Nucleic Acid

Nucleic acids are polynucleotides that, together with polysaccharides and polypeptides, form the true macromolecular fraction of any living tissue or cell. Along with proteins, they are the main constituents of chromosomes and are responsible for the transmission of characters from one generation to the next (a phenomenon known as heredity).

Structure of Nucleic Acids

The building blocks of nucleic acids are nucleotides that have three chemically distinct components - a heterocyclic compound, a monosaccharide, and a phosphoric acid or phosphate residue. The heterocyclic compounds found in nucleic acids are nitrogenous bases called adenine, guanine, uracil, cytosine, and thymine.

Adenine and guanine are substituted purines, whereas the others are substituted pyrimidines. The sugar found in polynucleotides is either β-D-ribose or β-D-2-deoxyribose, which we’ve already discussed before. A nucleic acid containing deoxyribose is known as deoxyribonucleic acid (DNA) while one that contains ribose is known as ribonucleic acid (RNA).

We’ll now dive into the expansive world of nucleic acids and study about these fascinating molecules in detail.

Purines, pyrimidines, and nucleosides

To begin our study of nucleic acids, we must learn more about a crucial part of these molecules: two classes of heterocyclic bases known as the purines and the pyrimidines. Pyrimidines are six-membered heterocyclic rings whereas purines contain both a five-membered and a six-membered ring. Because of the presence of nitrogen atoms in the ring, these compounds are known as heterocyclics and also as bases. 

In nature, we commonly find five important bases in nucleic acids—two purine bases (adenine and guanine) and three pyrimidine bases (cytosine, thymine, and uracil). Some “modified” versions of these bases, such as 5-fluorouracil, are used in cancer chemotherapy. The natural bases differ from each other in their ring substituents.

Every base has a lowermost nitrogen that is bonded to a hydrogen as well as two carbons. This particular –NH– group shares some chemical similarities with an alcohol (-OH) group. Just like two sugar molecules can be linked when an –OH group of one monosaccharide reacts with a second monosaccharide, a purine or pyrimidine molecule can be bonded to a sugar molecule by a reaction with the –NH– group.

A nucleoside is formed when either a purine or pyrimidine base is linked to a sugar molecule, usually β-D-ribose or β-D-2-deoxyribose. The base and sugar are bonded together between C-1 of the sugar and either the purine nitrogen at position 9 or the pyrimidine nitrogen at position 1 by eliminating a water molecule.

The nomenclature of each nucleoside underlines the importance of the base to the chemistry of the molecule. For example, adenine and β-D-ribose react to yield adenosine whereas cytosine and β-D-2 -deoxyribose yield deoxycytidine.

Nucleotides

Nucleotides are chemically phosphate esters of nucleosides. They consist of a purine or a pyrimidine base linked to a sugar, which itself is bonded to at least one phosphate group. The ester linkage may be formed with the hydroxyl group at position 2, 3, or 5 of ribose or at position 3 or 5 of deoxyribose. The linkage of two or more phosphate residues results in the formation of a high-energy phosphate anhydride bond.

Nucleotides play a crucial role in the transfer of energy during many metabolic processes. Adenosine diphosphate (ADP) and adenosine triphosphate (ATP) are extremely important nucleotides that store and release energy to our body’s cells and tissues. Part of the energy released from the biological oxidation of the food we eat is stored in the phosphate anhydride bonds of ADP and ATP.

Our body releases energy when required by reversibly hydrolysing the high-energy phosphate anhydride bonds in ADP and ATP. During the hydrolysis, there is a yield of about 35 kJ of energy per mole of ATP.  All natural processes such as muscle movement, nerve impulse conduction, vision, and even the maintenance of our heartbeats are dependent on energy obtained from ATP.

Deoxyribonucleic acid (DNA)

DNA is the very molecule that started the dance of life on earth as we know it today. It is a long polymer of deoxyribonucleotides whose length is usually defined as number of nucleotides (or a pair of nucleotides referred to as base pairs) present in it. The haploid content of human DNA is 3.3 × 10⁹ base pairs.

DNA was first discovered by Friedrich Meischer (1869), who named it “nuclein” as he observed that it was an acidic substance present in the nucleus. In 1953, James Watson and Francis Crick, based on the X-ray diffraction data put forth by Maurice Wilkins and Rosalind Franklin, proposed a simple but world famous double helical model for the structure of DNA that subsequently earned them the Nobel Prize.

One of the most important features of their model was the base pairing present between the two strands of polynucleotide chains. This model was also based on the observation of Erwin Chargaff that for a double-stranded DNA molecule, the ratios between adenine and thymine and guanine and cytosine are constant and equals one (known as Chargaff’s rule).

Important features of Watson and Crick’s model of DNA are as follows:

• It is made of two polynucleotide chains whose backbone is composed of sugar and phosphate, and the nitrogenous bases project inside.
• The two chains have anti-parallel polarity, meaning if one chain has the polarity 5'→3', then the other chain has the polarity 3'→5' and vice versa.
• The nitrogenous bases in the two strands are paired via hydrogen bonds (H-bonds) and form base pairs (bp). Adenine forms two hydrogen bonds with thymine from the opposite strand, and vice-versa. Similarly, guanine is bonded with cytosine via three H-bonds. As a result, a purine is always seen opposite to a pyrimidine. This leads to the creation of an approximately uniform distance between the two strands of the helix.
•  The two chains are coiled in a right-handed fashion. The pitch of the helix is 3.4 nm and there are about 10 bp in each turn. Consequently, the distance between a bp in a helix is around 0.34 nm.
• The plane of one base pair stacks over the other in the double helix. Apart from the H-bonds, this feature provides additional stability to the helical structure of DNA.

Packaging of the DNA molecule within the nucleus

The length of a DNA molecule is calculated to be approximately 2.2 metres – a length that is far greater than the dimension of a typical cell nucleus (approximately 10^–6 m). Natually, you might be wondering how such a long polymer has been packaged in such a small space.

The answer, dear reader, is a true miracle of nature. Even in prokaryotes (which lack a well-defined nucleus), the DNA is not scattered throughout the cell. Being negatively charged, the DNA is organised in large loops held by some positively charged proteins in a region known as the nucleoid. 

Eukaryotes have a more complex organisation in the form of a set of positively charged, basic proteins known as histones. These proteins are rich in two basic amino acid residues, lysine and arginine, that carry positive charges in their side chains. They are organised to form a unit of eight molecules known as a histone octamer.

The negatively charged DNA molecule is wrapped around the positively charged histone octamer to form a structure known as the nucleosome. A typical nucleosome contains 200 base pairs of the DNA helix. Nucleosomes constitute the repeating unit of chromatin that we see in the nucleus, which have a characteristic “beads-on-string” appearance when viewed under the electron microscope.

This beads-on-string structure is packaged to form chromatin fibres that are further coiled and condensed at the metaphase stage of cell division to form chromosomes. The packaging of chromatin at higher level requires an additional set of proteins that are collectively referred to as non-histone chromosomal (NHC) proteins.

Different forms of DNA

Scientists have discovered more than a dozen forms of DNA with unique structural features in nature, named after various English alphabets. Some of them are:

• B-DNA – It is the regular DNA molecule with right-handed coiling and 10 base pairs per turn.
• A-DNA – It has 11 base pairs per turn. The base pairs aren’t perpendicular to the axis but are tilted.
• C-DNA – It resembles B-DNA but has 9 base pairs per turn. 
• D-DNA – It is similar to B-DNA but has 8 base pairs per turn.
• Z-DNA – Unlike the other examples above, it demonstrates left-handed coiling.

Ribonucleic acid (RNA)

RNA is usually single-stranded and occasionally double-stranded (like in the rice dwarf virus and reovirus). Scientists have enough evidence to prove that RNA was the first genetic material on earth; essential life processes such as metabolism, translation, and splicing evolved around RNA. It served as a genetic material as well as an enzymatic catalyst in primitive living systems.

However, RNA – being a catalyst – was reactive and thus unstable in nature. As a result, DNA subsequently evolved from RNA with chemical modifications (such as the presence of thymine instead of uracil) and special repair mechanisms that render it more stable and a better choice to serve as the genetic material in living organisms. Today, RNA serves as the genetic material in certain groups of viruses.

There are three types of non-genetic RNA found in living systems:

Messenger RNA (mRNA)

Discovered by Jacob and Monod in 1961, mRNA is produced in the nucleus and harbors the genetic information for protein synthesis.

Ribosomal RNA (rRNA)

It is the largest type of RNA and forms around 80% of the entire cellular RNA. It is found in ribosomes where protein synthesis takes place.

Transfer RNA (tRNA)

Also known as soluble RNA or adaptive RNA, tRNA is the smallest type of RNA and forms around 10-15% of the total cellular RNA. tRNA molecules are found in the cytoplasm and are of as many types as the types of amino acids found in proteins (usually 20). They collect amino acids from the cytoplasm for protein synthesis during the process of translation.