期刊
BIOTECHNOLOGY LETTERS
卷 40, 期 2, 页码 359-367出版社
SPRINGER
DOI: 10.1007/s10529-017-2472-5
关键词
CB1954; Dinitrotoluene; Gene-directed enzyme-prodrug therapy; Metronidazole; NfsA; Nitroreductase; PnbA
资金
- Lottery Health Research Fund
- Wellington Medical Research Fund [2014/234]
- Royal Society of New Zealand Marsden Fund [VUW1502]
- Victoria University of Wellington PhD Scholarships
- Cancer Society of New Zealand
- Dick and Mary Earle Scholarship in Technology
To characterize the activities of two candidate nitroreductases, Neisseria meningitidis NfsA (NfsA_Nm) and Bartonella henselae (PnbA_Bh), with the nitro-prodrugs, CB1954 and metronidazole, and the environmental pollutants 2,4- and 2,6-dinitrotoluene. NfsA_Nm and PnbA_Bh were evaluated in Escherichia coli over-expression assays and as His(6)-tagged proteins in vitro. With the anti-cancer prodrug CB1954, both enzymes were more effective than the canonical O-2-insensitive nitroreductase E. coli NfsB (NfsB_Ec), NfsA_Nm exhibiting comparable levels of activity to the leading nitroreductase candidate E. coli NfsA (NfsA_Ec). NfsA_Nm is also the first NfsA-family nitroreductase shown to produce a substantial proportion of 4-hydroxylamine end-product. NfsA_Nm and PnbA_Bh were again more efficient than NfsB_Ec at aerobic activation of metronidazole to a cytotoxic form, with NfsA_Nm appearing a promising candidate for improving zebrafish-targeted cell ablation models. NfsA_Nm was also more active than either NfsA_Ec or NfsB_Ec with 2,4- or 2,6-dinitrotoluene substrates, whereas PnbA_Bh was relatively inefficient with either substrate. NfsA_Nm is a promising new nitroreductase candidate for several diverse biotechnological applications.
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