Maillard reaction

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Foods exposed to drying, frying, roasting, baking or broiling contain hundreds of chemical compounds and possess net mutagenic activity. [1] Full Free Text The Maillard reaction is responsible for many of these compounds, and many colors and flavors in foods. Well known Maillard reaction products include heterocyclic amines (HCAs) (including beta-carbolines), acrylamides and styrene, which may have antioxidant properties, but may also be mutagenic and/or neuroactive, or even neurotoxic and/or carcinogenic.

Principally, it is the reaction between an amine and a reducing sugar (yielding many heterocyclic and carbocyclic compounds[2]), usually requiring heat, but in practise it is way more complex than that. The Maillard reaction and lipid peroxidation are intimately interrelated, and the products of each reaction influence the other. They share intermediates and products, which are usually known as advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs). Polyunsaturated fats are most susceptible to lipid peroxidation, but also long saturated fats and mono-unsaturated fats are subject to lipid peroxidation. AGE/ALEs are analogous and participate similarly in both amino acid degradation and amino phospholipid/protein polymerization by identical mechanisms. In these systems, lipids and carbohydrates are competing in the chemical modification of amino phospholipids and proteins, in one general carbonyl pathway that can be initiated by both lipids and carbohydrates.[3]

Aging is the outcome of the contest between chemistry and biology in living systems. Proteins with long life spans serve as cumulators of exposure to chemical damage, detectable as AGEs / ALEs. Damage to DNA accumulates as chemically "silent" (undetectable) errors in repair-insertions, deletions, substitutions, transpositions, and inversions in DNA sequences-that affect the expression and structure of proteins. These mutations are random, vary from cell to cell, and are passed forward from one cell generation to another, compromising the structure and function of biomolecules throughout the body.[4]

Precursors

In cooked foods, the Maillard reaction is heat induced, but Maillard reaction products are also formed inside the human body (endogenously). Endogenously, the degradation products (mainly alpha-oxoaldehydes) of glycolytic intermediates, glycated proteins and lipid peroxidation may all cause glycation of protein (including peptide hormones[5]) and nucleotides, forming AGEs/ALEs. So that sugars, protein as well as lipids may be the source of Maillard reaction precursors. In cooked foods, amino and carbonyl groups are the most potent Maillard precursors. Amino groups (or the biogenic amines, or ammonium) of amino acids (bound in peptides or proteins, or free; cooking reduces free amino acid content[6]) predominantly react with carbonyl groups of reducing sugars (or lipid derived carbonyls) to form AGEs; advanced glycation end-products (or ALEs; advanced lipoxidation end-products). AGE immunoreactivity can increase exponentially when protein or fat is cooked with carbohydrates.[7] Due to the loss of amino acid residues, the Maillard reaction decreases protein quality and it also decreases protein digestibility. Maillard products can also inhibit the uptake and metabolism of free amino acids and of other nutrients such as zinc.Full Free Article

  • Asparagine may readily form acrylamide.
  • Aspartic acid may also form acrylamide.[8]
  • Arginine and histidine may yield Maillard reaction products with anti-oxidant properties.[9]
  • Glutamine readily forms heterocyclic amines (HCAs), but may also yield 3-butenamide.[10]
  • Glutamic acid may readily form HCAs or HMF (a melanoid intermediate), acrylamide (with glucose or fructose)[11] or 2-Pyrrolidinone.[12]
  • Tryptophan and tyrosine readily form heterocyclic amines (HCAs), particularly in the presence of creatine.
  • Phenylalanine may readily form HCAs or styrene.
  • Alanine may react with glyoxylic acid to form 3-amino-4,5-dimethylfuran-2,3-dione[13](a melanoid), or with 1-DG forming several products.[14]
  • beta-Alanine may yield acrylamide through the acrylic acid pathway.[15]
  • Lysine may readily form pent-4-en-1-amine or CEL, or react with furfural to form furpipate[16](a melanoid)
  • Glycine may form HCAs, or with pyruvic acid to form 3-amino-4,5-dimethylfuran-2,3-dione[17], with methylglyoxal to from DMHF at low pH[18], with ribose to form 2-acetylfuran [19], or other [a melanoidins (in reaction with glucose[20] or xylose[21]).
  • Cysteine may form 5-hydroxy-3-mercapto-2-pentanone in reaction with thiamine and xylose[22], or DMHF (a melanoid intermediate), in reaction with methylglyoxal at high pH[23], or acrylamide (in reaction with ammonia, after conversion into pyruvic acid > acrylic acid).[24]
  • Threonine may form furan or 2-methylfuran (melanoidins), with degraded hexoses.[25]
  • Serine may form furan with degraded hexoses[26], acrylamide (in reaction with ammonia, after conversion into pyruvic acid > acrylic acid)[27], or (mostly through glyceraldehyde) methylpyrazines and (mostly through 2,3-butanedione) 2,3-dimethylpyrazines.[28]
  • Carnosine may form acrylamide through the acrylic acid pathway [29], but by reacting with acrolein[30] (an aldehyde) it may prevent formation of other (cross-linking) AGEs[31]

Reactivity of amino acids in peptides depends on which group (N-terminal or alpha-Amino) or side chain is free.[32] Various reducing sugars vary in glycation activity. Pentoses are more reactive than hexoses, which are more reactive than disaccharides, though reactivity also depends on the reacting agent. Polyatomic anions (eg phosphate and carboxylate ions) contribute to the Maillard reaction by providing reactive intermediates directly from sugars.[33] Depending on the level of phosphate, the route of AGE formation may shift.[34] Unsaturated fatty acids also accelerate AGE/ALE formation.[35] Metals catalyze glycation[36] and also the autoxidation of sugars, yielding dicarbonyls.[37]

  • Pentoses: Arabinose, xylose, lyxose, ribose, ribulose, xylulose
  • Hexoses: Glucose, fructose, mannose, galactose, allose, altrose, gulose, idose, talose, sorbose, tagatose, psicose
  • Disaccharides: Sucrose (glucose-fructose), lactose (galactose-glucose), maltose (glucose-glucose), etc.
  • Glucose-1-phosphate; Compared to glucose, when pyrolized in the presence of glycine, will generate 9-fold more trimethylpyrazine, 5-fold more 2,3-dimethylpyrazine and 6-fold more acetol.[38]
  • Glucose-6-phosphate Compared to glucose, generates more melanoidins, 'stabilizing' deoxyosones (1-DG and 3-DG; highly reactive intermediates).[39]

Similar to sugars (and protein), fatty acids may be decomposed (through β-oxidation) to generate acetyl CoA (a Maillard inhibitor), which maybe converted (in the Krebs cycle) into Pyruvic acid (an alpha-keto acid) or alpha-Ketoglutaric acids which are potent Maillard precursors/intermediates. When a radical reacts with a non-radical, this always creates another radical (unless the non-radical is an anti-oxidant) Lipid peroxidation (including of phospholipids) is readily initiated by reactive oxygen species (ROS). When these radicals react with a (non-radical) fatty acid, this yields (but does not depend on[40]) another radical (hydroperoxide isomere)'. Such a radical chain reaction produces products of different stability[41], including (reactive) malondialdehyde. This chain reaction may be stopped by an anti-oxidant (or when 2 radicals react). All fats are subject to lipid peroxidation.

Inhibitors

Nutrients / food constituents that inhibit lipid peroxidation and/or AGE/ALE formation, and/or prevent damage / counteract the effects.

  • Vitamin B1 prevents cell death induced by stress from carbonyls directly, maybe because thiamin pyrophosphate restores pyruvate and alpha-ketoglutarate dehydrogenases inhibited by mitochondrial toxicity.[42]
  • Nicotinamide (vitamin B3) inhibits AGE formation.[43]
  • Antioxidants in general inhibit AGE formation[44] by reducing lipidperoxidation, and by counteracting reactive oxygen species (ROS), which accelerate some of the effects of AGEs [45].
  • Vitamin C inhibits the formation of mutagenic AGEs from glucose, glycine and creatinine.[46] On the other hand, a degradation product of vitamin C (L-threose) may also yield AGEs (formyl threosyl pyrrole) [47] and vitamin C (similar to metals) aids lipid peroxidation.[48]
  • Vitamin E protects heart phospholipids against peroxidative deterioration.[49] Vitamin E inhibits GO formation as a lipid peroxidation product[50] and substantially inhibits CML formation [51], or hardly.[52] Vitamin E levels correlate with endogenous secretory receptors in defending against plaque formation induced by AGEs.[53]
  • Thiols / Mercaptans (sulfhydryl compounds) in general inhibit AGE formation. Examples are: Glutathione, cysteine and co-enzyme-A.
  • Glutathione; Acetylcysteine (inhibits CML formation[54]) is derived from cysteine, and is a precursor in the formation of glutathione. Cysteine (binds to aldehydes) and glutathione inhibit the Maillard reaction more so than citric acid and oxalic acid. Though citric acid and oxalic acid also inhibit formation of the intermediates 3-DG and HMF.[55] Reactive intermediates such as GO, MGO, PGO and 3-DG, however, inhibit glutathione peroxidase (GPx) activity, by irreversively modifying arginine residues in GPx.[56]
  • Enzymes; Fructosyl amine oxidase enzymes have the ability to deglycate Amadori products (Maillard intermediates) [57], and the damage to tissue protein and nucleotides by alpha-oxoaldehydes is suppressed through inhibition of aldolase B, preventing accumulation of methylglyoxal (and subsequent AGE formation, incl. CEL).[58] and by the metabolism of alpha-oxoaldehydes by the glutathione-dependent enzyme glyoxalase I, aldo-keto reductases [59] Including degradation of MGO (and 3-DG) by aldehyde reductase [60] Full Free Text, 3-DG reductase [61] superoxide dismutase and catalase.[62] These enzymatic activities are part of the enzymatic defence against glycation.
  • Dietary restriction, by inhibiting glycoxidation rate[63] reduces oxidative stress by AGEs.[64] Caloric restriction reduces levels of CML and pentosidine in collagen[65], but also negatively affects wound healing.[66] Greater levels of pyridoxamine 5'-phosphate (a precursor of pyridoxamine) were found in liver, kidney and heart of dietary restricted animals.[67]
  • Vitamin B6 (Pyridoxal 5'-phosphate; PLP); PLP and pyridoxal are the most effective lipid glycation inhibitors.[68][69] Pyridoxamine, pyridoxine, pyridoxal and their 5'-phosphates are precursors for the active form of PLP or vitamin B6 (Pyridoxal 5'-phosphate). PLP is riboflavin-5′-phosphate dependent, derived from vitamin B2. (riboflavin-5′-phosphate inhibits mutagenicity of some HCA). A lack of dietary B6 increases damage by lipid peroxidation.[70] Vitamin B6 (in mg/100g) in raw foods: 0.96 (Souci et al) in sardine; 0.93 in yellowfin tuna; 0.85 in Skipjack tuna; 0.82 (Souci et al: 0.98) in wild Atlantic salmon (farmed: 0.60); 0.55 in wild Coho salmon (farmed: 0.66); 0.54 in walnuts (0.87 according to Souci et al); 0.53 in Hass avocado and beef tenderloin; 0.46 in bluefin tuna; 0.44 in King mackerel and chicken meat; 0.40 in wild Chinook salmon, Atlantic and Spanish mackerel; 0.37 in banana; 0.31 in hazelnuts; 0.30 in egg yolk; 0.29 in California avocado; 0.22 in grape juice and dutchcured herring; 0.17 in wild Sockeye salmon; 0.12 in mango; 0.10 in apple juice; 0.08 in Florida avocado; 0.05 in orange juice.[71]
  • Pyridoxamine acts on various pathways in the glycation process. It inhibits the formation of AGEs Full Free Text and the chemical modification of protein by ALEs during lipid peroxidation reactions.[72] Pyridoxamine chelates the metals crucial to the redox reaction.[73] Pyridoxamine traps and cleaves alpha-dicarbonyls (intermediates in glycoxidation and lipoxidation reactions).[74] It reacts with the carbonyl group in Amadori compounds and the strong stability of pyridoxamine complexes is the key in its post-Amadori inhibition action.[75] Pyridoxamine also traps reactive oxyen species (ROS)[76] In food, pyridoxamine is also present as pyridoxamine 5’-phosphate (PMP), which is converted to pyridoxamine by intestinal phosphatases. PMP (in nmol/g) in foods: 22.9 in dried small anchovy; 4.8 in chicken fillet; 4.2 in garlic; 2.6 in carrot; 1.0 in egg yolk. Pyridoxamine (in nmol/g) in foods: 2.3 in egg yolk; 2.2 in dried small anchovy, 2.0 in chicken fillet; 1.3 in carrot and 0.8 in garlic.[77] The raw meats (sashimi) of fatty seawater fishes contain a lot of PLP and/or PMP. Five portions of sushi with 20g of fatty seawater sashimi toppings would supply with vitamin B6 recommended by the Japanese RDA.[78]
  • alpha-Lipoic acid inhibits AGEs formation [79] by inhibiting lipid peroxidation.[80] alpha-Lipoic acid is endogenously derived from caprylic acid, which is endogenously synthesized and present in coconut oil (7.6%), palm kernel oil (4.8%) and sheep milk (0.12%). alpha-Lipoic acid acts with carnitine (from lysine and methionine), improving mitochondrial-supported bioenergetics and also improving general antioxidant status, attenuating any increase in oxidative stress with age.[81] alpha-Lipoic acid improves mitochondrial function [82] and reverses all three indexes of oxidative stress (protein carbonyls, lipidoxidation, oxidation-induced changes in synaptosomal membrane proteins) [83]
  • Carnitine in combination with alph-lipoic acid synergistically lower oxidative stress more than either compound alone.[84] Vitamin C is essential in the formation of carnitine from lysine or methionine. By far the highest levels of carnitine are found in red meat.
  • Taurine (from cysteine, fish or meat) inhibits AGE formation by inhibiting lipid peroxidation[85] and reducing serum glucose (by increasing glucose utilization).[86]
  • Phenols (in plant foods) may enhance or inhibit Maillard reaction product formation. Though green tea ameliorates plasma hydroperoxide levels, it enhances CML formation. In bovine serum albumin incubated with ribose, the natural phenol desgalactotigonin inhibits, whereas quercetin and acteoside enhance CML formation.[87] Phenolic compounds such as p-coumeric acid, caffeic acid, sinapic acid, and cinnamic acid may react with Maillard reaction intermediates, and the yielded compounds may inhibit oxide synthase (iNOS) and cyclooxygenase (COX)-2.[88] Phenolic antioxidants may inhibit formation of heterocyclic amines.[89]
  • Curcumin is a polyphenolic bioactive compound in turmeric. In fruit-flies, curcumin at 0.05% and 0.1% of diet increased mean lifespan by 6.2% to 25.8%, decreasing malondialdehyde levels, and increasing superoxide dismutase activity.[90]
  • Oleic acid; Supplementary oleic acid protects against endogenous lipid peroxidation by reducing the production of lipid peroxidation products and reducing oxidant stress induced injury.[91] Oleic acid in foods, as percentage of total fat: Hazelnuts 77%; Olive oil 72% (2% as free oleic acid); avocado 66%; rapeseed oil and Macadamia nuts 59%; sheabutter 45%; lard 41%, sesame oil 40%; beef 39%; egg yolks and palm oil 37%; cocoa butter 33%; Brazil nuts 32%; lamb 29%; maize oil 28%; chicken 27%; butter 25%; salmon 22%; sunflower oil and turkey 21%; soybean oil 20%; herring 19%; linseed oil 18%; tuna 17%; grapeseed oil and walnut oil 16%; walnuts 15%; palm kernel oil 14%; mackerel 13%; sardine 12%; coconut oil 7%.
  • Oleanolic acid (in garlic) inhibits pentosidine and CML formation.[92]
  • Capsaicin (8-methyl-N-vanillyl-6-nonemide), the major pungent in hot peppers (genus Capsicum) inhibits membrane lipid peroxidation (formation of malondialdehyde) and carbonyl formation in human red blood cells.[93]
  • Ursolic acid (in apples (particularly the peel), prunes, basil, rosemary, lavender, oregano, thyme) inhibits CML formation.[94]
  • Cholesterol increases rigidity of liposome membranes, making the membrane more resistant to radical attack.[95]
  • Furan fatty acids are, after consumption, incorporated in human tissue, acting as scavengers of lipidoxidation products (LOO* and LO* radicals). Furan fatty acids are present in algae and fish.[96]

Intermediates

Maillard intermediates that react with protein, nucleotides or basic phospholipids may be carbohydrate- (or protein-) or lipid-derived. The resulting end-products are advanced glycation end-products (AGE) and advanced lipoxidation end-products (ALE) respectively. Intermediates such as Amadori compounds and deoxyosones, are formed at percentage levels during model reactions.[97] Amadori compounds are a family of derivatives of aminodeoxysugars. Sugars that react with amino acids may form Amadori compounds (N-substituted 1-amino-1-deoxyketoses), which are labile Maillard intermediates. Major Amadori compounds in dried fruits are fructosylglutamate (from glucose + glutamate) in dried tomatoes (about 1.5%) and fructosylproline (glucose + proline) in dried apricots (about 0.2%).[98] Sulphiting (eg of dried fruits) may actually accelerate formation of Maillard compounds.[99] Transition metals accelerate the formation of Amadori compounds.[100]

  • Fructosamine (1-Amino-1-deoxy-D-fructose; from glucose and amines) is a key intermediate of the Maillard reaction, rendering a specific aroma, taste, and color formation.[101]
  • Fructoselysine may yield several AGEs, including pentosidine and CML.[102]
  • Xylulosylglycine from xylose and glycine.
  • N-(1-deoxy-D-fructos-1-yl)glycine (DFG)

Degradation of Amadori products yields dicarbonyls.[103] Carbonyls are also generated by lipid peroxidation and by autoxidation of sugars. Specific carbonyls, such as alpha-oxoaldehydes including glyoxals (GO, MGO, PGO etc) and deoxyosones (1-DG, 3-DG, 3-DP etc) are potent Maillard intermediates. Such potent alpha-dicarbonyls may be aldehydic or ketonic.[104] Reactive intermediates such as deoxyosones, GO and MGO are readily formed at 100°C.[105] alpha-Oxoaldehydes may form heterocyclic compounds in reaction with (guanidine derivatives from) protein-bound arginine or creatine.[106] alpha-Oxoaldehydes are up to 20,000-fold more reactive than glucose in glycation processes and react with proteins (predominantly arginine, while arginine residues are highly present in receptor and enzyme active sites), nucleotides and basic phospholipids to form AGE/ALEs (particularly hydroimidazolones, highly present in cellular and extracellular proteins).[107]


