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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Write structural formulas to represent the amino- and oxo-tautomers of a purine and of a pyrimidine and state which tautomer predominates under physiologic conditions.

  • Reproduce the structural formulas for the principal nucleotides present in DNA and in RNA and the less common nucleotides 5-methylcytosine, 5-hydroxymethylcytosine, and pseudouridine (ψ).

  • Represent D-ribose or 2-deoxy-D-ribose linked as either a syn or an anti conformer to a purine, name the bond between the sugar and the base, and indicate which conformer predominates under most physiologic conditions.

  • Number the C and N atoms of a pyrimidine ribonucleoside and of a purine deoxyribonucleoside, including using a primed numeral for C atoms of the sugars.

  • Compare the phosphoryl group transfer potential of each phosphoryl group of a nucleoside triphosphate.

  • Outline the physiologic roles of the cyclic phosphodiesters cAMP and cGMP.

  • Appreciate that polynucleotides are directional macromolecules composed of mononucleotides linked by 3′ → 5′-phosphodiester bonds.

  • Be familiar with the abbreviated representations of polynucleotide structures such as pTpGpT or TGCATCA, for which the 5′-end is always shown at the left and all phosphodiester bonds are 3′ → 5′.

  • For specific synthetic analogs of purine and pyrimidine bases and their derivatives that have served as anticancer drugs, indicate in what ways these compounds inhibit metabolism.

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BIOMEDICAL IMPORTANCE

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In addition to serving as precursors of nucleic acids, purine and pyrimidine nucleotides participate in metabolic functions as diverse as energy metabolism, protein synthesis, regulation of enzyme activity, and signal transduction. When linked to vitamins or vitamin derivatives, nucleotides form a portion of many coenzymes. As the principal donors and acceptors of phosphoryl groups in metabolism, nucleoside tri- and diphosphates such as ATP and ADP are the principal players in the energy transductions that accompany metabolic interconversions and oxidative phosphorylation. Linked to sugars or lipids, nucleosides constitute key biosynthetic intermediates. The sugar derivatives UDP-glucose and UDP-galactose participate in sugar interconversions and in the biosynthesis of starch and glycogen. Similarly, nucleoside-lipid derivatives such as CDP-acylglycerol are intermediates in lipid biosynthesis. Roles that nucleotides perform in metabolic regulation include ATP-dependent phosphorylation of key metabolic enzymes, allosteric regulation of enzymes by ATP, ADP, AMP, and CTP, and control by ADP of the rate of oxidative phosphorylation. The cyclic nucleotides cAMP and cGMP serve as the second messengers in hormonally regulated events, and GTP and GDP play key roles in the cascade of events that characterize signal transduction pathways. In addition to the central roles that nucleotides play in metabolism, their medical applications include the use of synthetic purine and pyrimidine analogs that contain halogens, thiols, or additional nitrogen atoms in the chemotherapy of cancer and AIDS, and as suppressors of the immune response during organ transplantation.

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CHEMISTRY OF PURINES, PYRIMIDINES, NUCLEOSIDES, & NUCLEOTIDES

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Purines & Pyrimidines Are Heterocyclic Compounds

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Purines and pyrimidines are nitrogen-containing heterocycles, cyclic structures that contain, ...

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