3 research outputs found
Biochemical Characterization of ArsI: A Novel C–As Lyase for Degradation of Environmental Organoarsenicals
Organoarsenicals such as the methylarsenical
methylarsenate (MAsÂ(V))
and aromatic arsenicals including roxarsone (4-hydroxy-3-nitrobenzenearsenate
or RoxÂ(V)) have been extensively used as an herbicide and growth enhancers
in animal husbandry, respectively. They undergo environmental degradation
to more toxic inorganic arsenite (AsÂ(III)) that contaminates crops
and drinking water. We previously identified a bacterial gene (<i>arsI</i>) responsible for aerobic demethylation of methylarsenite
(MAsÂ(III)). The gene product, ArsI, is an FeÂ(II)-dependent extradiol
dioxygenase that cleaves the carbon–arsenic (C–As) bond
in MAsÂ(III) and in trivalent aromatic arsenicals. The objective of
this study was to elucidate the ArsI mechanism. Using isothermal titration
calorimetry, we determined the dissociation constants and ligand-to-protein
stoichiometry of ArsI for FeÂ(II), MAsÂ(III), and aromatic phenylarsenite.
Using a combination of methods including chemical modification, site-directed
mutagenesis, and fluorescent spectroscopy, we demonstrated that amino
acid residues predicted to participate in FeÂ(II)-binding (His5–His62–Glu115)
and substrate binding (Cys96–Cys97) are involved in catalysis.
Finally, the products of RoxÂ(III) degradation were identified as AsÂ(III)
and 2-nitrohydroquinone, demonstrating that ArsI is a dioxygenase
that incorporates one oxygen atom from dioxygen into the carbon and
the other to the arsenic to catalyze cleavage of the C–As bond.
These results augment our understanding of the mechanism of this novel
C–As lyase
A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson’s Disease
Parkinson’s
disease (PD) is a progressive neurodegenerative
disorder, and development of disease-modifying treatment is still
an unmet medical need. Considering the implication of free ironÂ(II)
in PD, we report here the design and characterization of a novel hybrid
iron chelator, (−)-<b>12</b> (D-607) as a multitarget-directed
ligand against PD. Binding and functional assays at dopamine D<sub>2</sub>/D<sub>3</sub> receptors indicate potent agonist activity
of (−)-<b>12</b>. The molecule displayed an efficient
preferential ironÂ(II) chelation properties along with potent in vivo
activity in a reserpinized PD animal model. The compound also rescued
PC12 cells from toxicity induced by iron delivered intracellularly
in a dose-dependent manner. However, Fe<sup>3+</sup> selective dopamine
agonist 1 and a well-known antiparkinsonian drug pramipexole produced
little to no neuroprotection effect under the same experimental condition.
These observations strongly suggest that (−)-<b>12</b> should be a promising multifunctional lead molecule for a viable
symptomatic and disease modifying therapy of PD
A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson’s Disease
Parkinson’s
disease (PD) is a progressive neurodegenerative
disorder, and development of disease-modifying treatment is still
an unmet medical need. Considering the implication of free ironÂ(II)
in PD, we report here the design and characterization of a novel hybrid
iron chelator, (−)-<b>12</b> (D-607) as a multitarget-directed
ligand against PD. Binding and functional assays at dopamine D<sub>2</sub>/D<sub>3</sub> receptors indicate potent agonist activity
of (−)-<b>12</b>. The molecule displayed an efficient
preferential ironÂ(II) chelation properties along with potent in vivo
activity in a reserpinized PD animal model. The compound also rescued
PC12 cells from toxicity induced by iron delivered intracellularly
in a dose-dependent manner. However, Fe<sup>3+</sup> selective dopamine
agonist 1 and a well-known antiparkinsonian drug pramipexole produced
little to no neuroprotection effect under the same experimental condition.
These observations strongly suggest that (−)-<b>12</b> should be a promising multifunctional lead molecule for a viable
symptomatic and disease modifying therapy of PD