Formation of compound I in heme bound Aβ-peptides relevant to Alzheimer's disease

Pal, Ishita; Nath, Arnab; Roy, Madhuparna; Seal, Manas; Ghosh, Chandradeep; Dey, Abhishek; Dey, Somdatta Ghosh

doi:10.1039/c9sc01679a

Cited by 14 publications

(44 citation statements)

References 59 publications

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“…Briefly, there is an initial activation of H 2 O 2 with attendant formation of a high valent P •+ Fe IV =O species (Compound I), where P •+ indicates the porphyrin π-radical cation (Equation (1)). The involvement of compound I-like oxidant for heme-Aβ peptides complexes has been recently characterized [46]. The formation of this active species is followed by two one-electron oxidations of two substrate molecules (SH) (Equations (2) and ( 3)).…”

Section: Resultsmentioning

confidence: 99%

Condition-Dependent Coordination and Peroxidase Activity of Hemin-Aβ Complexes

et al. 2020

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The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aβ40 constructs. This influence on peroxidase activity was also demonstrated using 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aβ16 and Aβ40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aβ40-hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aβ16 and Aβ40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aβ on neurological disease progression.

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Section: Resultsmentioning

confidence: 99%

Condition-Dependent Coordination and Peroxidase Activity of Hemin-Aβ Complexes

et al. 2020

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“…The compound I species, formally described as an Fe IV O π cation radical, is one of the high valent intermediates formed during the peroxidase catalytic cycle. , It has recently been identified as the active oxidant in the peroxidase pathway of heme-Aβ . Use of meta -chloro perbenzoic acid (m-CPBA) in place of H 2 O 2 results in accumulation of enough amount of this transient species to allow its isolation and characterization using absorption (stopped-flow instrument for rapid kinetics monitoring), rR, and liquid He temperature EPR spectroscopies.…”

Section: Alzheimer’s Disease (Ad)mentioning

confidence: 99%

Second Sphere Interactions in Amyloidogenic Diseases

et al. 2022

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Amyloids are protein aggregates bearing a highly ordered cross β structural motif, which may be functional but are mostly pathogenic. Their formation, deposition in tissues and consequent organ dysfunction is the central event in amyloidogenic diseases. Such protein aggregation may be brought about by conformational changes, and much attention has been directed toward factors like metal binding, post-translational modifications, mutations of protein etc., which eventually affect the reactivity and cytotoxicity of the associated proteins. Over the past decade, a global effort from different groups working on these misfolded/unfolded proteins/peptides has revealed that the amino acid residues in the second coordination sphere of the active sites of amyloidogenic proteins/peptides cause changes in H-bonding pattern or protein–protein interactions, which dramatically alter the structure and reactivity of these proteins/peptides. These second sphere effects not only determine the binding of transition metals and cofactors, which define the pathology of some of these diseases, but also change the mechanism of redox reactions catalyzed by these proteins/peptides and form the basis of oxidative damage associated with these amyloidogenic diseases. The present review seeks to discuss such second sphere modifications and their ramifications in the etiopathology of some representative amyloidogenic diseases like Alzheimer’s disease (AD), type 2 diabetes mellitus (T2Dm), Parkinson’s disease (PD), Huntington’s disease (HD), and prion diseases.

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“…Previous reports from our group have shown that the Arg5 residue of the Aβ peptide serves as a source of protons due to the presence of the guanidinium group. [36][37][38] A site directed mutagenesis…”

Section: Dalton Transactions Frontiermentioning

confidence: 99%

“…Previous reports from our group have shown that the Arg5 residue of the Aβ peptide serves as a source of protons due to the presence of the guanidinium group. 36–38 A site directed mutagenesis study involving Arg5Asn revealed that in the absence of the Arg5 residue the rate of nitrite reduction by heme(III)–Cu( i )–Aβ undergoes an ∼2.5 times decrease (Fig. 10B).…”

Section: Reactivity Of Heme–cu–aβmentioning

confidence: 99%

“…36 Recent results show that compound I of heme-Aβ is the active oxidant responsible for its peroxidase activity and in fact, this compound I species of heme-Aβ is responsible for oxidizing neurotransmitters like serotonin in the presence of peroxides. [37][38][39] Furthermore, heme bound Aβ complexes are capable of generating significant amounts of PROS, thus rendering this complex a potential source of oxidative stress in AD brains. 25 Thus heme-Aβ is potentially capable of causing deleterious effects in AD patients (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

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