Isolation and Characterization of a TDP1 Inhibitory Peptide from the Marine Sponge Axinella sp

Authors

• LR Krumpe
• S Sunassee
• A Bermingham
• C Marchand
• KR Gustafson
• Y Pommier
• BR O'Keefe

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme target for the inhibition of topoisomerase I-DNA complex repair and for the repair of blocked 3’-ends resulting from alkylation and oxidative base damage. High-throughput screening of natural product-derived chemical libraries for inhibitors of TDP1 activity resulted in the discovery of a bioactive component from a marine sponge, Axinella sp. Bioassay-guided fractionation of the source extract was utilized to isolate the active component and resulted in the discovery of a peptide that inhibited TDP1 activity in biochemical assays. The primary structure of the peptide was determined using a combination of Edman degradation and tandem mass spectroscopy de novo peptide sequencing. The proposed amino acid sequence of the 4.9 kDa peptide is homologous to a 40 amino acid portion of a bacterially-derived DNA gyrase subunit B.

Scientific Focus Area: Molecular Biology and Biochemistry

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