Hypoxanthine, along with xanthine, is a breakdown product from purine metabolism. It is further degraded into uric acid. Diseases can occur both when its degradation to uric acid is inhibited and when its recycling via the salvage pathway is impaired.
What is hypoxanthine?
Hypoxanthine is a purine derivative and is formed during the degradation of the purine bases adenine and guanine. Along with xanthine, it is an intermediate in the synthesis of uric acid. Under the influence of xanthine oxidase, hypoxanthine is usually degraded first into xanthine and then into uric acid. Like all purine derivatives, it consists of two heterocyclic rings containing six and five atoms, respectively. There are a total of nine atoms in the rings. These are five carbon atoms and four nitrogen atoms. Two carbon atoms belong to both rings. A hydroxyl group is bonded to the carbon atom at position 6. Via stabilization effects, the molecule can exist in several tautomeric forms that are in equilibrium with each other. Hypoxanthine consists of solid transparent crystals that melt at 250 degrees. It does not dissolve in cold water or alcohol. However, it is readily soluble in hot water, acids or alkalis.
Function, action and tasks
Hypoxanthine, as mentioned, is an intermediate in the breakdown of purine bases. The enzyme xanthine oxidase oxidizes it to xanthine. Together with xanthine, it is then further degraded to uric acid with the help of xanthine oxidase. The difference between hypoxanthine and xanthine is that xanthine also has a hydroxyl group attached to position 2. Furthermore, hypoxanthine can be both degraded to uric acid and fed back into the purine metabolism via the salvage pathway. In contrast, xanthine is only degraded to uric acid. Hypoxanthine forms the nucleoside inosine with ribose. Inosine is incorporated into the anticodon of tRNA in very rare cases. In this context, it is used in the preparation of degenerate primers that initiate a polymerase chain reaction. It is a neutral base that can pair with all nucleic bases. However, pairing with cytosine is the most energetically favorable. Another important compound derived from hypoxanthine is inosine monophosphate. This compound is a phosphoric acid ester of inosine. Inosine monophosphate (IMP) represents a key intermediate for the synthesis of guanosine monophosphate (GMP) and adenosine monophosphate (AMP), both of which can be used again for nucleic acid synthesis. The synthesis of IMP occurs from hypoxanthine directly via the salvage pathway. The two enzymes AICAR formyltransferase/IMP cyclase and hypoxanthine-guanine phosphoribosyltransferase are largely responsible for this. Thus, hypoxanthine is at the interface between the degradation of purine bases to uric acid and the build-up of nucleic acids. Inosine monophosphate is also used as a flavor enhancer.
Formation, occurrence, properties, and optimal values
Hypoxanthine forms as an intermediate in purine metabolism and stands at the threshold between degradation and rebuilding of purine bases. When it is oxidized to xanthine by the enzyme xanthine oxidase, the back reaction to the nucleic bases adenine and guanine is no longer possible. Hypoxanthine is formed from the purine base adenine, while the degradation of guanine leads to xanthine. However, the reactions of the various nucleosides and nucleotides are interconnected by a complicated network. For example, adenosine nucleotides lead directly to hypoxanthine, with AMP as the key substance. However, GMP can also be converted to AMP via IMP and adenylosuccinate. AMP then leads to hypoxanthine via the formation of adenosine and inosine, among others. In addition to guanine and adenine, hypoxanthine can then also produce nucleotides again as nucleic acid building blocks via the salvage pathway.
Diseases and disorders
Several disorders may occur in association with hypoxanthine. During purine degradation, hypoxanthine and xanthine are produced equally. Hypoxanthine is converted to xanthine by xanthine oxidase. The same enzyme then degrades xanthine to uric acid. However, when xanthine oxidase is absent, xanthine and hypoxanthine accumulate in the blood. The uric acid levels are very low. However, mainly the concentration of xanthine increases, because hypoxanthine has the possibility to be recycled again via the salvage pathway. The clinical picture of xanthinuria develops. The excretion of xanthine in the urine can increase by 1500 percent.The levels of hypoxanthine also increase, but not nearly as much. The high concentrations of xanthine can damage the kidneys. With low fluid intake, kidney stones or stones in the urinary tract can form. The excretion of urinary crystals is also possible. In very severe cases, fatal kidney failure may occur. However, since xanthine and hypoxanthine have some water solubility, the best therapy is to drink plenty of fluids. Purine-rich foods such as fish, shellfish, legumes, or beer should be avoided. However, there are also more severe forms of xanthinuria. Thus, in addition to severe kidney disease, delayed mental development, autism or even tooth development disorders can occur. Since hypoxanthine can also be recycled via the salvage pathway, in contrast to xanthine, the disorders within this process lead to increased uric acid formation, because only the degradation pathway of the purine bases functions. The resulting hypoxanthine can only be oxidized into xanthine, which in turn converts into uric acid. Often there is a hereditary defect of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The uric acid concentration in the blood rises sharply, and precipitation of uric acid crystals in the joints can occur. The result is attacks of gout. In severe cases, Lesch-Nyham syndrome develops.
