Key Oncogenic Proteins Are Regulated By Enzyme-Driven Nitration

Background: Nitrase Therapeutics is unlocking the therapeutic potential of nitrases, a new class enzymes discovered by company that catalyze post-translation modification called nitration. Materials And Methods: Nitrases nitration, process which an NO2 group transferred from peroxynitrite to specific tyrosines on substrates (nitro-substrates). Nitration important modifier protein structure, function and localization. We have identified 30 putative nitrases. To identify nitrase activity specificity against nitro-substrates, we established biochemical assays. These assays consist dose response low nanomolar concentrations each incubated with micromolar peroxynitrite, physiological cofactor for 23 000 chip (HuProt). Nitro-substrates present are detected post-nitrase assay using anti-nitrotyrosine antibodies. Results: Using these assays, several nitrases regulate nitro-substrates known relevance tumor cell survival and/or evasion immune system. For example, found #3 catalyzes nitration Pak4. Pak4 implicated in driving oncogenic state as well contributing cells immunological surveillance. Nitrase#3 increases kinase activity. does not nitrate or Pak6, suggesting inhibition could provide niche mechanism selectively inhibit With this, it suggests NItrase through activation both tumor-autonomous immune-oncology mechanisms. Similarly, #12 activates RhoA. #11 Bax reduces its induced pore formation/induction cytochrome C release mitochondria. Inhibition either Nitrase, therefore, be slow progression NItrase#12/RhoA/Rock Nitrase#11/Bax dependent tumors. Conclusions: The inhibitors developing target potentially will help halt numerous diseases play role, including oncology. Conflict interest: Ownership: Irene Griswold-Prenner owns shares Therapeutics. Sami Hussain