INTERACTIONS OF LACTONE, CARBOXYLATE AND SELF-AGGREGATED FORMS OF CAMPTOTHECIN WITH HUMAN AND BOVINE SERUM ALBUMINS

Pronounced differences in the interactions of monomeric (lactone and c arboxylate) and the J-type self-aggregated form of camptothecin (CPT), an inhibitor of DIVA topoisomerase (topo) I, with human (HSA) and bov ine (BSA) serum albumins were observed by using circular dichroism (CD ) spectroscopy, HSA binding changes the geometry of the covalent struc ture of CPT due to hydrophobic contacts of the chromophore within the protein interior, The carbonyl group of the ring D of CPT (Fig. 1A) in teracts with the positively charged amino acid residues of HSA. Intera ction with HSA induces disaggregation of the J-type self-aggregates of CPT, On the other hand, neither heat-denatured HSA nor native BSA par ticipated in binding of the lactone or carboxylate or self-aggregate f orms of CPT, Analysis of HSA and BSA homology within the TIA and IIIA principle ligand-binding structural domains suggests that the binding site for the CPT chromophore is located in subdomain IIA, Hydrophobic contacts with Leu-203, Phe-211, and Ala-215 and electrostatic interact ions with Lys-199 and/or Arg-222 of HSA may play a key role in formati on of the drug-HSA complex. (C) 1997 Federation of European Biochemica l Societies.