Nucleic Acids: Structure, Synthesis, Replication, and Expression

Specific Objectives

This section outlines the foundational learning goals for understanding nucleic acids, including their structure, synthesis, and the molecular mechanisms of genetic information flow.

Nucleotides: General Structure

Definition and Components

Nucleotides are the basic building blocks of nucleic acids (DNA and RNA). Each nucleotide consists of three components:

• A nitrogenous base (purine or pyrimidine)

• A five-carbon sugar (ribose in RNA, deoxyribose in DNA)

• One or more phosphate groups

Nucleotides are essential for storing and transferring genetic information and serve as energy carriers (e.g., ATP).

Purines Versus Pyrimidines

Classification of Nitrogenous Bases

Nitrogenous bases are classified into two groups:

• Purines: Adenine (A) and Guanine (G); double-ring structure

• Pyrimidines: Cytosine (C), Thymine (T, in DNA), and Uracil (U, in RNA); single-ring structure

Type	Examples	Structure
Purines	Adenine, Guanine	Double-ring
Pyrimidines	Cytosine, Thymine, Uracil	Single-ring

Nucleotide Synthesis

Pathways of Synthesis

Nucleotides are synthesized by two main pathways:

• De novo synthesis: Building nucleotides from basic precursors (amino acids, CO2, etc.)

• Salvage pathway: Recycling free bases and nucleosides from nucleic acid breakdown

The salvage pathway is especially important in adults for purine synthesis.

Purine Salvage Pathway

Mechanism and Importance

The purine salvage pathway recycles purine bases (adenine, guanine, hypoxanthine) to form nucleotides, conserving energy and resources. The key enzyme is hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

Deficiency of Purine Salvage Pathway

Clinical Correlates

Deficiency in the purine salvage pathway, particularly HGPRT, leads to disorders such as Lesch-Nyhan syndrome and gout:

• Lesch-Nyhan syndrome: X-linked disorder with neurological dysfunction and self-mutilation due to HGPRT deficiency.

• Gout: Accumulation of uric acid crystals in joints, causing inflammation and pain (hyperuricemia).

DNA Structure

Double Helix and Base Pairing

DNA is a double-stranded helix with antiparallel strands (one runs 5' to 3', the other 3' to 5'). The backbone is composed of alternating sugar and phosphate groups, while the interior "rungs" are nitrogenous base pairs:

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

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

This complementary base pairing ensures accurate replication and information transfer.

DNA Replication

Mechanism and Enzymes

DNA replication is a semiconservative process, meaning each new DNA molecule contains one parental and one newly synthesized strand. Key steps include:

• Initiation: Helicase unwinds the DNA helix, creating a replication fork.

• Stabilization: Single-strand binding proteins prevent re-annealing.

• Relief of Tension: Topoisomerase prevents supercoiling ahead of the fork.

• Primer Synthesis: Primase synthesizes short RNA primers.

• Elongation: DNA polymerase III adds nucleotides in the 5' to 3' direction.

• Lagging Strand Synthesis: Okazaki fragments are synthesized discontinuously.

• Primer Removal and Ligation: DNA polymerase I replaces RNA primers with DNA; ligase seals nicks.

Ribonucleic Acid (RNA)

Structure and Types

RNA is typically single-stranded and contains ribose sugar and uracil (U) instead of thymine (T). Major types include:

• mRNA (messenger RNA): Encodes protein sequences

• tRNA (transfer RNA): Brings amino acids to ribosomes during translation

• rRNA (ribosomal RNA): Structural and catalytic component of ribosomes

Central Dogma of Molecular Biology

Flow of Genetic Information

The central dogma describes the flow of genetic information:

• DNA → RNA (transcription)

• RNA → Protein (translation)

Transcription

Process and Regulation

Transcription is the synthesis of RNA from a DNA template. Key steps include:

• Initiation: RNA polymerase binds to the promoter region, unwinds DNA, and begins RNA synthesis.

• Elongation: RNA polymerase adds ribonucleotides complementary to the DNA template (A pairs with U in RNA).

• Termination: RNA polymerase stops at a termination signal, releasing the RNA transcript.

After transcription, mRNA undergoes maturation (splicing, capping, polyadenylation) before translation.

Genetic Code

Codons and Properties

The genetic code is read in triplets (codons) on mRNA, each specifying an amino acid or a stop signal. Key features:

• Unambiguous: Each codon specifies only one amino acid

• Degenerate: Multiple codons can code for the same amino acid

• Universal: Nearly all organisms use the same code

Codon	Function
AUG	Start codon (Methionine)
UAA, UAG, UGA	Stop codons

Translation

Protein Synthesis

Translation is the process by which ribosomes synthesize proteins using mRNA as a template. Steps include:

• Initiation: mRNA binds to the ribosome; the start codon is recognized.

• Elongation: tRNAs bring amino acids to the ribosome, matching codons via their anticodons; peptide bonds form between amino acids.

• Termination: When a stop codon is reached, the polypeptide is released.

Post-translational modifications (e.g., trimming, phosphorylation, glycosylation) may occur.

Clinical Correlates

Inhibitors of Nucleic Acid and Protein Synthesis

Certain antibiotics target bacterial transcription and translation:

• Rifampin, Actinomycin: Inhibit RNA synthesis

• Streptomycin, Tetracycline, Chloramphenicol, Erythromycin: Inhibit protein synthesis

These agents are important in clinical medicine for treating bacterial infections.