A new human peptide deformylase inhibitable by actinonin.
Peptide deformylases (PDFs) have been investigated as potential specific targets for antibiotics, but the possible existence of a functional human PDF (HsPDF) presents a potential hurdle to the design of specific drugs. We have expression cloned a HsPDF that has deformylase activity, although it is a slower and catalytically less active enzyme than bacterial or plant PDFs. A cobalt-substituted form of HsPDF (but not nickel or zinc) is active, and the enzyme appears to be active at a pH between 6.0 and 7.2, a temperature range of 25-50 degrees C, and in a low KCl ionic strength buffer. Actinonin inhibits HsPDF activity with an IC50 of 43 nM and kills Daudi and HL60 human cancer cell lines with an LC50 of 5.3 and 8.8 microM, respectively. The inhibition of HsPDF may provide an explanation for the mechanism by which actinonin is cytotoxic against various human tumor cell lines.
Lee
Mona D
MD
Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Antczak
Christophe
C
Li
Yueming
Y
Sirotnak
Francis M
FM
Bornmann
William G
WG
Scheinberg
David A
DA
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D004795:Enzyme Stability; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000737:chemistry*; D007700:Kinetics; D008670:Metals; D013379:Substrate Specificity; D013696:Temperature
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008670:Metals; D000581:Amidohydrolases; C084507:peptide deformylase; C010531:actinonin