Nucleotide Metabolism

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  • 32.1 An Overview of Nucleotide Biosynthesis and Nomenclature

  • 32.2 The Pyrimidine Ring Is Assembled and Then Attached to a Ribose Sugar

  • 32.3 The Purine Ring Is Assembled on Ribose Phosphate

  • 32.4 Ribonucleotides Are Reduced to Deoxyribonucleotides

  • 32.5 Nucleotide Biosynthesis Is Regulated by Feedback Inhibition

  • 32.6 Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions

Charles V, Holy Roman Emperor (1519–1558), who also ruled as Charles I, king of Spain (1516–1556), was one of Europe’s most powerful rulers. Under his reign, the Aztec and Inca empires of the New World fell to the Spanish. Charles V also suffered from severe gout, a pathological condition caused by the disruption of nucleotide metabolism. This painting by Titian shows the emperor’s swollen left hand, which he rests gingerly in his lap. Recent analysis of a part of his finger, saved as a religious relic, confirms the diagnosis of gout.

In addition to being the building blocks of proteins and peptides, amino acids serve as precursors of many kinds of small molecules that have important and diverse biological roles. Let us briefly survey some of the biomolecules that are derived from amino acids (Figure 32.1).

Figure 32.1: Selected biomolecules derived from amino acids. The atoms contributed by amino acids are shown in blue.

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Histamine, a component of the immune system whose overproduction results in an allergic response, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine), which controls the rate of metabolic processes throughout the body, and epinephrine (adrenaline), the “fight or flight” hormone. Epinephrine is metabolized to 5,6-dihydroxyindole, which is a precursor of melanin, a complex polymeric pigment that is formed on exposure to sunlight and is the chemical basis of tanning. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD+ are synthesized from tryptophan. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. We now consider in more detail especially prominent biochemicals derived from amino acids—the nucleotide bases. Purines and pyrimidines are derived largely from amino acids and are the precursors of DNA, RNA, and various coenzymes.

We begin by examining nucleotide synthesis. The initial products of nucleotide synthesis are ribonucleotides, and we will see how ribonucleotides are converted into deoxyribonucleotides, the substrates for DNA synthesis. We then turn to the regulation of nucleotide synthesis. Finally, we consider pathological conditions that result from perturbations in nucleotide metabolism.