Nucleotides and Nucleosides Overview

Nucleotides - Roles

• Building blocks of nucleic acids (DNA, RNA) responsible for storing and transferring genetic information
• Mediators of energy storage and release in metabolic processes (ATP, ADP)
• Signaling molecules: essential chemical links for cell’s response to external stimuli (hormones, temperature, pressure)

Nucleotides - Building Blocks

• Three main structural elements
  • Nitrogen-containing base: purines and pyrimidines
  • Pentose sugar: ribose or deoxyribose
  • Phosphate group

Nucleotides - Bases

• Very stable heterocyclic compounds (aromatic character)
• Flat structures with π electrons
• Exist as tautomers (important for base pairing and chemical reactions)

Nucleosides

• Ribose and ribosides:
  • Ribose sugar is a five-carbon sugar found in RNA.
  • Ribosides are formed by linking a nitrogenous base to ribose.
  • Adenosine is an example of a nucleoside
• 2-deoxyribose and deoxyribosides:
  • Deoxyribose sugar is a five-carbon sugar found in DNA.
  • Deoxyribosides are formed by linking a nitrogenous base to deoxyribose.
  • Deoxyadenosine is an example of a deoxyribonucleoside.

Nucleosides - Conformation

• Sugar puckering: the 5-membered sugar ring can adopt various conformations
  • C2’-endo: favored conformation in A-DNA
  • C3’-endo: favored conformation in B-DNA
  • C2’-exo: favored conformation in Z-DNA
  • C3’-exo: favored conformation in some RNA structures

Nucleotides - Isomers

• Phosphate can be attached to different positions on the sugar
• Cyclic esters are possible (e.g., 3’,5’-cyclic AMP)

Nucleic Acids

• DNA and RNA
• Nucleotides linked via phosphodiester bonds
• Phosphate group is ionized at physiological pH, making nucleic acids polyacids
• Sequence is read from 5’ to 3’

Nucleic Acid Stability

• RNA is easily hydrolyzed by alkali because of its 2’-OH group
• DNA is resistant to alkali hydrolysis because it lacks the 2’-OH group
• RNA is older than DNA, but DNA was selected for genetic information storage due to its stability.

Base Pairing in Nucleic Acids

• DNA is a double helix with two antiparallel chains
• Bases are located inside the helix, and the phosphate backbone is located outside
• Base pairs are formed by hydrogen bonding: 2 for A-T, and 3 for G-C.

DNA Structure

• Discovered by J.D. Watson, F.C. Crick, M. Wilkins, and R. Franklin
• Right-handed double helix
• 10.5 base pairs per turn
• Diameter of 2 nm

DNA Forms

• Different forms of DNA exist depending on sequence and environment:
  • A-DNA: more compact, right-handed, favored in low humidity
  • B-DNA: classic double helix form, right-handed
  • Z-DNA: left-handed, favored in high salt concentrations

DNA Replication

• Process of copying DNA
• Requires enzymes like DNA polymerase and helicase

Unusual DNA Structures

• Palindromic DNA sequences: can form alternative structures with intra-strand base pairing (hairpins)
• Triplex DNA: involves three or even four DNA strands (Hoogsteen pairing)

RNA Structure

• Self-complementary sequences can form complex 3D structures
• Single-stranded molecule
• Exists in various conformations (e.g., tRNA, mRNA)

tRNA

• Adapter molecule in protein synthesis
• Covalently linked to an amino acid at one end
• Recognizes mRNA via its anticodon loop

mRNA

• Carries genetic information from DNA to ribosomes
• Contains recognition elements for ribosome binding and protein synthesis initiation

Unusual Base Pairs in RNA

• Non-Watson-Crick base pairs can form (e.g., G=U)

Nucleic Acid Chemistry

• Reversible denaturation: heat can separate DNA strands
• Renaturation: cooled strands can reassociate
• Hybridization: complementary DNA or RNA strands can pair
• Melting temperature (Tm): temperature at which 50% of DNA is denatured

Non-enzymatic Reactions of Nucleotides

• Spontaneous deamination and hydrolysis can occur:
  • Deamination: cytosine to uracil
  • Hydrolysis: purine bases can be lost
• Repair mechanisms usually handle these changes

Alkylation of DNA

• Methylation of DNA is a natural process used to regulate gene expression
• Excessive methylation can cause mutations and cancer
• Alkylating agents can damage DNA:
  • Methylators: add methyl groups
  • Dialkylating agents: add two reactive arms, leading to cross-linked DNA chains.

