topoisomerase
Summary
Topoisomerases are enzymes that resolve DNA supercoiling and topological problems during replication and transcription by transiently cutting and rejoining DNA strands. Bacterial topoisomerase II (DNA gyrase) is targeted by fluoroquinolones, while human topoisomerase II is targeted by chemotherapeutics like etoposide. Topoisomerase I is targeted by irinotecan/topotecan and is also associated with anti-Scl-70 antibodies in systemic sclerosis.
Detail
Topoisomerases regulate DNA topology (supercoiling) that arises during replication, transcription, and recombination. Type I topoisomerases cut one strand of DNA to relieve supercoiling without requiring ATP, while Type II topoisomerases (including bacterial DNA gyrase) cut both strands, pass another DNA duplex through the break, and reseal it, typically requiring ATP.
Clinical relevance: - Bacterial DNA gyrase (topoisomerase II) and topoisomerase IV are inhibited by fluoroquinolones (e.g., ciprofloxacin, levofloxacin), which are bactericidal and used for UTIs, GI infections, and some respiratory infections. Adverse effects include tendon rupture, QT prolongation, and cartilage damage (avoided in pregnancy/children). - Human topoisomerase II is inhibited by chemotherapeutic agents such as etoposide and teniposide, causing double-strand DNA breaks, leading to apoptosis in rapidly dividing cancer cells. Anthracyclines (e.g., doxorubicin) also inhibit topoisomerase II. - Human topoisomerase I is inhibited by irinotecan and topotecan, used in colorectal and ovarian cancers, respectively, causing single-strand breaks and replication fork collapse. - Anti-topoisomerase I antibody (anti-Scl-70) is a key serologic marker for diffuse systemic sclerosis (scleroderma), associated with pulmonary fibrosis and worse prognosis.
Understanding topoisomerase function is essential for understanding both antimicrobial and antineoplastic drug mechanisms, as well as autoimmune serology in rheumatology.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- Robbins and Cotran Pathologic Basis of Disease
- Lippincott Illustrated Reviews: Pharmacology
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