title: Possible peroxidase active site environment in amyloidogenic proteins: Native monomer or misfolded-oligomer; which one is susceptible to the enzymatic activity, with contribution of heme?
abstract: Amyloid states of many proteins complex with heme and exhibit significant non-specific peroxidase activity, compared to free heme. Neurotransmitter deficiency, generation of neurotoxins, altered activity/metabolism of key enzymes and cellular DNA damage are possible evidences highlighting the importance of the uncontrollable peroxidase activity in Alzheimer's disease (AD)-involved brain cells. Despite extensive experimental work was carried out on this field, discrepancy on chronological precedence of amyloid aggregation and oxidative reactions as well as the mechanism involved in the peroxidase-induced oxidative stress is still not completely understood. In this study, we highlight further that heme cofactor readily complexes with structural intermediates of amyloid aggregates of ovalbumin, lactoglobulin and crystallin and report the ability of "heme-amyloid aggregate/oligomer") to produce peroxidase-like active site. Histidine side chains are also proposed as both distal and proximal residues required for proper function of these peroxidase systems. Taking uncontrollable peroxidase activity of "Aβ-heme" complex into account, it appears that this process, as a new opened dimension in AD pathologic research, provides structural/mechanistic basis for more efficient therapeutic strategies against neurodegenerative diseases.
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran. Electronic address: rkhodarahmi@mbrc.ac.ir.
authors.forename: Reza
authors.initials: R
authors.lastname: Khodarahmi
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ashrafi-Kooshk
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Sina
authors.initials: S
authors.lastname: Khodarahmi
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Students' Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Seyyed Abolghasem
authors.initials: SA
authors.lastname: Ghadami
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Mostafaie
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D006418:Heme / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009195:Peroxidase / Q000378:metabolism*; D066329:Protein Aggregates; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D066329:Protein Aggregates; D006418:Heme; D009195:Peroxidase
keywords: Amyloid aggregation; Heme; Peroxidase activity