Alkylating Agents - Cancer Therapy

• Alkylating agents are toxic but can be used as antineoplastics (anti-cancer drugs)
• Used to damage cancer cell DNA and prevent their replication

Inhibitors of DNA Transcription

• Intercalating agents: insert between base pairs, bending the DNA and preventing transcription (e.g., doxorubicin)

Damage of DNA by UV Radiation

• UV radiation can cause chemical changes in DNA via photochemical reactions
• Responsible for a significant portion of environmentally-induced DNA damage
• Xeroderma pigmentosum: a genetic disorder caused by the lack of a UV-specific endonuclease that repairs thymine dimers.

Other Functions of Nucleotides

• Components of coenzymes (e.g., NAD+, FAD)

• Essential for metabolic reactions (e.g., ATP, GTP)

• Signaling molecules (e.g., cAMP)### Nucleotides: Building Blocks of Life

• Structure: Consist of a nitrogenous base, a five-carbon sugar (pentose), and one to three phosphate groups.

• Nucleosides: Similar to nucleotides but lack the phosphate group.

• Nitrogenous Bases: Adenine (A), guanine (G), cytosine (C), thymine (T) (found in DNA), and uracil (U) (found in RNA).

• DNA: Composed of deoxyribose sugar, A, G, C, and T.

• RNA: Composed of ribose sugar, A, G, C, and U.

• Unusual Nucleosides in DNA/RNA: Present in small amounts and play a role in regulation and structure.

Phosphate Isomers:

• Different positions of phosphate groups in nucleotides affect their function.

Nucleic Acid Structure

• DNA: Double helix, composed of two antiparallel strands held together by hydrogen bonds between complementary bases (A-T, G-C).
• RNA: Primarily single-stranded, may form complex secondary structures, with diverse functions.
• DNA Forms: A, B, and Z DNA. Differ in their helix geometry and structure.

Unusual DNA Structures

• Non-B DNA forms: Can arise due to sequence, environment, or protein binding. Include cruciform, triplex, and quadruplex structures.
• RNA Secondary Structure: Complex folding patterns create functional domains like loops, stems, and bulges.

Messenger RNA (mRNA) Structure

• 5′ cap: Modified guanine nucleotide, protecting from degradation.
• Coding sequence: Contains the genetic information for protein synthesis.
• Poly(A) tail: String of adenine residues, enhancing stability.

DNA Denaturation

• Reversible process where hydrogen bonds between base pairs are broken, disrupting the double helix.
• Melting Temperature (Tm): Temperature at which half the DNA strands are denatured.
• Hybridization: Complementary DNA strands can re-associate after denaturation.

Non-Enzymatic Reactions of Nucleotides

• Hydrolysis: Cleavage of phosphodiester bonds, breaking down nucleic acids.
• Depurination: Loss of purine bases (A and G), leading to DNA damage.
• Deamination: Conversion of cytosine to uracil, can lead to mutations.

UV Radiation Damage to DNA

• Pyrimidine dimers: Abnormal covalent bonds between adjacent thymine or cytosine bases, hindering replication.
• Xeroderma pigmentosum: Genetic disorder causing sensitivity to UV radiation, increasing skin cancer risk.

Additional Functions of Nucleotides

• Signal transduction
• Energy metabolism: ATP (adenosine triphosphate) as the primary energy carrier.
• Coenzyme function: NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) in redox reactions.

Explore the fundamental roles of nucleotides in genetics, energy transfer, and signaling. Learn about the structural components of nucleotides and nucleosides, including their nitrogenous bases and sugar structures. Understand their significance in metabolic processes and cellular responses.