ORCID Profile
0000-0001-5326-4008
Current Organisation
Washington University in St. Louis School of Medicine
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Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3CC42700E
Abstract: Partially reduced oxygen species (PROS), produced by reduced heme bound Aβ peptides, can cause oxidative stress and synaptic damage in the brain, which is one of the key pathological features of Alzheimer's disease. In situ oxidation of the heme center by a physiological redox agent like Cytochrome c (Cyt c) can significantly suppress neurotoxic PROS formation. Thus, Cyt c can potentially act as a neuroprotective agent against AD.
Publisher: American Chemical Society (ACS)
Date: 23-04-2013
DOI: 10.1021/IC4001413
Abstract: Deposition of human amylin or islet amyloid polypeptide (hIAPP) within the β-cells of the pancreatic islet of Langerhans is implicated in the etiology of type 2 diabetes mellitus (T2Dm). Accumulating evidences suggest that increased body iron stores, iron overload, and, in particular, higher heme-iron intake is significantly associated with higher risk of Type 2 diabetes mellitus (T2Dm) (PloS One2012, 7, e41641). Some key pathological features of T2Dm, like iron dyshomeostasis, iron accumulation, mitochondrial dysfunction, and oxidative stress are very similar to the cytopathologies of Alzheimer's disease, which have been invoked to be due to heme complexation with amyloid β peptides. The similar etiology and pathogenic features in both Alzheimer's disease (AD) and T2Dm indicate a common underlying mechanism, with heme playing an important role. In this study we show that hIAPP can bind heme. His18 residue of hIAPP binds heme under physiological conditions and results in an axial high-spin active site with a trans-axial water derived ligand. Arg11 is a key residue that is also essential for heme binding. Heme(Fe(2+))-hIAPP complexes are prone to produce partially reduced oxygen species (PROS). The His18 residue identified in this study is absent in rats which do not show T2Dm, implicating the significance of this residue as well as heme in the pathology of T2Dm.
Publisher: Elsevier BV
Date: 2013
Publisher: Wiley
Date: 22-11-2022
DOI: 10.1111/JNC.15713
Abstract: The two hallmarks of Alzheimer's disease (AD) are amyloid‐β (Aβ) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Aβ drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non‐fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure‐based nosologic classification, but less emphasis was given to non‐filamentous co‐aggregates of insoluble proteins in the fractions derived from post‐mortem human brains. Here, we revisited sarkosyl‐soluble and ‐insoluble extracts to characterize tau and Aβ species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl‐insoluble pellets were greatly enriched with Aβ 42 at almost equimolar levels to N‐terminal truncated microtubule‐binding region (MTBR) isoforms of tau with multiple site‐specific post‐translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl‐insoluble materials with a 10‐fold higher concentration than N‐terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation‐prone N‐terminal and proline‐rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site‐specific phosphorylation pT 181 (~22%) and pT 217 (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non‐filamentous form (N‐terminal intact tau) co‐localized with Aβ in the sarkosyl‐insoluble pellets along with tau filaments (N‐truncated MTBR tau). Our results suggest a model that Aβ and tau interact forming globular aggregates, from which filamentous tau and Aβ emerge. These characterizations contribute towards unravelling the sequence of events which lead to end‐stage AD changes. image
Publisher: American Chemical Society (ACS)
Date: 14-09-2021
Publisher: Springer Science and Business Media LLC
Date: 24-09-2014
DOI: 10.1007/S00775-014-1193-7
Abstract: Serotonin (5-HT) is an essential neurotransmitter for cognitive functions and formation of new memories. A deficit in 5-HT dependent neuronal activity is somewhat specific for Alzheimer's disease. Metal-mediated oxidative degradation of neurotransmitters by Aβ bound to metals has been investigated. Heme-bound Aβ is found to catalyze the oxidative degradation of 5-HT leading to the formation of neurotoxic products dihydroxybitryptamine and tyrptamine-4,5-dione. The catalytic degradation of 5-HT is of first order with respect to both heme-Aβ and H2O2, and the maximum rate of 5-HT oxidation is obtained at physiological pH (pH 7-7.5). pH perturbation of the binding affinity of heme-Aβ complex for 5-HT indicates that the binding of the substrate (5-HT) is not the rate-determining step. Arg5 acts as a second-sphere residue facilitating the O-O bond cleavage, the mutation of which leads to a decrease in the rate of 5-HT oxidation. The pull effect of the Arg5 residue tends to facilitate the generation of the active oxidant, Compound I, below neutral pH, while the ionization of the phenol group of the substrate facilitates the generation of the active substrate above neutral pH. A combination of these two opposing effects results in the highest activity at physiological pH. Apart from the Arg5 residue, the Tyr10 residue is found to play a vital role in the 5-HT oxidation by heme-Aβ complexes.
