@entity69888 (CL), a @entity5730 natural product, alkylates DNA through its @entity4299 moiety and exhibits both anticancer and antibacterial activities. We have examined CL action in the presence of topoisomerase IV from @entity328 . CL promoted irreversible enzyme-mediated DNA cleavage leading to single- and double-stranded DNA breaks at specific sites. Reaction required the @entity5730 function: no cleavage was seen using a @entity12683 -substituted analogue. Moreover, drug-induced DNA breakage was not observed using a mutant topoisomerase IV (ParC @entity69889 ) unable to form a cleavage complex with DNA. Sequence analysis of 102 single-stranded DNA breaks and 79 double-stranded breaks revealed an overwhelming preference for G at the -1 position, i.e. immediately 5' of the enzyme DNA scission site. This specificity contrasts with that of topoisomerase IV cleavage with antibacterial quinolones. Indeed, CL stimulated DNA breakage by a @entity1536 -resistant topoisomerase IV (ParC @entity65136 ). Overall, the results indicate that topoisomerase IV facilitates selective irreversible CL attack at @entity2774 and that its cleavage complex differs markedly from that of @entity1 topoisomerase II which promotes both irreversible and reversible CL attack at @entity2774 and @entity5538 , respectively. The unique ability to form exclusively irreversible DNA breaks suggests topoisomerase IV may be a key intracellular target of CL in bacteria.

Clerocidin interacts with the cleavage complex of XXXX topoisomerase IV to induce selective irreversible DNA damage.

@entity1 :: ('9606', 'Species') :: ['mammalian'] @entity69889 :: ('p|SUB|Y|118|F', 'ProteinMutation') :: ['Y118F'] @entity4299 :: ('CHEBI:32955', 'Chemical') :: ['epoxide'] @entity5730 :: ('CHEBI:23849', 'Chemical') :: ['diterpenoid'] @entity2774 :: ('MESH:D006147', 'Chemical') :: ['guanine'] @entity65136 :: ('p|SUB|S|79|F', 'ProteinMutation') :: ['S79F'] @entity12683 :: ('MESH:C031721', 'Chemical') :: ['naphthalene'] @entity5538 :: ('MESH:D003596', 'Chemical') :: ['cytosine'] @entity69888 :: ('MESH:C039027', 'Chemical') :: ['Clerocidin'] @entity328 :: ('1313', 'Species') :: ['Streptococcus pneumoniae'] @entity1536 :: ('CHEBI:23765', 'Chemical') :: ['quinolone']
@entity328 :: (1313,Species) :: ['Streptococcus pneumoniae']
