title: Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships.
abstract: Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain.
authors: †Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Noemi
authors: N
authors: Kedei
authors: ‡Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
authors: Matthew B
authors: MB
authors: Kraft
authors: ‡Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
authors: Gary E
authors: GE
authors: Keck
authors: §Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors: Cherry L
authors: CL
authors: Herald
authors: §Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors: Noeleen
authors: N
authors: Melody
authors: §Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors: George R
authors: GR
authors: Pettit
authors: †Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, United States.
authors: Peter M
authors: PM
authors: Blumberg
mesh_terms: D000818:Animals; D054713:Bryostatins / Q000737:chemistry*; D002013:Bryozoa / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010703:Phorbol Esters; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism
chemical_list: D054713:Bryostatins; D010703:Phorbol Esters; C000600477:neristatin 1; C046785:bryostatin 1; D011493:Protein Kinase C