Nucleic Acids

Introduction 

• Nucleic acids are high–molecular-weight biological macromolecules that store, transmit, and express genetic information.

• Chemically, they are polymers of nucleotides joined by 3′–5′ phosphodiester bonds.

• Each nucleotide is composed of a nitrogenous base, pentose sugar, and phosphate group.

• Two major types exist: DNA, the genetic material, and RNA, which mediates gene expression and protein synthesis.

• Nucleic acids follow the central dogma of molecular biology: DNA → RNA → Protein.

• They are essential for cellular function, heredity, and regulation of biological processes.

Historical Background

• 1869 – Friedrich Miescher first isolated nucleic acid (“nuclein”) from pus cells

• 1953 – Watson and Crick proposed the double-helical structure of DNA, establishing the molecular basis of heredity

• Subsequent discoveries established the central dogma of molecular biology

Types of Nucleic Acids

There are two principal types of nucleic acids:

1. Deoxyribonucleic Acid (DNA)

   • Primary genetic material in humans and most organisms

   • Located mainly in the nucleus, also in mitochondria

   • Chemically stable and self-replicating

2. Ribonucleic Acid (RNA)

   • Involved in expression of genetic information

   • Found in nucleus and cytoplasm

   • Chemically less stable, functionally diverse

Chemical Nature

• Nucleic acids are polyanionic molecules due to phosphate groups

• Contain:

  • Nitrogenous bases (purines and pyrimidines)

  • Pentose sugars (ribose or deoxyribose)

  • Phosphate backbone

• Exhibit directionality: 5′ → 3′

Biological Importance

Nucleic acids are essential for:

• Storage of genetic information (DNA)

• Replication and inheritance

• Protein synthesis (via RNA)

• Cell differentiation and development

• Regulation of gene expression

• Evolution and mutation

Nucleotides

Nucleotides are low–molecular-weight organic compounds that serve as the basic structural units (monomers) of nucleic acids. They also perform independent and crucial metabolic functions beyond being building blocks of DNA and RNA.

Components of a Nucleotide

Each nucleotide is composed of three essential components:

A. Nitrogenous Base

• Heterocyclic aromatic compounds containing nitrogen.

• Two classes:

  • Purines (double-ring):

    • Adenine (A), Guanine (G)

  • Pyrimidines (single-ring):

    • Cytosine (C), Thymine (T), Uracil (U)

• DNA bases: A, G, C, T

• RNA bases: A, G, C, U

B. Pentose Sugar

• A 5-carbon monosaccharide

• Types:

  • β-D-2-deoxyribose → DNA

  • β-D-ribose → RNA

• Difference:

  • Ribose has –OH at 2′ carbon

  • Deoxyribose has –H at 2′ carbon

• Sugar carbons are numbered 1′ to 5′

C. Phosphate Group

• Derived from phosphoric acid

• Attached mainly to the 5′ carbon of the sugar

• One, two, or three phosphate groups may be present:

  • Monophosphate (AMP)

  • Diphosphate (ADP)

  • Triphosphate (ATP)

• Responsible for:

  • Negative charge

  • Acidic nature

  • High energy bonds

Nucleoside vs Nucleotide

Biologically Important Functions of Nucleotides

A. Structural Role

• Building blocks of DNA and RNA

B. Energy Currency

• ATP – universal energy carrier
• GTP – protein synthesis and signal transduction

C. Coenzymes

• NAD⁺ / NADP⁺ – oxidation–reduction reactions
• FAD / FMN – electron transport
• Coenzyme A – acyl group transfer

D. Second Messengers

• cAMP – hormone signaling
• cGMP – smooth muscle relaxation

E. Activated Intermediates

• UDP-glucose – glycogen synthesis
• CDP-choline – phospholipid synthesis

Acid–Base Properties

• Nucleotides behave as weak acids
• Phosphate groups ionize at physiological pH
• Contribute to:
  • Buffering capacity
  • Electrostatic interactions

Clinical Significance

• Defects in nucleotide metabolism cause:
  • Gout (purine metabolism disorder)
  • Severe combined immunodeficiency (SCID)
• Targets of many drugs:
  • Anticancer agents
  • Antiviral drugs
  • Immunosuppressants

Structure of DNA

• DNA (Deoxyribonucleic acid) is a double-stranded, helical nucleic acid that serves as the primary genetic material in humans and most organisms.

• It is composed of deoxyribonucleotides linked by 3′–5′ phosphodiester bonds.

Watson–Crick Model (1953)

The accepted structural model of DNA proposed by Watson and Crick is based on X-ray diffraction data.

Structural Features

1. Double-stranded helix

2. Antiparallel strands

   • One strand runs 5′ → 3′

   • The other runs 3′ → 5′

3. Right-handed helix (B-DNA)

4. Sugar–phosphate backbone on the outside

5. Nitrogenous bases on the inside

Base Pairing

• Complementary base pairing occurs via hydrogen bonds:

  • Adenine (A) pairs with Thymine (T) → 2 hydrogen bonds

  • Guanine (G) pairs with Cytosine (C) → 3 hydrogen bonds

• This ensures the specificity and stability of the DNA molecule.