Publisher: Oxford University Press (OUP)
Date: 09-03-2021
DOI: 10.1093/BRAINCOMMS/FCAB028
Abstract: Plaques that characterize Alzheimer’s disease accumulate over 20 years as a result of decreased clearance of amyloid-β peptides. Such long-lived peptides are subjected to multiple post-translational modifications, in particular isomerization. Using liquid chromatography ion mobility separations mass spectrometry, we characterized the most common isomerized amyloid-β peptides present in the temporal cortex of sporadic Alzheimer’s disease brains. Quantitative assessment of amyloid-β N-terminus revealed that & 80% of aspartates (Asp-1 and Asp-7) in the N-terminus was isomerized, making isomerization the most dominant post-translational modification of amyloid-β in Alzheimer’s disease brain. Total amyloid-β1–15 was ∼85% isomerized at Asp-1 and/or Asp-7 residues, with only 15% unmodified amyloid-β1–15 left in Alzheimer’s disease. While amyloid-β4–15 the next most abundant N-terminus found in Alzheimer’s disease brain, was only ∼50% isomerized at Asp-7 in Alzheimer’s disease. Further investigations into different biochemically defined amyloid-β-pools indicated a distinct pattern of accumulation of extensively isomerized amyloid-β in the insoluble fibrillar plaque and membrane-associated pools, while the extent of isomerization was lower in peripheral membrane/vesicular and soluble pools. This pattern correlated with the accumulation of aggregation-prone amyloid-β42 in Alzheimer’s disease brains. Isomerization significantly alters the structure of the amyloid-β peptide, which not only has implications for its degradation, but also for oligomer assembly, and the binding of therapeutic antibodies that directly target the N-terminus, where these modifications are located.
Publisher: American Chemical Society (ACS)
Date: 06-09-2019
DOI: 10.1021/ACS.ANALCHEM.9B02986
Abstract: Dityrosine cross-linking of Aβ peptides and α-synuclein is increasingly becoming recognized as a biomarker of neuropathological diseases. However, there remains a need for the development of analytical methods that enable the specific and selective identification of dityrosine cross-linked proteins and peptides in complex biological s les. Here, we report that the gas-phase fragmentation of protonated dityrosine cross-linked peptides under ultraviolet photodissociation (UVPD) tandem mass spectrometry (MS/MS) conditions results in the cleavage across C
Publisher: American Chemical Society (ACS)
Date: 11-07-2012
DOI: 10.1021/JA303930F
Abstract: The water-soluble hydrophilic part of human Aβ peptide has been extended to include a C-terminal cysteine residue. Utilizing the thiol functionality of this cysteine residue, self-assembled monolayers (SAM) of these peptides are formed on Au electrodes. Atomic force microscopy imaging confirms formation of small Aβ aggregates on the surface of the electrode. These aggregates bind redox active metals like Cu and cofactors like heme, both of which are proposed to generate toxic partially reduced oxygen species (PROS) and play a vital role in Alzheimer's disease. The spectroscopic and electrochemical properties of these Cu and heme bound Aβ SAM are similar to those reported for the soluble Cu and heme bound Aβ peptide. Experiments performed on these Aβ-SAM electrodes clearly demonstrate that (1) heme bound Aβ is kinetically more competent in reducing O(2) than Cu bound Aβ, (2) under physiological conditions the reduced Cu site produces twice as much PROS (measured in situ) than the reduced heme site, and (3) chelators like clioquinol remove Cu from these aggregates, while drugs like methylene blue inhibit O(2) reactivity of the heme cofactor. This artificial construct provides a very easy platform for investigating potential drugs affecting aggregation of human Aβ peptides and PROS generation by its complexes with redox active metals and cofactors.
