Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions

NADP+ is derived from NAD+ by phosphorylation of the 2 -hydroxyl group of the adenine ribose moiety. This transfer
+
of a phosphoryl group from ATP is catalyzed by NAD kinase.
Flavin adenine dinucleotide (FAD) is synthesized from riboflavin and two molecules of ATP. Riboflavin is
phosphorylated by ATP to give riboflavin 5 -phosphate (also called flavin mononucleotide, FMN). FAD is then formed
from FMN by the transfer of an AMP moiety from a second molecule of ATP.
The AMP moiety of coenzyme A also comes from ATP. A common feature of the biosyntheses of NAD+, FAD, and
CoA is the transfer of the AMP moiety of ATP to the phosphate group of a phosphorylated intermediate. The
pyrophosphate formed in these condensations is then hydrolyzed to orthophosphate. As in many other biosyntheses,
much of the thermodynamic driving force comes from the hydrolysis of the released pyrophosphate.
III. Synthesizing the Molecules of Life
25. Nucleotide Biosynthesis
25.6. Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions
Nucleotides are vital to a host of biochemical processes. It is not surprising, then, that disruption in nucleotide
metabolism would have a variety of physiological effects.
25.6.1. Purines Are Degraded to Urate in Human Beings
The nucleotides of a cell undergo continual turnover. Nucleotides are hydrolytically degraded to nucleosides by
nucleotidases. The phosphorolytic cleavage of nucleosides to free bases and ribose 1-phosphate (or deoxyribose 1phosphate) is catalyzed by nucleoside phosphorylases. Ribose 1-phosphate is isomerized by phosphoribomutase to
ribose 5-phosphate, a substrate in the synthesis of PRPP. Some of the bases are reused to form nucleotides by salvage
pathways. Others are degraded to products that are excreted (Figure 25.17). For example, AMP is degraded to the free
base hypoxanthine through deamination and hydrolytic cleavage of the glycosidic bond. Xanthine oxidase, a
molybdenum- and iron-containing flavoprotein, oxidizes hypoxanthine to xanthine and then to uric acid. Molecular
oxygen, the oxidant in both reactions, is reduced to H2O2, which is decomposed to H2O and O2 by catalase. Uric acid
loses a proton at physiological pH to form urate. In human beings, urate is the final product of purine degradation and is
excreted in the urine. High serum levels of urate induce gout, a disease in which salts of urate crystallize and damage
joints and kidneys (Figure 25.18). Allopurinol, an inhibitor of xanthine oxidase, is used to treat gout in some cases.
The average serum level of urate in humans is close to the solubility limit. In contrast, prosimians (such as lemurs)
have tenfold lower levels. A striking increase in urate levels occurred in the evolution of primates. What is the
selective advantage of a urate level so high that it teeters on the brink of gout in many people? It turns out that urate has a
markedly beneficial action. Urate is a highly effective scavenger of reactive oxygen species. Indeed, urate is about as
effective as ascorbate (vitamin C) as an antioxidant. The increased level of urate is humans compared with prosimians
and other lower primates may contribute significantly to the longer life span of humans and to lowering the incidence of
human cancer.
25.6.2. Lesch-Nyhan Syndrome Is a Dramatic Consequence of Mutations in a SalvagePathway Enzyme
Mutations in genes that encode nucleotide biosynthetic enzymes can reduce levels of needed nucleotides and can
lead to an accumulation of intermediates. A nearly total absence of hypoxanthine-guanine
phosphoribosyltransferase has unexpected and devastating consequences. The most striking expression of this inborn
error of metabolism, called the Lesch-Nyhan syndrome, is compulsive self-destructive behavior. At age 2 or 3, children
with this disease begin to bite their fingers and lips and will chew them off if unrestrained. These children also behave
aggressively toward others. Mental deficiency and spasticity are other characteristics of the Lesch-Nyhan syndrome.
Elevated levels of urate in the serum lead to the formation of kidney stones early in life, followed by the symptoms of
gout years later. The disease is inherited as a sex-linked recessive disorder.
The biochemical consequences of the virtual absence of hypoxanthine-guanine phosphoribosyl transferase are an
elevated concentration of PRPP, a marked increase in the rate of purine biosynthesis by the de novo pathway, and an
overproduction of urate. The relation between the absence of the transferase and the bizarre neurologic signs is an
enigma. Specific cells in the brain may be dependent on the salvage pathway for the synthesis of IMP and GMP. Indeed,
transporters of the neurotransmitter dopamine are present at lower levels in affected individuals. Alternatively, cells may
be damaged by the accumulation of intermediates to abnormal levels. The Lesch-Nyhan syndrome demonstrates that the
salvage pathway for the synthesis of IMP and GMP is not gratuitous. Moreover, the LeschNyhan syndrome reveals that
abnormal behavior such as self-mutilation and extreme hostility can be caused by the absence of a single enzyme.
Psychiatry will no doubt benefit from the unraveling of the molecular basis of such mental disorders.
III. Synthesizing the Molecules of Life
25. Nucleotide Biosynthesis
25.6. Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions