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A possible mechanism for redox control of human neuroglobin activity.

ABSTRACT: Neuroglobin (Ngb) promotes neuron survival under hypoxic/ischemic conditions. In vivo and in vitro assays provide evidence for redox-regulated functioning of Ngb. On the basis of X-ray crystal structures and our MD simulations, a mechanism for redox control of human Ngb (hNgb) activity via the influence of the CD loop on the active site is proposed. We provide evidence that the CD loop undergoes a strand-to-helix transition when the external environment becomes sufficiently oxidizing, and that this CD loop conformational transition causes critical restructuring of the active site. We postulate that the strand-to-helix mechanics of the CD loop allows hNgb to utilize the lability of Cys46/Cys55 disulfide bonding and of the Tyr44/His64/heme propionate interaction network for redox-controlled functioning of hNgb.

SUBMITTER: Morozov AN

PROVIDER: S-EPMC4114473 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A possible mechanism for redox control of human neuroglobin activity.

Morozov Alexander N AN Roach James P JP Kotzer Margarita M Chatfield David C DC

Journal of chemical information and modeling 20140619 7

Neuroglobin (Ngb) promotes neuron survival under hypoxic/ischemic conditions. In vivo and in vitro assays provide evidence for redox-regulated functioning of Ngb. On the basis of X-ray crystal structures and our MD simulations, a mechanism for redox control of human Ngb (hNgb) activity via the influence of the CD loop on the active site is proposed. We provide evidence that the CD loop undergoes a strand-to-helix transition when the external environment becomes sufficiently oxidizing, and that t ...[more]

PMID: 24855999

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Project description:RRx-001 (also known as ABDNAZ, 1-bromoacetyl-3,3-dinitroazetidine) is a novel aerospace-derived compound currently under investigation in several ongoing Phase II studies. In a Phase I trial, it demonstrated anti-cancer activity and evidence of resensitization to formerly effective therapies in heavily pre-treated patients with relapsed/refractory solid tumors. With a pharmacologically unprecedented dinitroazetidine scaffold, RRx-001 generates reactive oxygen and nitrogen species (ROS and RNS) and nitric oxide (NO), elicits changes in intracellular redox status, modulates tumor blood flow, hypoxia and vascular function and triggers apoptosis in cancer cells. Here, the effect of RRx-001 on the epigenome of SCC VII cancer cells was investigated. RRx-001 at 0.5 and 2 μM significantly decreased global DNA methylation, i.e., 5-methylcytosine levels, in SCC VII cells determined by analysis with an enzyme-linked immunosorbent assay (ELISA). Consistently, 0.5-5 μM RRx-001 significantly decreased Dnmt1 and Dnmt3a protein expression determined using Western blot in a dose- and time-dependent manner. In addition, global methylation profiling identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM RRx-001 compared to control cells. Twenty-three target sites were hypomethylated and 22 hypermethylated by >10% in the presence of at least two different concentrations of RRx-001. Moreover, RRx-001 at 2 μM significantly increased global acetylated histone H3 and H4 levels in SCC VII cells after 24 hour treatment determined by a fluorometric assay, suggesting that RRx-001 regulates global acetylation in cancer cells. These results demonstrate that, in contrast to the traditional “one drug one target” paradigm, RRx-001 has multi(epi)target features, which contribute to its anti-cancer activity and may rationalize the resensitization to previously effective therapies observed in clinical trials and serve as a unifying mechanism for its anticancer activity.

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A possible mechanism for redox control of human neuroglobin activity.

Publications

A possible mechanism for redox control of human neuroglobin activity.

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