Human Topoisomerase I Inhibitors

Abstract

Topoisomerases are ubiquitous enzymes that solve topological problems due to DNA (deoxyribonucleic acid) supercoiling occurring during the replication, transcription, recombination and chromatin remodelling processes. Human topoisomerase IB (Topo IB) is the selective target of camptothecin, a natural compound from which two powerful anticancer drugs, topotecan and irinotecan, are produced. Camptothecin acts as an interfacial inhibitor interacting with both the enzyme and DNA stabilising the covalent enzyme–DNA complex, and slowing down the religation of the broken DNA strands brings cells to death. Topo IB is also important for transcription of genes involved in neurodevelopment, and its inhibition during critical stages of brain development may be responsible for neurodevelopmental disorders.

Key Concepts

  • Topoisomerases are crucial enzymes essential in the relaxation of supercoiled DNA.
  • Human topoisomerase IB cuts a single DNA strand forming a transient enzyme–DNA cleavage complex.
  • Camptothecin is a natural compound of which human topoisomerase IB is the only cellular target.
  • Camptothecin can trap the enzyme–DNA cleavage complex bringing cells to death.
  • Two camptothecin derivatives have been approved by the US Food and Drug Administration: topotecan for ovarian and lung cancers and irinotecan for colorectal cancer.
  • Camptothecin and its derivatives act as interfacial inhibitors interacting with both the enzyme and the DNA.
  • Single topoisomerase mutation may induce resistance to camptothecin.
  • New non‐camptothecin derivatives are under development.
  • The cytotoxic activity of camptothecin increases in the presence of other compounds inhibiting enzymes involved in DNA repair.
  • Inhibition of topoisomerase IB has also a strong influence on the modulation expression of groups of genes associated with autism.

Keywords: topoisomerase; supercoiled DNA; camptothecin; anticancer drugs; neurodevelopmental disorders

Figure 1. Scheme of the DNA cleavage reaction from topoisomerase IB highlighting the formation of the DNA–enzyme cleavage complex. The detail of the covalent bond between tyrosine 723 and the 3′ end of the strand is also highlighted.
Figure 2. (a) Scheme of the topoisomerase IB sequence representing the domains in different colours (white: N‐terminal; yellow, blue and red: core domain, green: linker domain). The core domain is subdivided into subdomain 1: yellow, subdomain 2: blue and subdomain 3: red. The five residues forming the catalytic pentad are represented by stars with tyrosine 732, undergoing the nucleophilic attack, represented by a black star. (b) 3D structure of topoisomerase in covalent complex with a linear DNA double strand. The colour code is the same as that of the sequence.
Figure 3. Scheme of the catalytic cycle of the Topo I enzyme, showing the different steps required to relax a supercoiled DNA substrate.
Figure 4. Chemical formula of the active and inactive forms of camptothecin (a); of topotecan and SN38 (b) and of some derivatives representing the indenoisoquinolines family (c).
Figure 5. 3D structure of the ternary Topo I–DNA–topotecan complex. In the upper part the stacking of the drug with the DNA bases at the nicked site is highlighted; in the lower part the protein–drug hydrogen bonds are highlighted.
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Further Reading

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Vokálová L, Durdiaková J and Ostatníková D (2015) Topoisomerases interlink genetic network underlying autism. International Journal of Developmental Neuroscience 47: 361–368.

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Desideri, Alessandro(Aug 2016) Human Topoisomerase I Inhibitors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026795]