Inhibitors of template biosynthesis

Mechanisms of Biosynthesis Suppression

Inhibitors halt matrix processes in three main ways:

1. Structurally modify the matrix itself (DNA or RNA) and ribosomes.
2. Inactivate key enzymes.
3. Reduce the production of starting substrates (nucleoside triphosphates).

Any of these pathways is fatal: stopping macromolecule synthesis deprives the cell of the ability to grow and divide. Despite their high toxicity, many of these substances have found application in medicine as drugs.

Antibacterial drugs (Antibiotics)

Antibiotics possess high selectivity. Due to differences in the structure of enzymes and ribosomes between eukaryotes and prokaryotes, they target bacteria without affecting mammalian cells.

• Rifampicin (Rifampicin) binds to the $\beta$-subunit of bacterial DNA-dependent RNA polymerase. It blocks transcription initiation, depriving the bacterium of all types of RNA (mRNA, tRNA, rRNA).
• Chloramphenicol (Chloramphenicol) and erythromycin attack the 50S subunit of the bacterial ribosome. The former inhibits peptidyl transferase, preventing peptide bond formation, while the latter prevents translocation.
• Tetracycline binds to the 30S subunit, blocking the access of aminoacyl-tRNA to the A-site.
• Fluoroquinolones specifically suppress bacterial DNA synthesis.

Antineoplastic agents

Unlike antibiotics, drugs for treating malignant neoplasms have low selectivity. The therapeutic effect is achieved because tumor cells synthesize DNA and RNA faster, and their membranes are more permeable. However, these drugs also destroy healthy rapidly dividing cells, which explains their toxicity (blood stem cells, GI mucosa, and hair follicles suffer).

• Intercalators (doxorubicin, daunomycin) have a cyclic structure and intercalate between complementary base pairs (G:::C) of DNA, disrupting its template function. Doxorubicin additionally generates reactive oxygen species and causes macromolecule breaks.
• Camptothecin (Camptothecin) forms a complex with DNA topoisomerase I. The enzyme is stabilized on the DNA, breaks are not ligated, and replication stops.
• Melphalan alkylates the DNA molecule, while bleomycin causes chromosomal breaks and fragmentation.
• Vinblastine prevents mitosis by arresting cells in the G2 phase.

Bacterial toxins and natural poisons

Some inhibitors are lethal to humans because they specifically shut down eukaryotic processes.

• $\alpha$-Amanitin (the poison of the death cap mushroom — Amanita phalloides) selectively blocks RNA polymerase II, completely halting messenger RNA synthesis in eukaryotes.
• Diphtheria toxin (produced by Corynebacterium diphtheriae) acts as an enzyme after activation in the body. It catalyzes ADP-ribosylation: it transfers an ADP-ribose moiety from $NAD^+$ to elongation factor EF2. Inactivation of this factor brings the ribosome to a dead stop at the translocation stage — the growing peptide chain gets stuck in the A-site, and protein synthesis in the pharyngeal mucosa cells ceases.

Viruses and the interferon system

Upon infection with viruses (smallpox, influenza, poliomyelitis), the host cell ceases synthesis of its own nucleic acids and switches all resources to assembling viral particles.

In response, eukaryotic cells secrete interferons. These proteins trigger a mechanism to halt protein synthesis in order to prevent viral replication:

1. A protein kinase is induced in the infected cell, which phosphorylates the translation initiation factor IF2.
2. Additionally, the activity of ribonucleases increases, which cleave messenger and ribosomal RNAs.

As a result, the operation of the protein-synthesizing apparatus is completely blocked, and the infected cell dies, halting the spread of the infection.

Class and exam questions

What else to study on this topic

• Mechanism of reactive oxygen species generation by doxorubicin
• DNA alkylation by melphalan and fragmentation by bleomycin
• Cell cycle arrest in the G2 phase by vinblastine
• The role of fluoroquinolones in inhibiting bacterial DNA synthesis
• Prospects for developing targeted delivery of antitumor antibiotics

Other topics in the section "Template Biosyntheses"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.