Molecular Structure of Nucleic Acids | Biochemistry

In this article we will discuss about the molecular structure of nucleic acids, explained with the help of suitable diagrams.

Nucleic acids are macromolecules present in all living cells, either in free state, or in combination with proteins to form nucleoproteins. Besides, the simplest viruses consist exclusively of a molecule of nucleic acid enclosed in a protein shell. We will see in the following that nucleic acids are of fundamen­tal importance because they are either carriers of genetic information, or agents enabling the expression of this information.

Nucleic acids are polymers consisting of units called nucleotides; they are hence called polynucleotides. It may be recalled here that nucleotides are not only compounds leading to nucleic acids on polymerization, but also substan­ces which can play an important role in intermediate metabolism, say, for energy storage (ATP), or as coenzymes (NAD⁺, NADP⁺, FAD, coenzyme A; see figs. 2-16,2-17,2-18), or for the synthesis of polysaccharides or of lipids (see for example, the role of UDP glucose in the synthesis of glycogen, or the role of CDP-choline in the synthesis of phosphatidyl-choline, or in the control of various processes (see for example, the role of cyclic AMP as relay of hormonal action).

Nucleotides differ from monomers which constitute the other macro- molecules already studied (glucose of starch or glycogen, amino acids of proteins) in that they can themselves be further hydrolyzed into their 3 con­stituents: nitrogenous heterocyclic base, pentose and phosphoric acid. We will study these constituents, at least the first two, in some more details, but we may state at the outset that two types of nucleic acids are distinguished depending on whether the pentose is deoxyribose or ribose.

1) The deoxyribonucleic acids (DNAs) which are mainly found in the chromosomes in the nucleus of plant and animal cells; in procaryotes (bacteria, blue-green algae) it is also DNA which forms the chromosomes. Some viruses, especially bacterial viruses (or bacteriophages) and animal viruses have a genome consisting of DNA. Furthermore, DNA is also found in mitochondria of plant and animal cells and in chloroplasts of photosynthetic organisms.

2) The ribonucleic acids (RNAs), mainly found in the cytoplasm of cells. There are various types of ribonucleic acids (ribosomal ribonucleic acids, transfer ribonucleic acids, messenger ribonucleic acids) involved in the expres­sion of genetic information. Besides, some viruses, especially plant viruses and also some animal viruses and bacteriophages, have a genome consisting of RNA.

Pentoses:

In ribonucleic acids, the sugar is β-D-ribose, in deoxyribonucleic acids it is β -2-deoxy-D-ribose (see fig. 6-1). These 2 sugars are of the D-series due to their configuration on carbon 4 which is the carbon next to the one carrying the primary alcohol group.

They are represented in the β -form because it is in this form that they are found in nucleotides (and therefore in nucleic acids). Let us point out that 2-O-methyl-pentoses are sometimes found in some ribonucleic acids.

Nitrogenous Bases:

All nitrogenous bases derive from 2 heterocyclic bases, purine and pyrimidine; we therefore have:

1. Purine Bases or Substituted Purines:

The two principal purine bases found in deoxyribonucleic acids as well as ribonucleic acids are adenine and guanine (see fig. 6-2). There are also other purine bases, but they are found only in some nucleic acids (especially the transfer ribonucleic acids or tRNAs) and in small quantities, hence their name, rare bases or abnormal bases or minor bases (see fig. 6-2); they are often methylated derivatives of the two major bases, but there are some having more complex structures (for example, isopentenyl-adenine, which is a cytokinine with hormonal activity in plants); about fifty minor bases (purine and pyrimidine bases) are known at present.

2. Pyrimidine Bases or Substituted Pyrimidines:

Cytosine and uracil are found in ribonucleic acids; cytosine and thymine, in deoxyribonucleic acids. One also finds, particularly in the deoxyribonucleic acids of some bacteriophages, abnormal bases like 5-hydroxvmethylcytosine (see fig. 6-3) instead of cytosine (in even T phages: T₂, T₄, T₆), or hydroxy- methyluracil instead of thymine (in some phages infecting B. subtilis).

Among the rare bases found in the transfer ribonucleic acids, one must cite dihydrouracil and thymine (the latter is a normal base in deoxyribonucleic acids and a rare base in ribonucleic acids).

3. Tautornerism of Bases:

The structure of oxygen-containing bases is given in figures 6-2 and 6-3 in the keto (or lactam) form. This is the common form at the physiological pH, but as shown by figure 6-4, there is equilibrium between this form and the enol (or lactim) form.

