Identification of N epsilon-Carboxymethyllysine as a Degradation Product of Fructoselysine in Glycated Protein

The chemistry of Maillard or browning reactionosf glycated proteins was studied using the model compound, Nu-formyl-W-fructoselysine(f FL), an analog of glycated lysine residues in protein. Incubation of fFL (15 mM) at physiological pH and temperature in 0.2 M phosphate buffer resulted in formation of lVcarboxymethyllysine (CML) in about 40% yield after 15 days. CML was formed by oxidative cleavage of fFL between C-2 and C-3 of the carbohydrate chain and erythronic acid (EA) was identified a s , the split product formed in the reaction. Neither CML nor EA was formed from fFL under a nitrogen atmosphere. The rate of formation of CML was dependent on phosphate concentration in the incubation mixture and the reaction was shown to occur by a free radical mechanism. CML was also identified by amino acid analysis in hydrolysates of both poly-L-lysine and bovine pancreatic ribonuclease glycated in phosphate buffer under air. CML was also detected in human lens proteins and tissue collagens by HPLC and the identification was confirmed by gas chromatography/mass spectroscopy. The presence of both CML and EA in human urine suggests that they are formed by degradation of glycated proteins in vivo. The browning of fFL incubation mixtures proceeded to a greater extent under a nitrogen versus an air atmosphere, suggesting that oxidative degradation of Amadori adducts to form CML may limit the browning reactions of glycated proteins. Since the reaction products, CML and EA, are relatively inert, both chemically and metabolically, oxidative cleavage of Amadori adducts may have a role in limiting the consequences of protein glycation in the body

Oxidative Degradation of Glucose Adducts to Protein: Formation of 3-(N\u3csup\u3ee\u3c/sup\u3e-Lysino)-Lactic Acid from Model Compounds and Glycated Proteins

The chemistry of Maillard or browning reactions of glycated proteins is being studied in model systems in vitro in order to characterize potential reaction pathways and products in biological systems. In previous work with the Amadori rearrangement product N alpha-formyl-N epsilon-fructoselysine (fFL), an analog of glycated lysine residues in proteins, we showed that fFL was oxidatively cleaved between C-2 and C-3 of the carbohydrate chain to yield N epsilon-carboxymethyllysine (CML) and D-erythronic acid. We then detected CML in proteins glycated in vitro, as well as in human lens proteins and collagen in vivo (Ahmed, M. U., Thorpe, S. R., and Baynes, J. W. (1986) J. Biol. Chem. 261, 4889-4894). This work provided an explanation for the origin of CML in human urine and evidence for non-browning pathways of the Maillard reaction in vivo. In this report we describe the identification of a second set of products resulting from oxidative cleavage of fFL between C-3 and C-4 of the sugar chain, i.e. 3-(N epsilon-lysino)-lactic acid (LL) and D-glyceric acid. The formation of LL from fFL was increased at slightly acid pH, representing about 30% of the yield of CML at pH 6.4, compared with 4% at pH 7.4 in phosphate buffer. By gas chromatography-mass spectroscopy, LL was detected in proteins glycated in vitro and then identified as a natural product in human lens proteins and urine. Our results indicate that oxidative degradation of Amadori adducts toproteins occurs in vivo, leading to formation and excretion of CML and LL. These non-browning pathways for reaction of Amadori compounds may be physiologically relevant mechanisms for averting potentially damaging consequences of the Maillard reaction

Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe