Table 2. Conclusion Molecular aging of proteins is a complex phenomenon that involves many distinct chemical reactions whose contribution to the development of long-term complications of metabolic or chronic diseases has been well established. References 1. Nonenzymatic posttranslational protein modifications in ageing. Exp Gerontol ; 43 : — Baynes JW. The clinical chemome: a tool for the diagnosis and management of chronic disease. Clin Chem ; 50 : — 7. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes.
Cardiovasc Diabetol ; 7 : Advanced glycation end-products: a review. Diabetologia ; 44 : — Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun ; : — Ahmed N , Thornalley PJ. Advanced glycation endproducts: what is their relevance to diabetic complications?
Diabetes Obes Metab ; 9 : — Advanced oxidation protein products as a novel molecular basis of oxidative stress in uraemia. Nephrol Dial Transplant ; 14 Suppl 1 : 76 — 8. Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes. Diabetologia ; 48 : — Oxidative stress and covalent modification of protein with bioactive aldehydes.
J Biol Chem ; : — Lyons TJ. Semin Vasc Med ; 2 : — Advanced lipid peroxidation end products in oxidative damage to proteins: potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol ; : 6 — Carbamoylation of amino acids and proteins in uremia. Kidney Int Suppl ; 78 : S — 7. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med ; 13 : — Biochemistry of amino acid racemization and clinical application to musculoskeletal disease. Clin Biochem ; 39 : — Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications.
Atherosclerosis ; : 9 — Chem modification of proteins by lipids in diabetes. Clin Chem Lab Med ; 41 : — Grillo MA , Colombatto S. Advanced glycation end-products AGEs : involvement in aging and in neurodegenerative diseases. Amino Acids ; 35 : 29 — Harding JJ. Viewing molecular mechanisms of ageing through a lens. Ageing Res Rev ; 1 : — Hein GE. Glycation endproducts in osteoporosis: is there a pathophysiologic importance? Clin Chim Acta ; : 32 — 6. Role of protein tyrosine nitration in neurodegenerative diseases and atherosclerosis.
Arch Pharm Res ; 32 : — Advanced oxidation protein products accelerate atherosclerosis through promoting oxidative stress and inflammation. Arterioscler Thromb Vasc Biol ; 26 : — Oxidative stress in diabetes and Alzheimer's disease. J Alzheimers Dis ; 16 : — Takeuchi M , Yamagishi S. Thornalley PJ. Advanced glycation end products in renal failure. J Ren Nutr ; 16 : — Enhanced activation of and increased production of matrix metalloproteinase-9 by human blood monocytes upon adhering to carbamylated collagen. FEBS Lett ; : 13 — 6. Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils.
Chem Biol ; 13 : — Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy. Diabetes ; 54 : — Glycation of proteins as a source of superoxide. Diabete Metab ; 14 : 25 — Autoantibody against N epsilon - carboxymethyl lysine: an advanced glycation end product of the Maillard reaction.
Diabetes ; 48 : — 9. OpenUrl Abstract. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation ; : — N epsilon -carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response. Mol Nutr Food Res ; 52 : — 8. Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kinetics. Anal Biochem ; : 68 — Mol Nutr Food Res ; 51 : — Protein glycation: a firm link to endothelial cell dysfunction. Circ Res ; 95 : — 8.
Binding of long-term glycated low density lipoprotein and AGE-albumin by peripheral monocytes and endothelial cells. J Recept Signal Transduct Res ; 19 : — Structural modifications of HDL and functional consequences. Atherosclerosis ; : 1 — 7. Little RR. Clin Chem Lab Med ; 41 : — 8. Evaluation of GHb assays in France by national quality control surveys.
Diabetes Care ; 21 : — Frantzen F. Chromatographic and electrophoretic methods for modified hemoglobins. Quantitation of glycosylated hemoglobin by boronate affinity chromatography. Diabetes ; 33 : 73 — 6. Potential of electrospray mass spectrometry for quantifying glycohemoglobin. Clin Chem ; 43 : — 8. Clin Chem Lab Med ; 40 : 78 — Diabetes Care ; 30 : — Fructosamine: a new approach to the estimation of serum glycosylprotein. An index of diabetic control. Clin Chim Acta ; : 87 — Reliable determination of furosine in human serum and dialysate proteins by high-performance liquid chromatography.
J Chromatogr B Biomed Appl ; : — A novel advanced glycation index and its association with diabetes and microangiopathy. Metabolism ; 54 : — 7. Diabetologia ; 52 : — Measurement of pentosidine in human plasma protein by a single-column high-performance liquid chromatography method with fluorescence detection. Chromatographic assay of glycation adducts in human serum albumin glycated in vitro by derivatization with 6-aminoquinolyl- N -hydroxysuccinimidyl-carbamate and intrinsic fluorescence.
Biochem J ; : 15 — Two immunochemical assays to measure advanced glycation end-products in serum from dialysis patients. Clin Chem Lab Med ; 43 : — Protein kinases and phosphatases in the control of cell fate. Enzyme Res ; Dalton S. Signaling networks in human pluripotent stem cells. Curr Opin Cell Biol ; 25 — Human embryonic stem cell phosphoproteome revealed by electron transfer dissociation tandem mass spectrometry.
Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell ; 5 — Post-translational modulation of pluripotency. J Mol Cell Biol ; 4 — Human embryonic stem cells. J Cell Sci ; Pt 1 :5— Alkaline phosphatase-positive colony formation is a sensitive, specific, and quantitative indicator of undifferentiated human embryonic stem cells.
Stem Cells ; 26 — A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis. A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase. PLoS One ; 4 :e Phosphatase and tensin homolog regulates the pluripotent state and lineage fate choice in human embryonic stem cells. Stem Cells ; 29 — Quadruplex-single nucleotide polymorphisms Quad-SNP influence gene expression difference among individuals. Nucleic Acids Res ; 40 — A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk.
PLoS One ; 7 :e Carcinogenesis ; 30 — Choura M, Rebai A. J Recept Signal Transduct Res ; 29 — J Clin Oncol ; 27 — Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus. Hum Mol Genet ; 13 — Am J Hum Genet ; 73 — Protein tyrosine phosphatase-1B gene PTPN1 : selection of tagging single nucleotide polymorphisms and association with body fat, insulin sensitivity and the metabolic syndrome in a normal female population.
Diabetes ; 54 — A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. Biochemistry ; 45 — Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture.
Cell Stem Cell ; 8 — Acetylation and deacetylation of non-histone proteins. Gene ; — Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov ; 1 — The many roles of histone deacetylases in development and physiology: implications for disease and therapy.
Post Translational Modifications: An Overview
Nat Rev Genet ; 10 — Role of histone deacetylases in vascular cell homeostasis and arteriosclerosis. Cardiovasc Res ; 90 — Global transcription in pluripotent embryonic stem cells. Cell Stem Cell ; 2 — Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes.
Stem Cells ; 28 — Butyrate promotes induced pluripotent stem cell generation. A novel regulatory factor recruits the nucleosome remodeling complex to wingless integrated Wnt signaling gene promoters in mouse embryonic stem cells. NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment.
Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates. Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2. Mol Cell Biol ; 27 — Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. J Cell Biol ; — PLoS Biol ; 10 :e Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo.
Roy S, Tenniswood M. Site-specific acetylation of p53 directs selective transcription complex assembly. Cancer Res ; 69 — Sirtuin 1 regulation of developmental genes during differentiation of stem cells. SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse. Cancer Cell ; 21 — Mol Cancer Ther ; 9 — EMBO J ; 21 — Cell Metab ; 6 — SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization.
Wang F, Tong Q. Mol Biol Cell ; 20 — Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miRa and p53 pathways. Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci ; — The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptional network. Zhong X, Jin Y.
Critical roles of coactivator p in mouse embryonic stem cell differentiation and Nanog expression. HAT cofactor trrap maintains self-renewal and restricts differentiation of embryonic stem cells. Stem Cells ; 31 — J Immunol ; — Kruppel-like factor 4 is acetylated by p and regulates gene transcription via modulation of histone acetylation. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest ; — Mol Cell Biol ; 28 — PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy.
Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. Genes Dev ; 19 — North BJ, Verdin E. Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation. The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes.
Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow. Circulation ; — SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae. Boros IM. Histone modification in Drosophila. Brief Funct Genomics ; 11 — Stallcup MR. Role of protein methylation in chromatin remodeling and transcriptional regulation.
Oncogene ; 20 — Histone lysine methylation dynamics: establishment, regulation and biological impact. Mol Cell ; 48 — Protein arginine methylation in mammals: who, what and why. Mol Cell ; 33 :1— Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. Genomic maps and comparative analysis of histone modifications in human and mouse. Genome-wide map of nucleosome acetylation and methylation in yeast. Role of histone H3 lysine 27 methylation in Polycomb-group silencing.
Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains.
Chemistry of Reactive Oxygen Species and Production of Reactive Aldehydes
Mol Cell ; 12 — A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev ; 18 — Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell ; 1 — Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell fate potential of human pluripotent stem cells is encoded by histone modifications.
Cell Stem Cell ; 9 — Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell ; 12 — A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. CARM1 is required in embryonic stem cells to maintain pluripotency and resist differentiation. Stem Cells ; 27 — Histone arginine methylation regulates pluripotency in the early mouse embryo.
Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Genes Dev ; 25 — EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell ; 32 — The histone demethylase UTX regulates stem cell migration and hematopoiesis.
Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol ; 14 — Cell Res ; 23 — Lysine methylation: beyond histones. Acta Biochim Biophys Sin ; 44 — Mol Cell ; 29 — Lysine methylation regulates the pRb tumour suppressor protein.
Oncogene ; 29 — Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res ; 38 — Lau PN, Cheung P. Histone code pathway involving H3 S28 phosphorylation and K27 acetylation activates transcription and antagonizes polycomb silencing. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.
Download references. Reprints and Permissions. International Journal of Molecular Sciences Molecular Omics Scientific Reports Advanced search. Skip to main content. Subjects Cell signalling Pluripotency Pluripotent stem cells Post-translational modifications. Abstract Post-translational modifications PTMs are known to be essential mechanisms used by eukaryotic cells to diversify their protein functions and dynamically coordinate their signaling networks.
Introduction The ability to self-renew indefinitely and differentiate into all cells of the body makes human pluripotent stem cells hPSCs , including human embryonic stem cells hESCs and induced pluripotent stem cells hiPSCs , valuable for research and clinical applications that require specific cell types. Figure 1.
Full size image. Figure 2. Protein glycosylation in hPSCs Glycoproteins and protein glycosylation It is well known that protein glycosylation plays a critical role in the regulation of protein structure 22 , signal transduction 23 , cell-cell and cell-environment interactions 24 , 25 , 26 , immune responses 27 , 28 , hormone action 29 , cancer progression 30 and embryonic development 31 , Figure 3.
Protein phosphorylation in hPSCs Protein phosphorylation and signaling cascades Similar to protein glycosylation, protein phosphorylation is involved in the regulation of a broad spectrum of cellular processes and states. Figure 4. Figure 5. Protein methylation in hPSCs Overview of protein methylation The identity of the enzymes causing protein methylation remained unknown until the heterogeneous nuclear ribonucleoprotein hnRNP methyltransferase 1 HMT1, also known as RMT1 was first discovered in Saccharomyces cerevisiae less than 20 years ago Figure 6.
Figure 7. The oxidation of carbohydrates provides intermediates for reactions with proteins in the formation of advanced glycation end products, some of which are reactive toward protein 6. Direct protein carbonylation can be achieved through a variety of reactions. Oxidation of amino acid side chains with metals and hydrogen peroxide is known to cause the formation of semialdehyde amino acids, with the majority of these reactions occurring with lysine, arginine, and proline residues 7. Alternatively, protein carbonylation can result from an indirect mechanism involving the hydroxyl radical-mediated oxidation of lipids.
