DNA topoisomerase 1 (LdTopI) (LdTopI)

Leishmania donovani type I DNA topoisomerase (LdTopI) is an essential enzyme that regulates DNA supercoiling during replication, transcription, and recombination by inducing transient single-strand breaks (Bose Dasgupta et al., 2008, J. Biol. Chem.). A defining feature of this enzyme in Leishmania and related trypanosomatids is its unique heterodimeric structure, composed of a large subunit (LdTopIA) and a small subunit (LdTopIB), which contrasts with the monomeric Type IB topoisomerases found in humans (Das et al., 2004, Mol. Biochem. Parasitol.). This structural distinction provides a significant opportunity for selective drug targeting to treat visceral leishmaniasis, a potentially fatal parasitic infection (Majumder et al., 2005, Biochem. J.). Inhibitors such as camptothecin and certain flavonoids act as topoisomerase poisons by stabilizing the covalent DNA-enzyme cleavage complex, leading to irreversible DNA damage and parasite apoptosis (Chowdhury et al., 2002, Biochem. J.). Research continues to focus on exploiting the heterodimer interface and the unique C-terminal domain of the small subunit to develop more effective and less toxic therapeutic agents (Bose Dasgupta et al., 2008, J. Biol. Chem.).

Other names

DNA topoisomerase IBType IB DNA topoisomeraseLdTopIA/LdTopIB heterodimerDNA topoisomerase 1

The mechanism involves the inhibition of the enzyme's ability to relax supercoiled DNA. Drugs can act as topoisomerase poisons by stabilizing the transient covalent complex between the enzyme and DNA (the cleavable complex), preventing DNA re-ligation and causing lethal strand breaks during replication (Chowdhury et al., 2002, Biochem. J.). Alternatively, catalytic inhibitors may block the initial binding of the enzyme to DNA or the cleavage step itself (Majumder et al., 2005, Biochem. J.).