Publisher: American Chemical Society (ACS)
Date: 07-12-2012
DOI: 10.1021/IC302131N
Abstract: Reduced Cu and heme has been invoked to be involved in Alzheimer's disease (AD). Recently the Aβ peptides have been demonstrated to bind heme and Cu simultaneously, and this complex produces significantly more toxic partially reduced oxygen species (PROS) than the Cu or heme-bound Aβ peptides. Here a combination of absorption, EPR, and resonance Raman spectroscopy along with kinetic assays are used to investigate the interaction of nitric oxide (NO) with the physiologically relevant form of Cu and heme-bound Aβ peptides, since a down-regulation of nitric oxide synthase activity is observed in patients suffering from AD. The data indicate that NO oxidizes the Cu(I) sites, making them less toxic toward PROS generation and releases heme from the Aβ peptides ameliorating the effects of heme binding to Aβ peptides associated with AD. This process involves a tyrosine-mediated electron transfer between the Cu and heme sites. These results provide a mechanistic pathway for the possible protective role of NO in AD.
Publisher: Frontiers Media SA
Date: 12-2021
DOI: 10.3389/FIMMU.2021.796584
Abstract: Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neoantigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O -linked N-acetylglucosamine (GlcNAc). Just like neoantigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from the JY B cell lymphoblastoid cell line, a concise albeit comprehensive list of O -GlcNAcylated HLA class I peptides. This cumulative list of O -GlcNAcylated HLA peptides were derived from normal and cancerous origin, as well as tissue specimen. Remarkably, the overlap in detected O -GlcNAcylated HLA peptides as well as their source proteins is strikingly high. Most of the O -GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. From this list, we extract that O -GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B*07:02 allele. This allele loads peptides with a Proline residue anchor at position 2, and features a binding groove that can accommodate well the recently proposed consensus sequence for O -GlcNAcylation, P(V/A/T/S)g(S/T), essentially explaining why HLA-B*07:02 is a favoured binding allele. The observations drawn from the compiled list, may assist in the prediction of novel O -GlcNAcylated HLA antigens, which will be best presented by patients harbouring HLA-B*07:02 or related alleles that use Proline as anchoring residue.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C6MT00214E
Abstract: Iron (Fe) is the most abundant transition metal ion in the human body and its role, in the form of heme, has been implicated in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2Dm). Heme binds both amyloid beta (Aβ) and human islet amyloid polypeptide (hIAPP) to form heme-Aβ and heme-hIAPP complexes, respectively, and form reactive oxygen species (ROS) like H
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3CC49571J
Abstract: Self-assembled monolayers of the water soluble hydrophilic part of naturally occurring amylin and its Arg11 mutant have been assembled on an Au surface, which are found to efficiently catalyze selective 4e(-)/4H(+) O2 reduction reaction (ORR) upon binding heme with a kcat of ∼10(7) M(-1) s(-1) under ambient conditions, where the Arg11 residue plays the key role of proton transfer in determining the rate of ORR.
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1039/C8MT00223A
Abstract: The binding of Cu, Fe or Zn to alpha-synuclein has been implicated in neurodegenerative disease, such as Parkinson's.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2CC37626A
Abstract: Redox active metals (Fe and Cu) and cofactors (heme) bind to Aβ peptides and react with O(2) in their reduced state leading to oxidative stress in the brain. In this study we cryogenically trap and characterize a Fe-O(2) intermediate, using resonance Raman spectroscopy, involved in reactive oxygen species formation by Aβ peptides. This is the first reaction intermediate relevant to Alzheimer's disease to be reported.