Polyunsaturated acyl chains of phospholipids or polyunsaturated fatty acids such as arachidonic acid and linoleic acid are highly susceptible to peroxidation and breakdown through non-enzymatic Hock cleavage, forming a variety of lipid-derived aldehydes and ketones 8. Lipid peroxidation products can diffuse across membranes, allowing the reactive aldehyde-containing lipids to covalently modify proteins localized throughout the cell and relatively far away from the initial site of ROS formation.
Recent studies have suggested that protein carbonylation formed from lipid-derived aldehydes is more prevalent than that formed via direct amino acid side chain oxidation 9. The cellular metabolism of lipid peroxidation products and the fates of their protein targets are diagramed in Fig. Because of the presence of electron-withdrawing functional groups, the double bond of 4-HNE or 4-ONE serves as a site for Michael addition with the sulfur atom of cysteine, the imidizole nitrogen of histidine, and, to a lesser extent, the amine nitrogen of lysine.
There is some evidence for reaction with arginine as well, albeit to a lesser extent than with lysine. Although 4-HNE has historically been the most well studied lipid peroxidation product 11 , 4-ONE is also highly reactive In the case of 4-ONE, modification of lysine residues through 1,2-addition Schiff base formation and the addition of water to the double bond can also result in ketoamide adducts In addition, oxidation by aldehyde dehydrogenase or reduction by alcohol dehydrogenase, aldehyde reductase, or aldose reductase converts free aldehydes into less toxic molecules.
The resulting aliphatic carbonyl adducts on cysteine, histidine, or lysine residues may alter the activity of protein targets or cause them to become degraded by the proteasome. A variety of antioxidant enzymes and proteins function to eliminate reactive lipid peroxidation products Lipid hydroperoxides can be reduced via peroxiredoxins and glutathione peroxidases, thereby preventing reactive aldehyde formation.
Although aldehyde dehydrogenase converts 4 R -HNE into a carboxylic acid and alcohol dehydrogenase, and aldehyde reductase and aldose reductase convert the aldehyde into the corresponding alcohol 18 — 20 , leading to markedly reduced reactivity of the lipid, a major route of detoxification is via glutathionylation by GST.
Lipid peroxidation products have been shown to have a wide variety of effects on cells in vitro depending upon the concentration utilized, and as such, interpretation of experimental results must be considered cautiously. Because the side chains of Cys, His, and Lys are often used in catalysis, the most common effect of protein carbonylation is enzyme inactivation.
The modification of the adipocyte FABP as well as the epithelial isoform by 4-HNE occurs on a conserved cysteine residue Cys , decreases the protein's affinity for fatty acids, and may contribute to obesity-linked insulin resistance 24 , The inactivation of thioredoxin and thioredoxin reductase through modification of their active-site cysteine and selenocysteine residues by 4-HNE and acrolein has been linked to dysregulation of cellular redox status and stress signaling 31 — Likewise, the inactivation of glutathione peroxidase by modification with methylglyoxal on an arginine residue at its glutathione-binding site amplifies oxidative stress by increasing peroxide levels in the cell In addition, Hsp90 and protein-disulfide isomerase have also recently been shown to be inactivated by modification with reactive aldehydes 35 , Targeted degradation of carbonylated proteins occurs via at least two different mechanisms.
The 20 S ubiquitin-independent proteasome, which degrades misfolded proteins based on its ability to detect exposed hydrophobic residues, is responsible for the degradation of many carbonylated proteins However, the 26 S proteasome has also been demonstrated to have a role in the degradation of modified proteins after they have undergone ubiquitination, as is the case for alcohol dehydrogenase Although targeted degradation minimizes the amount of carbonylated proteins during conditions of mild oxidative stress, the 4-HNE modification and inhibition of the proteasome machinery itself amplify the accumulation of modified and misfolded proteins during conditions of increased ROS Although carbonylation most typically inactivates protein targets, such modification can also result in a gain of function for certain metabolic signaling systems.
For example, transcriptional activation of antioxidant-response genes is up-regulated by protein carbonylation. Several genes containing antioxidant-responsive elements are activated by 4-HNE-linked processes. Nrf2 N F-E2- r elated f actor 2 is a central transcription factor involved in the regulation of antioxidant-responsive element-containing genes that are often activated in response to oxidative stress.
Once freed from inhibition by Keap1, Nrf2 translocates to the nucleus and activates the expression of antioxidant-responsive element-containing genes, increasing antioxidant defenses The 4-HNE modification of extracellular signal-regulated kinase ERK on His inhibits its ability to become phosphorylated and, as a result, decreases its kinase activity Reactive aldehydes have also been reported to stimulate the activities of certain kinases.
In addition, the epidermal growth factor receptor is activated by 4-HNE in the absence of ligand binding by inducing clustering and autophosphorylation However, the specific amino acid targets and mechanisms responsible for both epidermal growth factor receptor and JNK activation by 4-HNE are still unclear and warrant future investigation. The emergence of two modern ionization technologies, matrix-assisted laser desorption ionization and electrospray ionization, has enabled the direct structural analysis of aldehyde modification in single-protein models as reviewed previously 10 , Although these techniques have proven useful for investigating protein carbonylation in simple in vitro model systems, studies of these proteins do not necessarily reflect accurately their endogenous modification state.
Therefore, to better understand the role of carbonyl modifications in vivo , more advanced methods are required to characterize directly modified proteins isolated from complex biological systems. Similar to the proteomic study of other post-translational modifications to proteins, reactive carbonyl-modified components generally make up a relatively small proportion of the total proteins within a complex biological sample.
Therefore, methods to enrich for this subset of modified proteins prior to MS analysis are generally necessary. Proteomic methods that have been described for carbonylated protein analysis in complex systems are summarized in supplemental Fig. Specific detection of gel-separated reactive carbonyl-containing proteins is then achieved via immunoblotting, in some cases using antibodies that directly recognize the carbonyl modification on the protein e.
In other cases, reactive carbonyls are labeled covalently with nucleophilic hydrazide- or hydrazine-based probes. These groups have highly specific reactivity with aldehydes and to a far lesser extent, other carbonyls such as ketones , forming a covalent Schiff base that can then be reduced to a highly stable carbon—nitrogen single bond.
Identifying and Analyzing Posttranslational Modifications | SpringerLink
Many times, two gels are run in parallel, and one is immunoblotted to visualize the migration pattern of carbonylated proteins, whereas the other is stained for total protein so that spots corresponding to the locations of the carbonylated proteins can be excised, in gel-digested with trypsin, and identified by mass spectrometry. Ferrington and Kapphahn 39 identified subunits of rat liver 20 S proteasome containing HNE adducts by a similar antibody-based detection method, providing important details regarding the catalytic site-specific inhibition of the proteasome by 4-HNE. This approach was also used in the identification of in vivo 4-HNE-modified retinal proteins from young and old rat eyes, cultured ARPE19 cells, and human donor eyes An alternative method for visualizing oxidized proteins, relying on similar hydrazide chemistry, was also developed using biotinylation and avidin-fluorescein isothiocyanate affinity staining A limitation of all hydrazide-based labeling methods described above is the general reactivity of hydrazide to all reactive carbonyl modifications, precluding the identification of the exact type of carbonyl modification e.
Despite the contributions of 2DGE-based methods to proteomic studies of reactive carbonyl-modified proteins, 2DGE has a number of well described 54 limitations as a general platform for large-scale proteomic studies, including analysis of membrane and low-abundance proteins. For these methods, carbonylated proteins are enriched from complex mixtures using affinity methods outlined in blue boxes in supplemental Fig.
This general gel-free method has been used in a number of different studies. One of the first descriptions identified proteins in aged mouse brain homogenates
Related Posttranslational Covalent Modifications of Proteins
Copyright 2019 - All Right Reserved