Nucleosides:

Nucleosides result from the linkage of a purine or pyrimidine base with ribose or deoxyribose. This linkage joins nitrogen 9 of the purine base, or nitrogen 1 of the pyrimidine base with carbon 1′ of pentose.

Pentose is in the form of furanose and the glycosidic linkage is in the β-form. With ribose one has ribonucleosides (or ribosides); with dexoyribose, deoxyribonucleosides (or deoxyribosides). The structures of these two types of nucleosides are il­lustrated by the examples of figure 6-5.

The table below indicates the nomenclature of the main nucleosides. It will be noted that purine nucleosides have the suffix “osine” and the pyrimidine nucleosides, the suffix “idine”.

Nucleosides-Monophosphates:

Nucleotides are the phosphoric esters of nucleosides. Depending on the nature of the pentose one will have ribonucleotides (or ribotides) and deoxyribonucleotides (or deoxyribotides).

Mild hydrolysis of a nucleotide can be carried out in two ways:

A ribonucleoside has 3 positions which can be phosphorylated (hydroxyls of carbons 2′, 3′ and 5′) while a deoxyribonucleoside can be phosphorylated only in two places (3′ and 5′). These various isomers of nucleosides-monophos-phates exist (see examples of figure 6-6).

Besides, there are cyclic nucleotides where the phosphoric acid molecule esterifies two hydroxyls of the pentose at a time (for example, the OH groups in 2′ and 3′, or in 3′ and 5′); the most important is cyclic AMP (see fig. 6-6) which plays a role in various regulation mechanisms, but cyclic GMP also exists.

The nomenclature of the principal nucleosides-monophosphates is indi­cated in the table below; these are 5′ isomers, but the other isomers are denoted in identical manner by simply replacing 5′ by 2′ or 3′ respectively.

Nucleosides-Di- and Triphosphates:

A second phosphate group can be bound to the phosphate of a nucleoside­-5’ – monophosphate, thus forming a ribo- or a deoxyribonucleoside-5′-diphos­phate (ZDP or dZDP); a third phosphate can also be added to the second, forming a ribo- or a deoxyribonucleoside-5′-triphosphate (ZTP or dZTP).

Ex­amples of this type of nucleotides are represented in figure 6-7 (they are sometimes called nucleosides-polyphosphates, although the number of phos­phate groups bound to the nucleoside does not exceed 3, barring very rare exceptions).

A compound called 5′-diphospho-guanosine (2′, 3′)-diphosphate (ppGpp), or sometimes, guanosine tetraphosphate, has recently been characterized; it has two phosphate groups bound in 5′ and two bound in 2′ (or 3′) of guanosine. This compound accumulates in some auxotrophic mutants of E.coli when the latter are deprived of the essential aminoacid, and protein synthesis and forma­tion of the two ribosomal RNAs of high molecular weight are inhibited.

Primary Structure of Nucleic Acids:

In deoxyribonucleic acids as in ribonucleic acids, the nucleotides are joined by 3′-5′ pliosphodiester bonds; in other words each phosphate group (except those situated at the end of chains) is esterified to the 3′ hydroxyl group of a pentose and to the 5′ hydroxyl group of the next pentose.

This mode of binding between nucleotides is demonstrated by titration experiments which reveal that in the polynucleotide each phosphate group has only one free acid OH, and by the fact that enzymatic hydrolysis of nucleic acids yields either nucleosides-5′- monophosphates, or nucleosides-3′-monophosphates, depending on the en­zyme used.

As shown by figure 6-8, the polyribonucleotide chain therefore consists of alternating ribose and phosphate residues. This chain is absolutely identical for all ribonucleic acids, only its length can vary. The DNA chains have the same structure, with deoxyribose in place of ribose. It is observed that the bases do not participate in the chain linkages but it should not be concluded that they are unimportant.

On the contrary, the order in which the bases follow one another along the chain, called base sequence (or nucleotide sequence) is characteristic of a nucleic acid (just as the sequence of amino acids is charac­teristic of a protein), and that genetic information in fact resides in the base sequence.

Figure 6-8 shows the detailed structure of a fragment of RNA, and also its schematic representation (where a single line denotes pentose) which reflects the main features and is much more convenient to write. This oligo-ribonucleotide fragment can also be denoted — very explicitly — as follows: pUpApCp.

It will be noted that in this mode of writing, a “p” to the left of the capital letter designating the nucleoside signifies that the phosphate group is bound to the 5′ carbon of the pentose, and a “p” to the right of the capital letter represents a phosphate bound to the 3′ carbon of the pentose of the nucleoside considered.