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Lysinuric protein intolerance
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Lysine depletion may be improved with supplemental L-lysine-HCl (0.05–0.5 mmol/kg, three times per day) [58], but this is limited by malabsorption and intestinal tolerance. ɛ-N-Acetyllysine has been shown to increase plasma concentrations of lysine [59]. Increase may also be accomplished by the IV administration of lysine [60].
The Modification of Arginine
Published in Roger L. Lundblad, Claudia M. Noyes, Chemical Reagents for Protein Modification, 1984
Roger L. Lundblad, Claudia M. Noyes
Of particular interest has been the observations of Fonda and Cheung29 that the reaction of arginine with phenylglyoxal is greatly accelerated in bicarbonate-carbonate buffer systems. Figure 13 shows the reaction of phenylglyoxal with N-acetylarginine, A’-acetyllysine and N-acetylcysteine in 0.083 M sodium bicarbonate, pH 7.5. Reaction is only seen, for all practical purposes, with the arginine derivative. L-Arginine reacted in the same manner suggesting that modification of the α-amino group did not occur under these conditions. Figure 14 compares the rate of reaction of phenylglyoxal with arginine in bicarbonate buffer with that in other buffer systems (borate, Veronal, /V-efhylmorpholine). The reaction appears to be first order with respect to bicarbonate (Figure 15). The reaction of methylglyoxal with arginine is also enhanced by bicarbonate (Figure 16) while a similar effect is not seen with either glyoxal or 2,3-butanedione. The molecular basis for this specific buffer effect is not clear at this time nor is it known whether reaction with α-amino functional groups occurs at a different rate than with other solvent systems used for this modification of arginine with phenylglyoxal. Feeney and co-workers10 reported that p-nitrophenylglyoxal (prepared from p-nitroacetophenone — see Reference 31) reacts with arginine in 0.17 sodium pyrophosphate — 0.15 M sodium ascorbate, pH 9.0 to yield a derivative which absorbs at 475 nm. There is also reaction with histidine (the imidazole ring is critical for this reaction in that the 1-methyl derivative yielded a derivative which absorbed at 475 nm while the 3-methyl derivative did not). Free sulfhydryl groups also yielded a product with absorbance at 475 nm, but its absorbance was only 3% of that of the arginine. Branlant and co-workers32 have used p-carboxyphenyl glyoxal in bicarbonate buffer at pH 8.0 to modify aldehyde reductase. Saturation kinetics were noted with the use of this reagent.
Current trends in protein acetylation analysis
Published in Expert Review of Proteomics, 2019
Issa Diallo, Michel Seve, Valérie Cunin, Frédéric Minassian, Jean-François Poisson, Sylvie Michelland, Sandrine Bourgoin-Voillard
Aberrant acetylation of metabolic enzymes leads to metabolic disorders, such as obesity and diabetes. For instance, resveratrol has beneficial effects to treat obesity-related disorders or insulin resistance by decreasing the acetylation level of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a known SIRT1 target and regulator of mitochondrial biogenesis [131,132]. This was demonstrated by using immunoprecipitation of PGC-1α from liver extracts combined with western blotting against acetyllysine. Using a similar approach, another investigation found that the SIRT1720 drug targeted to activate SIRT1 has promising protective effects from diet-induced obesity and insulin resistance. These protective effects are mediated by enhancing oxidative metabolism in skeletal muscle, liver and brown adipose tissue through deacetylation of PGC-1α, forkhead box O1 (FOXO1), and p53 [133]. Other authors confirmed the deacetylation of the downstream SIRT1 targets including PGC-1α, FOXO1 and FOXO3 transcription factors in clinical management of type 2 diabetes with metformin, thiazolidinediones and exercise [134]. Using a similar approach, other authors reported that an increase of farnesoid X receptor (FXR) acetylation level plays a key role in metabolic diseases since it altered drastically FRX interaction with SIRT1 and p300 [135]. Kosanam et al. [136] used western blot to demonstrate an exacerbated lysine acetylation patterns in diabetic kidneys compared with control tissues without identifying acetylated proteins. To identify the acetylated proteins related to acetylation pattern modifications, the authors used an acetylomics approach based on MS methods combined with immune-purification using anti-acetyllysine antibodies. The use of this approach in a single experiment allowed to identify acetylated protein patterns specific to diabetic rats (47 lysine acetylated proteins in the kidneys of diabetic rats while only 11 lysine acetylated proteins were identified in control kidneys) and to conclude that the majority of the 47 acetylated proteins specifically identified in diabetic rats were metabolism enzymes and that cell dysfunctions associated with diabetes may be reversed by increasing deacetylase activity. Although acetylomics requires more quantity of sample and consumes more time for a single experiment, this information may be achieved on a set of proteins simultaneously only by acetylomics and not western blotting analyses. Based on the essential role of acetylation in metabolic disorders as described previously, acetylation may be used as promising therapy to treat metabolic disorders. In this context, acetylomics seems the most dedicated method to determine acetylation patterns by identifying and quantifying acetylated proteins. For example, a recent patent describes the design of a new anti-acetyllysine antibody used for treating metabolic disorders [137].