Publisher: American Chemical Society (ACS)
Date: 07-08-2015
DOI: 10.1021/ACS.ACCOUNTS.5B00102
Abstract: Redox active iron is utilized in biology for various electron transfer and catalytic reactions essential for life, yet this same chemistry mediates the formation of partially reduced oxygen species (PROS). Oxidative stress derived from the iron accumulated in the amyloid plaques originating from amyloid β (Aβ) peptides and neurofibrillary tangles derived from hyperphosphorylated tau proteins has been implicated in the pathogenesis of Alzheimer's disease (AD). Altered heme homeostasis leading to dysregulation of expression of heme proteins and heme deposits in the amyloid plaques are characteristic of the AD brain. However, the pathogenic significance of heme in neurodegeneration in AD has been unappreciated due to the lack of detailed understanding of the chemistry of the interaction of heme and Aβ peptides. As a result, the biochemistry and biophysics of heme complexes of Aβ peptides (heme-Aβ) remained largely unexplored. In this Account, we discuss the active site environment of heme bound Aβ complexes, which involves three amino acid residues unique in mammalian Aβ (Arg5, Tyr10, and His13) and missing in Aβ from rodents, which do not get affected by AD. The histidine residue binds heme, while the arginine and the tyrosine act as key second sphere residues of the heme-Aβ active site that play a crucial role in its reactivity. Generation of PROS, enhanced peroxidase activity, and oxidation of neurotransmitters such as serotonin (5-HT) are all found to be catalyzed by heme-Aβ in in vitro assays, and these reactivities can potentially be linked to the observed neuropathologies in AD brain. Association of Cu with heme-Aβ leads to the formation of heme-Cu-Aβ. The heme-Cu-Aβ complex produces a greater amount of PROS than reduced heme-Aβ or Cu-Aβ alone. Nitric oxide (NO), a signaling molecule, is found to ameliorate the detrimental effects of heme-Aβ and Cu bound heme-Aβ complexes by detaching heme from the heme-Aβ complex and releasing it into the environment solution. Heme-Aβ complexes show fast electron transfer with oxidized cytochrome c and rapid heme transfer with apomyoglobin and aponeuroglobin. NO, cytochrome c, and apoglobins can all lead to reduction in PROS generated by reduced heme-Aβ. Synthetic analogues of heme, offering a hydrophobic distal environment, have been used to trap oxygen bound intermediates, which provides insight into the mechanism of PROS generation by reduced heme-Aβ. Artificial constructs of Aβ on nonbiological platforms are used not only to stabilize metastable and physiologically relevant large and small amyloid aggregates but also to monitor the interaction of various drug candidates with heme and Cu bound Aβ aggregates, representing a tractable avenue for testing therapeutic agents targeting metals and cofactors in AD.
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Chemical Society (ACS)
Date: 27-01-2016
DOI: 10.1021/ACS.INORGCHEM.5B02683
Abstract: Recent evidence has established the colocalization of amyloid-rich plaques and heme-rich deposits in the human cerebral cortex as a common postmortem feature in Alzheimer's disease (AD). The amyloid β (Aβ) peptides have been shown to bind heme, and the resultant heme-Aβ complexes can generate toxic partially reduced oxygen species (PROS) and exhibit peroxidase activity. The heme-Aβ active site exhibits a concentration-dependent equilibrium between a high-spin mono-His-bound species similar to a peroxidase-type active site and a bis-His-bound six-coordinate low-spin species similar to that of a cytochrome b type active site. The ν(Fe-His) (241 cm(-1)) vibration has been identified in the high-spin heme-Aβ active site by resonance Raman spectroscopy. The formation of the low-spin heme-Aβ species is promoted by the His14 and noncoordinating second-sphere Arg5 residues. The high-spin state produces more PROS than the low-spin species. Nonbiological constructs modeling different forms of Aβ (oligomers, fibrils, etc.) suggest that the detrimental high-spin state is likely to dominate under most physiological conditions.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2022
DOI: 10.1007/S00216-022-04055-X
