Warfarin modulates the nitrite reductase activity of ferrous human serum heme-albumin

Human serum heme-albumin (HSA-heme-Fe) displays reactivity and spectroscopic properties similar to those of heme proteins. Here, the nitrite reductase activity of ferrous HSA-heme-Fe [HSA-heme-Fe(II)] is reported. The value of the second-order rate constant for the reduction of NO- 2 to NO and the concomitant formation of nitrosylated HSA-heme-Fe(II) (i.e., kon) is 1.3 M-1 s-1 at pH 7.4 and 20 \ub0C. Values of kon increase by about one order of magnitude for each pH unit decrease between pH 6.5 to 8.2, indicating that the reaction requires one proton. Warfarin inhibits the HSA-heme-Fe(II) reductase activity, highlighting the allosteric linkage between the heme binding site [also named the fatty acid (FA) binding site 1; FA1] and the drug-binding cleft FA2. The dissociation equilibrium constant for warfarin binding to HSA-heme-Fe(II) is (3.1 \ub1 0.4) 7 10-4 M at pH 7.4 and 20 \ub0C. These results: (1) represent the first evidence for the NO- 2 reductase activity of HSA-heme-Fe(II), (2) highlight the role of drugs (e.g., warfarin) in modulating HSA(-heme-Fe) functions, and (3) strongly support the view that HSA acts not only as a heme carrier but also displays transient heme-based reactivity

The rate of stellar tidal disruption flares from SDSS data

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Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β-Amyloid Toxicity

Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an “open gate” mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α-ring surfaces and influencing gating dynamics. Docking studies coupled with STD-NMR experiments showed that H-bonds and π-π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α-ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH-SY5Y cells from β-amyloid (Aβ) toxicity. ESI-MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dose-dependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment