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Pyridoxamine protects against glucose-induced protein damage

dc.creatorMathis, Missy Elaine
dc.description.abstractNon-enzymatic modification by glucose of proteins induces protein damage through the formation of advanced glycation end products (AGEs). AGEs have been implicated in the pathogenesis of a number of diseases including diabetes. Pyridoxamine (PM) is an in vitro inhibitor of the formation of AGEs, which acts by blocking the conversion of the Amadori intermediate to AGEs. In both animal experiments and human clinical trials, PM has shown promising results in delaying the onset of diabetic renal disease. The goal of this study was to use model proteins to gain insight into how glucose modifications alter protein functionality and how PM prevents the loss of protein function. Biochemical analyses of ribonuclease, lysozyme, bovine serum albumin, and ubiquitin provided insight into the damaging effects of glucose modifications on protein function, which included the formation of the prominent AGE, carboxymethyllysine (CML), and the degradation and cross-linking of proteins. PM prevented CML formation, protected protein integrity, and preserved enzyme function. Mass spectrometry analyses show that in lysozyme residues K-96 and K-97 are more susceptible to CML formation, and PM protects against CML formation on these residues. Notably, K-96 and K-97 are in close proximity to the active site, suggesting that CML, but not Amadori, formation near the active site is detrimental to lysozyme activity. Also, PM was found to protect against the oxidation of tryptophan residues, W-62 and W-63. We suggest that the same mode of PM protection may also occur in vivo and may be responsible for PM efficacy.
dc.subjectadvanced glycation end products
dc.subjectmass spectrometry
dc.subjectglucose modifications
dc.subjectprotein function
dc.subjectVitamin B6 -- Physiological effect
dc.titlePyridoxamine protects against glucose-induced protein damage
dc.contributor.committeeMemberDavid E. Ong
dc.type.materialtext University
dc.contributor.committeeChairBilly G. Hudson

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