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      Methylglyoxal produces more changes in biochemical and biophysical properties of human IgG under high glucose compared to normal glucose level

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          Abstract

          Hyperglycaemia triggers increased production of methylglyoxal which can cause gross modification in proteins’ structure vis-a-vis function though advanced glycation end products (AGEs). The AGEs may initiate vascular and nonvascular pathologies. In this study, we have examined the biochemical and biophysical changes in human IgG under normal and high glucose after introducing methylglyoxal into the assay mixture. This non-enzymatic reaction mainly engaged lysine residues as indicated by TNBS results. The UV results showed hyperchromicity in modified-IgG samples while fluorescence data supported AGEs formation during the course of reaction. Shift in amide I and amide II band position indicated perturbations in secondary structure. Increase carbonyl content and decrease in sulfhydryl suggests that the modification is accompanied by oxidative stress. All modified-IgG samples showed more thermostability than native IgG; the highest Tm was shown by IgG-high glucose-MGO variant. Results of ANS, Congo red and Thioflavin T dyes clearly suggest increase in hydrophobic patches and aggregation, respectively. SEM and TEM images support aggregates generation in modified-IgG samples.

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          Most cited references55

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          Determination of carbonyl content in oxidatively modified proteins.

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            Mechanisms of tryptophan fluorescence shifts in proteins.

            Tryptophan fluorescence wavelength is widely used as a tool to monitor changes in proteins and to make inferences regarding local structure and dynamics. We have predicted the fluorescence wavelengths of 19 tryptophans in 16 proteins, starting with crystal structures and using a hybrid quantum mechanical-classical molecular dynamics method with the assumption that only electrostatic interactions of the tryptophan ring electron density with the surrounding protein and solvent affect the transition energy. With only one adjustable parameter, the scaling of the quantum mechanical atomic charges as seen by the protein/solvent environment, the mean absolute deviation between predicted and observed fluorescence maximum wavelength is 6 nm. The modeling of electrostatic interactions, including hydration, in proteins is vital to understanding function and structure, and this study helps to assess the effectiveness of current electrostatic models.
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              Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose.

              The glycation of proteins by glucose has been linked to the development of diabetic complications and other diseases. Early glycation is thought to involve the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiff's base and fructosamine adducts. The formation of the alpha-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone, in early glycation was investigated. Glucose (50 mM) degraded slowly at pH 7.4 and 37 degrees C to form glyoxal, methylglyoxal and 3-deoxyglucosone throughout a 3-week incubation period. Addition of t-BOC-lysine and human serum albumin increased the rate of formation of alpha-oxoaldehydes - except glyoxal and methylglyoxal concentrations were low with albumin, as expected from the high reactivity of glyoxal and methylglyoxal with arginine residues. The degradation of fructosyl-lysine also formed glyoxal, methylglyoxal and 3-deoxyglucosone. alpha-Oxoaldehyde formation was dependent on the concentration of phosphate buffer and availability of trace metal ions. This suggests that alpha-oxoaldehydes were formed in early glycation from the degradation of glucose and Schiff's base adduct. Since alpha-oxoaldehydes are important precursors of advanced glycation adducts, these adducts may be formed from early and advanced glycation processes. Short periods of hyperglycaemia, as occur in impaired glucose tolerance, may be sufficient to increase the concentrations of alpha-oxoaldehydes in vivo.
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                Author and article information

                Contributors
                Role: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: MethodologyRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Supervision
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 January 2018
                2018
                : 13
                : 1
                : e0191014
                Affiliations
                [1 ] Department of Biochemistry, J.N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
                [2 ] Department of Biosciences, Jamia Millia Islamia, New Delhi, India
                Rosalind Franklin University of Medicine and Science, UNITED STATES
                Author notes

                Competing Interests: Z. Arif, Moinuddin and K. Alam are salaried employees of the Aligarh Muslim University. M.A. Khan is salaried employees of the Jamia Millia Islamia, New Delhi. No other potential conflicts of interest are to be declared.

                Author information
                http://orcid.org/0000-0001-9729-9966
                Article
                PONE-D-17-27444
                10.1371/journal.pone.0191014
                5774746
                29351321
                004ed9d3-fde5-4127-ab9e-1eef1fba7e8d
                © 2018 Khan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 August 2017
                : 27 December 2017
                Page count
                Figures: 10, Tables: 4, Pages: 21
                Funding
                Funded by: CSIR, New Delhi
                Award ID: 09/112 (0506)/2013-EMR-I
                Award Recipient :
                Funded by: Indian Council of Medical Research, New Delhi
                Award ID: 61/01/2011-BMS
                Award Recipient :
                MAK is thankful to the CSIR, New Delhi for NET-Junior/Senior Research Fellowship awarded vide letter no. 09/112 (0506)/2013-EMR-I.The major part of the work was supported by an Indian Council of Medical Research, New Delhi research grant no. 61/01/2011-BMS to KA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Glucose
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amides
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amides
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Glycation
                Research and Analysis Methods
                Microscopy
                Electron Microscopy
                Scanning Electron Microscopy
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Carbohydrate Metabolism
                Glucose Metabolism
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amino Acids
                Aromatic Amino Acids
                Tryptophan
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amino Acids
                Aromatic Amino Acids
                Tryptophan
                Biology and Life Sciences
                Biochemistry
                Proteins
                Amino Acids
                Aromatic Amino Acids
                Tryptophan
                Biology and Life Sciences
                Cell Biology
                Oxidative Stress
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Absorption Spectroscopy
                Custom metadata
                All relevant data are within the paper and its Supporting Information file.

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