Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Amino Acids and Nucleotides
Purine Base Salvage

Free purine and pyrimidine bases are continuously produced in Cells As a result of the aforementioned metabolic breakdown of NUCLEOTIDES. A significant portion of these free purine bases does not undergo further degradation, but is instead reutilized—that is, used again for the Synthesis of purine nucleotides. In this case, nucleotides are formed quite differently than via the de novo Biosynthesis pathway discussed above. The purine ring of adenine synthesized de novo is built onto ribose-5-phosphate step by step through a long sequence of reactions. The salvage pathway from preformed products is much simpler. It involves just a single reaction in which free adenine reacts with 5-phosphoribosyl-1-pyrophosphate (PRPP), leading to The formation of an adenine nucleotide

Class="center">Adenine + PRPP → AMP + PP_i.

Free guanine is reutilized in the same manner with the help of a different enzyme

Guanine + PRPP → GMP + PP_i.

Interestingly, this salvage pathway of nucleotide synthesis is not only simpler than de novo synthesis, but also more "energy-efficient," as it requires a lower consumption of ATP energy.

Hypoxanthine, which is a deamination product of adenine, can also be reutilized using the same enzyme involved in guanine reutilization. In this case, inosinic acid (IMP) is formed

Hypoxanthine + PRPP →

→ IMP + PP_i.

The enzyme catalyzing the last two reactions is called hypoxanthine-guanine phosphoribosyltransferase. Children can suffer from an X-linked genetic defect in which this enzyme is absent. This type of enzyme deficiency (occurring exclusively in boys) leads to severe and highly unusual consequences. It manifests (typically around the age of two) as a distinct set of pathological symptoms known as Lesch-Nyhan syndrome, named after medical student Michael Lesch and pediatrician William Nyhan from the Johns Hopkins School of Medicine, who discovered this condition through fascinating biochemical studies and described it in 1964. Children with this genetic defect suffer from intellectual disability and lack of motor coordination. Furthermore, they are extremely aggressive. What is more, this aggression is often directed against themselves: they can easily mutilate themselves by biting their Lips, fingers, and toes.

Lesch-Nyhan disease is also remarkable from a metabolic perspective. As noted above, There are two pathways for purine nucleotide synthesis: the de novo pathway, in which the purine ring system is built step-by-step, and the salvage pathway, which involves the simple assembly of purine nucleotides from free Purines and PRPP. In Lesch-Nyhan disease, the salvage pathway is non-functional, yet de novo synthesis proceeds and Purine nucleotides are still produced. It turns out that the complications arise not from a shortage of purine nucleotides, but rather from their "overproduction" due to a disruption in some yet-unknown regulatory mechanism. This excess of purine nucleotides leads to an overaccumulation of uric acid and PRPP. Why this defect—affecting what seems to be a secondary metabolic pathway—so profoundly alters a child's behavior remains unknown. Very little can currently be done to help the victims of Lesch-Nyhan disease. Introduction/32.html">Genetic Engineering Methods can only "cure" in vitro cells taken from such patients (Ch. 30).