Dimensions of B-DNA

• Diameter: 2 nm

• Distance between base pairs: 0.34 nm

• One complete turn: 3.4 nm

• Approximately 10 base pairs per turn

Major and Minor Grooves

• DNA helix has:

  • Major groove – wide, rich in genetic information

  • Minor groove – narrow

• Important for:

  • Protein binding

  • Transcription factor recognition

Types of DNA

Function of DNA

1. Storage of Genetic Information

• DNA stores hereditary information in the form of genes.

• Information is encoded in the sequence of bases.

2. Self-Replication

• DNA can replicate accurately during cell division.

• Ensures transmission of genetic material to daughter cells.

3. Template for Transcription

• DNA serves as a template for RNA synthesis.

• Leads to formation of:

  • mRNA

  • tRNA

  • rRNA

4. Control of Protein Synthesis

• DNA indirectly controls protein synthesis by:

  • Determining amino acid sequence

  • Regulating gene expression

5. Genetic Stability and Variation

• Maintains genetic continuity

• Mutations introduce genetic diversity

• Basis of evolution and adaptation

6. Clinical and Biomedical Importance

• DNA damage leads to:

  • Cancer

  • Genetic disorders

• Basis of:

  • PCR

  • DNA fingerprinting

  • Gene therapy

  • Recombinant DNA technology

Organisation of DNA

• In eukaryotic cells, DNA is highly organized and compacted to fit within the nucleus.

• Approximately 2 meters of DNA is packed into a nucleus of about 10 µm diameter.

• DNA associates with histone and non-histone proteins to form chromatin.

Chromatin

• Chromatin is a nucleoprotein complex composed of:

  • DNA

  • Histone proteins

  • Non-histone proteins

• Functions:

  • Packaging of DNA

  • Regulation of gene expression

  • Protection of genetic material

Histone Proteins

• Small, basic proteins rich in lysine and arginine

• Types:

  • Core histones: H2A, H2B, H3, H4

  • Linker histone: H1

• A positive charge helps in binding negatively charged DNA

Nucleosome: Fundamental Unit of Chromatin

• DNA is wrapped around a histone octamer:

  • 2 × H2A

  • 2 × H2B

  • 2 × H3

  • 2 × H4

• 147 base pairs of DNA wrap around the histone core

• Linker DNA (20–80 bp) connects adjacent nucleosomes

• Histone H1 stabilizes the nucleosome structure

Levels of DNA Packing

1. DNA double helix (2 nm)

2. Nucleosome fiber (10 nm) – “beads on a string”

3. 30 nm fiber – solenoid or zig-zag model

4. Looped domains attached to scaffold proteins

5. Condensed chromatin

6. Metaphase chromosome

Euchromatin and Heterochromatin

A. Euchromatin

• Lightly stained

• Transcriptionally active

• Gene-rich regions

• Early replicating DNA

B. Heterochromatin

• Darkly stained

• Transcriptionally inactive

• Gene-poor regions

• Late replicating DNA

• Types:

  • Constitutive (centromeres, telomeres)

  • Facultative (inactive X chromosome – Barr body)

Chromosomes

• Highly condensed form of chromatin

• Visible during cell division

• Each chromosome has:

  • Centromere

  • Telomeres

  • p and q arms

Functional Significance of DNA Organisation

• Efficient packaging of DNA

• Protection from physical damage

• Regulation of gene expression

• Facilitates replication and transcription

• Ensures proper chromosome segregation

RNA Structure and Function

• RNA (Ribonucleic acid) is a single-stranded nucleic acid involved primarily in the expression of genetic information.

• It acts as an essential intermediary between DNA and protein synthesis.

• RNA is present in the nucleus, cytoplasm, and ribosomes.

Structure of RNA

1. Basic Components

RNA is a polymer of ribonucleotides, each consisting of:

• Nitrogenous base

• Ribose sugar

• Phosphate group

2. Nitrogenous Bases

• Purines: Adenine (A), Guanine (G)

• Pyrimidines: Cytosine (C), Uracil (U)

• Thymine is absent in RNA and replaced by uracil

3. Sugar

• Contains β-D-ribose

• Has a –OH group at the 2′ carbon, making RNA:

  • Less stable than DNA

  • More reactive chemically

4. Structural Features

• Usually single-stranded

• Exhibits secondary and tertiary structures due to:

  • Intra-strand base pairing

• Has 5′ → 3′ polarity

• Sugar-phosphate backbone with 3′–5′ phosphodiester bonds

Types of RNA and  Their Functions

1. Messenger RNA (mRNA)

• Carries genetic information from DNA to ribosomes

• Contains codons (triplet nucleotide sequences)

• Short-lived molecule

• Template for protein synthesis

 Function: Determines amino acid sequence of proteins

2. Transfer RNA (tRNA)

• Smallest RNA molecule

• Clover-leaf structure

• Key structural parts:

  • Amino acid acceptor arm

  • Anticodon loop

  • D-loop and TΨC loop

• Each tRNA is specific for one amino acid

 Function: Transfers specific amino acids to ribosomes during translation

3. Ribosomal RNA (rRNA)

• Most abundant RNA (~80%)

• Combines with proteins to form ribosomes

• Provides:

  • Structural framework

  • Catalytic activity (peptidyl transferase)

 Function: Site of protein synthesis

Other functions of RNAs 

Functions of RNA 

1. Expression of genetic information

2. Protein synthesis

3. Gene regulation

4. Catalytic activity (ribozymes)

5. Development and differentiation

6. Defense mechanisms (RNA interference)

Comparisons: DNA vs RNA