Abstract: Isomerization of aspartic acid (Asp) residues in long-lived proteins is a key feature associated with neurodegenerative proteinopathies such as Alzheimer's disease (AD). Recently, using ultra high-performance liquid chromatography (UHPLC) coupled with drift tube ion mobility mass spectrometry (DTIMS-MS), we documented the extensive Asp isomerization in amyloid-beta (Aβ) peptides depositing in the extracellular cortical plaques (senile plaques) of the AD brain. Aβ
Publisher: American Chemical Society (ACS)
Date: 24-09-2013
DOI: 10.1021/IC401771J
Abstract: A combination of absorption, electron paramagnetic resonance (EPR), and resonance Raman (rR) spectroscopy has been used to study the interaction of heme-Aβ and apomyoglobin (apoMb). The absorption spectrum of oxidized heme bound Aβ, characterized by a split Soret band at 364 and 394 nm, shifts to 408 nm on incubation with apoMb, characteristic of Myoglobin (Mb). The ν4, ν3, and ν2 bands in the rR spectrum of heme-Aβ are observed at 1376, 1495, and 1570 cm(-1), which shift to 1371, 1482, and 1563 cm(-1), respectively on incubating with apoMb, implying formation of Mb. Similarly, heme transfer from reduced heme-Aβ to apoMb resulting in the formation of deoxyMb was also observed. Thus, spectroscopic data show that apoMb can sequester heme from heme-Aβ complexes both in oxidized and in reduced forms. Heme uptake by apoMb from native heme-Aβ(1-40) and Aβ(1-16) in both oxidized and reduced forms follow a biphasic reaction kinetics likely representing heme transfer from two dominating conformers of heme-Aβ in solution. The rate constants for the two steps involved in heme uptake by apoMb from heme-Aβ(1-40) are 11.5 × 10(4) M(-1) s(-1) and 7.5 × 10(3) M(-1) s(-1) while from heme-Aβ(1-16) are 6.0 × 10(4) M(-1) s(-1) and 7.5 × 10(3) M(-1) s(-1). The rate constants for heme uptake by apoMb from reduced heme-Aβ(1-40) are 3.7 × 10(4) M(-1) s(-1) and 6.8 × 10(3) M(-1) s(-1) while for reduced heme-Aβ(1-16) are 2.0 × 10(4) M(-1) s(-1) and 6.0 × 10(3) M(-1) s(-1). The heme uptake from heme-Aβ by apoMb leads to a dramatic reduction of PROS generation by the reduced heme-Aβ complexes.
Publisher: American Chemical Society (ACS)
Date: 18-05-2017
DOI: 10.1021/ACS.ANALCHEM.7B00941
Abstract: The use of mass spectrometry coupled with chemical cross-linking of proteins has become a powerful tool for proteins structure and interactions studies. Unlike structural analysis of proteins using chemical reagents specific for lysine or cysteine residues, identification of gas-phase fragmentation patterns of endogenous dityrosine cross-linked peptides have not been investigated. Dityrosine cross-linking in proteins and peptides are clinical markers of oxidative stress, aging, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In this study, we investigated and characterized the fragmentation pattern of a synthetically prepared dityrosine cross-linked dimer of Aβ(1-16) using ESI tandem mass spectrometry. We then detailed the fragmentation pattern of dityrosine cross-linked Aβ(1-16), using collision induced dissociation (CID), higher-energy collision induced dissociation (HCD), electron transfer dissociation (ETD), and electron capture dissociation (ECD). Application of these generic fragmentation rules of dityrosine cross-linked peptides allowed for the identification of dityrosine cross-links in peptides of Aβ and α-synuclein generated in vitro by enzymatic peroxidation. We report, for the first time, the dityrosine cross-linked residues in human hemoglobin and α-synuclein under oxidative conditions. Together these tools open up the potential for automated analysis of this naturally occurring post-translation modification in neurodegenerative diseases as well as other pathological conditions.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7DT01700F
Abstract: Binding of Cu( ii ) not only drives the conversion of the benign bis-His bound low spin heme( iii )–Aβ complex to the detrimental mono-His high spin form, even in the presence of excess Aβ, but it also forms the most toxic heme( iii )–Cu( ii )–Aβ species.
Location: Australia
Location: United States of America
No related grants have been discovered for Soumya Mukherjee.