Nucleic Acids Nucleosides and Nucleotides

The most important biological role of ribose and 2-deoxyribose is to act as structural components of polymeric RNA and DNA, respectively. Thus, this is an opportune time to shift our attention to the role of 5-carbon furanoses in the structure and formation of nucleosides, nucleotides, and the polymeric nucleic acids formed from the ribo and deoxyribo forms of the nucleotides. However, before we turn our attention to these genetically crucial macromolecules we need to introduce the het-erocyclic compounds, or so called, nucleic acid bases, into our discussion.

It is important to identify their role in forming the reactive species known as nucleosides and nucleotides, the nucleosides being the precursors to their respective nucleotide and the nucleotides being the building blocks of the nucleic acids, DNA and RNA.

The main biologically significant heterocyclic organic compounds are known in biology as nucleic acid bases and are derived from the parent compounds purine and pyrimidine whose structures are shown in Fig. 1.12. Substitutions on the purine heterocyclic result in formation of the purine bases adenine and guanine, while substitutions on pyrimidine lead to the common pyrimidine bases uracil, cytosine, and thymine. In cells, the purines and pyrimidines mainly exist covalently bound to either ribose or 2-deoxyribose and phosphate to produce the biologically active form of the bases.

When coupled to ribose (as shown in Fig. 1.12) or to 2-deoxyribose (not shown) the resulting compounds are known as ribonucleosides (e.g., adenosine and uridine) and deoxyribonucleosides (e.g., deoxyadenosine and deoxyuridine). In most biosynthetic reactions, the nucleosides enter reactions in the form of their mono-, di-, or triphosphate adducts on the number 6 carbon of the furanose ring, which are then known as mono-, di-, or triphospho nucleotides. Examples of the latter structures are illustrated in Fig. 1.13 for the adenosine nucleotide series, adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP). It is important to note that the phosphate moiety in AMP is bound to ribose via an ester link while the interphosphate linkages in ADP and ATP are formally anhydride bonds. The significance of this observation is that the standard free energy of hydrolysis of esters is about —3 kcal/mol, while under comparable conditions the standard free energies of hydrolysis of the anhydride bonds in ATP are about —7.5 kcal/mol, and thus the phospho anhydride bonds of all nucleotides are known as high-energy phosphate bonds.

Nucleotide triphosphates, mainly ATP, provide much of the thermo-dynamic driving power for metabolic reactions as shown in Chap. 5. For example, glucose is a relatively inert molecule and requires activation before it can participate in metabolic reactions. Biologically, activation is effected by reaction with ATP as shown in Eq. (1.17).

ATP + Glucose S ADP + Glucose-6-phosphate

Since AG°' for hydrolysis of ATP into ADP and phosphate is about — 7 kcal/mol and since AG°' for the coupled reaction shown in Eq. (1.17) is about —4 kcal/mol, it follows that about 3 kcal/mol of ATP energy is

Purine

Adenine NH2

Adenine NH2

OH OH Adenosine

H2N N

Guanine O

Guanine O

OH OH Guanosine

OH OH Guanosine

CH CH

Pyrimidine

H Uracil

ON O

Cytosine

ON O

Thymine O

ON O

.CH3

OH OH Uridine

OH OH Cytidine

OH OH Thymidine

Figure 1.12 Nucleic acids and nucleosides. The nucleic acid bases adenine and guanine are derived from purine, the nucleic acid bases uracil, cytosine, and thymine are derived from pyrimidine. When covalently bonded to a furanose, either ribose or 2-deoxyribose, they are called nucleosides.

Anhydride

Figure 1.13 Examples of mono-, di-, and triphosphonucleotides. Adenosine triphosphonucleotide, or ATP, has a very high (negative) free energy of hydrolysis and thus is used to provide usable free energy to drive many biosynthetic reactions. The deoxy forms of the nucleotides (which lack the shaded OH groups) are involved in the formation of DNA while the hydroxy forms are used to construct RNA. The "high energy"phosphoanhy-dride bonds of the nucleotides are used to drive the synthesis of the polymers.

used to drive the synthesis of glucose-6-phosphate and thus allows glucose to be "activated" and enter metabolism. Reactions of this nature, where energy resident in a nucleotide triphosphate bond is used to drive an otherwise unlikely, biological reaction, are ubiquitous in nature.

From a reproductive biology perspective, the high-energy bonds of the triphosphonucleotides are likely to be viewed as most important in driving the synthesis of genes, that is, DNA, as well as the various species of RNAs that are critical in expressing the biological messages of inheritance that are coded in DNA (see Chap. 7). The general reaction involved in forming the nucleic acids is shown in Eq. (1.18) where "n" high energy triphosphonucleotides are shown to combine to yield a polymer linked by ester bonds that contain the same number of bases plus twice the number of free phosphate residues as in the original triphos-phonucleotide reactant pool.

n (triphosphonucleotides) N (phosphodiester polymer)n bases

A 4-nucleotide section of a single strand of a DNA molecule is diagramed in Fig. 1.14 illustrating individual phosphoester bonds and the phosphodiester linkages involved in producing nucleic acid polymers. Notice that the polymer backbone is composed of alternating 2'-deoxyribose furan rings and phosphodiester linkage, and that the acid OH group on the phosphates are largely in the dissociated form (O) resulting in a highly negatively charged nucleic acid backbone structure. Unlike glycogen, there are no regular covalent branch points in nucleic acid polymers and thus the nucleic acid molecules, ranging in base content from several thousand to many millions, are exceedingly long molecular strands which in cells are very efficiently packaged into a variety of compact structures that are described in Chap. 7. In cells, nucleic acids exist in many molecular forms and are highly modified by chemical reactions on the purine and pyrimidine rings. Chapter 7 outlines the structure and role of the nucleic acids including DNA, messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA), as well as other more recently recognized species that are critical players in regulating the expression of genes.

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