BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULAR PRECURSORS

CHAPTER 22. NUCLEOTIDE BIOSYNTHESIS

This chapter is devoted to the Biosynthesis of NUCLEOTIDES. These compounds participate in nearly all biochemical processes.

1. They are the activated precursors of DNA and RNA.

2. Nucleotide derivatives are activated intermediates in many biosynthetic reactions. For example, UDP-glucose and CDP-diacylglycerols are precursors of Glycogen and phosphoacylglycerols (phosphoglycerides), respectively.

3. The adenine nucleotide ATP is the universal energy currency in biological systems.

4. Adenine nucleotides are components of three major Coenzymes: NAD⁺, FAD, and CoA.

5. Nucleotides serve as regulators of METABOLISM. Cyclic AMP is a ubiquitous universal mediator of the action of many Hormones. Covalent modifications mediated by ATP molecules alter The activity of certain Enzymes; Examples include the phosphorylation of Glycogen synthase and the adenylylation of Glutamine Synthetase.

22.1. Nomenclature of Bases, Nucleosides, and Nucleotides

A nucleotide consists of a nitrogenous base, a sugar residue, and one or more phosphate groups. The nitrogenous base is a derivative of purine or pyrimidine. The two major Purines are adenine and guanine, and the three major Pyrimidines are cytosine, uracil, and thymine (Fig. 22.1).

Class="center">Fig. 22.1. Structures of the major purines and pyrimidines

A nucleoside consists of a purine or pyrimidine base linked to a pentose. The pentose is either D-ribose or β-D-2-deoxyribose. In a nucleoside, the C-1 glycosidic carbon atom of the pentose is bonded to the N-1 of a pyrimidine or the N-9 of a purine base. In all nucleosides found in living Cells, this N-glycosidic bond is in the β-configuration.

The pentose in ribonucleosides is ribose, whereas in deoxyribonucleosides it is deoxyribose. The major ribonucleosides are adenosine, guanosine, uridine, and cytidine. The major deoxyribonucleosides are deoxyadenosine, deoxyguanosine, deoxythymidine, and deoxycytidine. Note that in deoxy compounds, uracil is replaced by its methylated analog, thymine.

A nucleotide is a phosphate ester of a nucleoside. In a nucleotide, at least one hydroxyl group of the pentose is esterified. Most commonly, the hydroxyl group at C-5 of the pentose is esterified. Such a compound is called a nucleoside 5'-phosphate, or a 5'-nucleotide. Primed numbers designate the atoms of the pentose, while unprimed numbers designate the atoms of the purine or pyrimidine ring. The type of pentose is indicated by a prefix in the name (5'-ribonucleotide or 5'-deoxyribonucleotide).

Fig. 22.2. Structures of the major ribonucleosides

Fig. 22.3. Structures of the major deoxyribonucleosides

The nucleotide formed by the Esterification of the 5'-hydroxyl group of adenosine is adenosine 5'-phosphate, which is often called adenylate. Although the term 'adenylic acid' is sometimes used, it is preferable to call this compound adenylate because the phosphate group is ionized at physiological pH. The standard abbreviation for this compound is AMP (for adenosine monophosphate). The common names of the other major 5'-ribonucleotides are guanylate (GMP), uridylate (UMP), and cytidylate (CMP). The major 5'-deoxyribonucleotides are called deoxyadenylate (dAMP), deoxyguanylate (dGMP), deoxythymidylate (dTMP), and deoxycytidylate (dCMP). The prefix 'd' in these Abbreviations indicates that they refer to 2'-deoxyribonucleotides.

In a nucleoside 5'-diphosphate, a diphosphate group is attached to the 5'-hydroxyl of the pentose by an ester bond, whereas in a nucleoside 5'-triphosphate, a triphosphate group is attached to this hydroxyl. Thus, the series of adenine ribonucleotides consists of the following compounds: adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP), and adenosine 5'-triphosphate (ATP). The corresponding deoxyribonucleotides are deoxyadenosine 5'-monophosphate (dAMP), deoxyadenosine 5'-diphosphate (dADP), and deoxyadenosine 5'-triphosphate (dATP). The nomenclature of bases, nucleosides, and nucleotides is summarized in Table 22.1.

Table 22.1. Nomenclature of nitrogenous bases, nucleosides, and nucleotides

22.2. The purine ring is synthesized from amino acids, tetrahydrofolate derivatives, and CO₂

The purine ring of purine nucleotides is assembled from various precursors (Fig. 22.4). Glycine provides the C-4, C-5, and N-7 atoms. The N-1 atom is derived from aspartate. Two other nitrogen atoms, N-3 and N-9, originate from the amide group of the glutamine side chain. Activated tetrahydrofolate derivatives supply C-2 and C-8, while CO₂ serves as the source of C-6.

Fig. 22.4. Water/144.html">Origin of the purine ring atoms