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Interaction of the cyanobacterial thiazoline‐containing lipid curacin A with bovine brain tubulin
Author(s) -
Ludueña Richard F.,
Prasad Veena,
Roach Mary C.,
Banerjee Mohua,
Yoo HyeDong,
Gerwick William H.
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199703)40:3<223::aid-ddr2>3.0.co;2-m
Subject(s) - podophyllotoxin , colchicine , tubulin , iodoacetamide , chemistry , microtubule , stereochemistry , binding site , biochemistry , biology , microbiology and biotechnology , enzyme , cysteine , genetics
Curacin A is a thiazoline‐containing lipid from the marine cyanobacterium Lyngbya majuscula. Despite being a potent inhibitor of microtubule assembly and of colchicine binding to tubulin, curacin A bears little or no structural resemblance to colchicine or to any other tubulin ligand. We investigated the interaction of curacin A with bovine brain tubulin using three different approaches. We first examined its effect on the intra‐chain formation of a cross‐link in β‐tubulin by N,N′‐ ethylenebis(iodoacetamide). Formation of this cross‐link, between cys 239 and cys 354 , is blocked by colchicine and its A‐ring analogues as well as by various other inhibitors of colchicine binding; C‐ring analogues do not inhibit its formation. Curacin A strongly inhibited formation of this cross‐link. Second, we examined the effect of curacin A on the time‐dependent exposure of sulfhydryl groups on tubulin as measured by alkylation with iodo[ 14 C]acetamide. Curacin A inhibited this very strongly, more so than either colchicine or podophyllotoxin. Last, we investigated the effect of curacin A on the time‐dependent exposure of hydrophobic areas on the tubulin molecule. We found that curacin A had only a small effect on this process, comparable in magnitude to that of podophyllotoxin. Curacin A thus appears to have an unusual interaction with tubulin. Its binding site on tubulin is likely to overlap with that of the A‐ring of colchicine. Drug Dev. Res. 40:223–229, 1997. © 1997 Wiley‐Liss, Inc.