome. In women, the genetic defect may be present, but only breaks out as a disease if both X chromosomes are affected, which is relatively rare. In most cases, the second X chromosome compensates for the defect in the first.
Diseases and disorders
The syndrome is manifested by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. Due to the genetic defect, the enzyme is not produced. Due to the mutation and a lack of recycling and conversion of the bases guanine and hypoxanthine, an accumulation of purine bases occurs, which have to be built up more and excreted by the body. The breakdown occurs via the intermediate product xanthine, which is converted into uric acid and excreted via the kidneys. If this process is restricted, uric acid crystals form in the area of the joints, which then trigger increased attacks of gout. The enzyme is no longer produced, the uric acid level in the tissues and blood increases, and the central nervous system is disturbed. At birth, Lesch-Nyhan syndrome is not directly visible. Only after about ten months is a conspicuous leg position recognizable and the child’s tendency to move little and develop more slowly mentally. The syndrome manifests itself in mild and severe manifestations. Increased uric acid secretion and mild gout attacks are the milder form; in severe manifestations, self-injury, severe mental impairment, and aggression occur. Self-injury takes place through finger or lip bites.In the case of bites to the extremities, it is often observed that the affected individuals limit their autoaggression to one hand only. The aggression, in turn, is then particularly often directed against close persons such as siblings or parents. The most severe manifestation of the disease is characterized by multiple neurological dysfunctions and a very pronounced tendency to self-mutilation. The syndrome manifests as spasticity, dystonia, hypotonia, choreoathetosis, and increased reflexivity. Mental characteristics and development are severely impaired. To a particularly drastic extent, the syndrome can also lead to death in this condition. The disease is diagnosed by a medical picture. The uric acid level in urine and blood is measured, as well as the activity of hypoxanthine-guanine phosphoribosyltransferase in tissues and blood. The latter is severely reduced and may also be present prenatally. Therapy of the disease is difficult. There is no cure and without treatment the child will die in the first years of life. In some cases, the milk teeth have to be extracted as a preventive measure. Other therapeutic approaches include lowering uric acid levels with drugs such as allopurinol, which acts as an inhibitor of gout. Although this does not recycle the purine bases, it does improve the breakdown of uric acid. Likewise, the respective disorders, infections and nerve damage are treated and a special diet is advised, which mostly avoids meat and is low in purine. Research is also being done in the area of psychosomatic concomitants through deep brain stimulation. Medicine hopes that this will prevent aggression and self-mutilation. Kelley-Seegmiller syndrome, in turn, is the mildest form of hypoxanthine-guanine phosphoribosyltransferase deficiency. Here, too, too much uric acid is produced, leading to premature gout. The first signs of the syndrome are orange crystals in the child’s diaper, urinary tract infections, and urolithiasis. During puberty, gout or acute arthritis then develops. Mental underdevelopment and self-attacks, as seen in Lesch-Nyhan syndrome, are not the case; at most, attention deficits may occur. Early treatment usually allows affected individuals to live a normal life expectancy.