  • Glucosone (D-arabino-hexos-2-ulose) induces lipid peroxidation, involving metal ions.[108]
  • 2,3-butanedione is formed from glucose.[109]
  • 2,3-pentanedione may be formed from glucose, or from alanine plus D-glucose, pyruvaldehyde or glyceraldehyde.[110]
  • 3-deoxygalactosone (3-DGal) and galactosone are 1,2-dicarbonyls from the degradation of galactose, at high concentrations in milk products, commercial apple juice (from 3-DG) and beer.[111]
  • 3-deoxyglucosone (3-deoxy-D-erythro-hexos-2-ulose; 3-DG; a 2-oxoaldehyde from glucose-glutamic acid, or from fructose without amino groups[112]) 3DG accelerates the advanced stage of the Maillard reaction.[113]Full Free Text Its levels (and of Pyrraline) are increased in diabetes [114] Free Full Text and uremic patients.[115] 3-DG may yield pyrraline, pentosidine, CML and imidazolones.[116] Human aldehyde reductase (ALR) is an enzyme in our blood that rapidly detoxifies 3-DG when it is formed through the Maillard reaction in the human body.[117] 3-DG is detoxified by reduction to 3-DF (3-deoxyfructose) and subsequently reduced to 3-deoxy-hexitols (3-DH).[118]
  • 1-deoxyglucosone (1-DG; 1-deoxy-D-erythro-hexo-2,3-diulose, an alpha-dicarbonyl) Its degradation mainly yields lactic acid and glyceric acid[119], but may also yield acetic acid released as sugar fragment.[120]
  • 3-deoxypentosone (3-DP)
  • 3-deoxy-2-hexosulose may react with phenolic compounds.[121]
  • 1-deoxyhexo-2,3-diulose (an alpha-dicarbonyl) Its degradation is a key intermediate in Maillard chemistry, yielding carboxylic acids (glyceric acid, acetic acid; stable Maillard end-products), as well as unstable, reactive Maillard intermediates such as dicarbonyls (3,4-dihydroxy-2-oxobutanal, 1-hydroxybutane-2,3-dione, and 4-hydroxy-2-oxobutanal) and hydroxycarbonyls (acetol).[122]
  • Dideoxyosones may result from dicarbonyls reacting with amino acids. Lysine, for example, may yield N6-(2,3-dihydroxy-5,6-dioxohexyl)-L-lysine, N6-(5,6-dihydroxy-2,3-dioxohexyl)-L-lysine or N6-(2,3-dihydroxy-4,5-dioxohexyl)-L-lysine, which subsequently may yield quinoxalines.[123] Notably N6-(2,3-dihydroxy-5,6-dioxohexyl)-l-lysinate is formed from lysine, which is highly reactive. It may yield glucosepane.[124]
  • Glyoxal (GO) is a lipid peroxidation product [125] and forms on autoxidation of glucose, and may yield CML.[126]
  • Methylglyoxal (MGO, or 2-oxopropanal or pyruvaldehyde) is a metabolite of glucose (aldehyde), but also a ketone (from lipidoxidation). MGO readily binds to free (or bound in proteins) arginine, lysine, and cysteine, leading to the formation of Maillard reaction end-products (AGEs and ALEs). MGO is associated with hypertension.[127] Acute hyperglycemia increases MGO levels 1.27-fold, and resulting CML levels by 21%.[128] Serum MGO levels are elevated in diabetes patients.[129] Several commercial beverages contain very high levels of MGO.[130] Ammonolysis of MGO may render formamide, which may react with 2-aminopropanal (from MGO) to give carcinogenic 4- or 5-methylimidazole.[131]
  • Phenylglyoxal (PGO)
  • 5-hydroxy-3-mercapto-2-pentanone from thiamine, cysteine, and xylose.[132]
  • Oxazolidin-5-one from phenylalanine and glycolaldehyde[133]
  • Acrolein is a lipidoxidation product and ALE intermediate; it may yield HNE[134] and FDP-lysine.[135]
  • Malondialdehyde (MDA) is a lipidoxidation product and ALE intermediate. Its highly reactive and a marker for oxidative stress, as it is generated from reactive oxygen species (ROS) degrading polyunsaturated fats. Its present in heated edible oils such as sunflower and palm oils. As transition metals catalyze lipid peroxidation, increased levels of zinc correspond with malondialdehyde levels in carps.[136]
  • 4-Hydroxy-2-nonenal (4-HNE) is an ALE intermediate; the primary alpha,beta-unsaturated hydroxyalkenal formed during lipidoxidation of polyunsaturated fats. (others are: 4-oxo-trans-2-nonenal, 4-hydroxy-trans-2-hexenal, 4-hydroperoxy-trans-2-nonenal and 4,5-epoxy-trans-2-decenal).

While the concentration of glucose Amadori products is relatively constant with age, glycoxidation products (protein oxidized by glycation products) accumulate in long-lived proteins in human tissue.[137] Glycoxidation reactions proceed by multiple routes. [138]

End-products

The formation of AGEs/ALEs is linked to aging of tissues and organs in general and to several diseases such as diabetes mellitus and Alzheimer's disease[139]; A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity.[140] Good glycemic control limits damage due to AGEs/ALEs.[141] AGEs/ALEs are indicators of tissue aging.[142] Food-derived AGEs contribute to Alzheimer's Disease.[143] Some people argue that fluorescent AGEs (such as CML) may represent AGEs in general [144], but fluorescent AGEs may only represent endogenously formed AGEs, formed at low temperatures, and not AGEs formed at much higher temperatures. Maillard end-products include heterocyclic amines (HCAs) (such as IQ, MeIQ, MeIQx etc[145], acrylamides, styrene, melanoidins and many other compounds.

  • 5-methylimidazoline-4-one (MG-H1; non-toxic), from arginine and methylglyoxal.[146]
  • 4(5)-Methylimidazole is readily formed from ammonia and methylglyoxal. Its a carcinogenic found in commercial cola soft drinks; from 0.30 μg/mL to 0.36 μg/mL[147]
  • glyceraldehyde-derived pyridinium (GLAP; toxic) induces reactive oxygen species (ROS) production in HL-60 cells.[148]
  • Pyrraline (ε-2-(formyl-5-hydroxymethyl-pyrrol-1-yl)-L-norleucine) is an AGE formed from 3-deoxyglucosone in the non-enzymatic reaction between glucose and the epsilon-amino group of lysine residues on proteins.[149] Pyrraline is found predominantly in the sclerosed extracellular matrix of glomerular and arteriolar renal tissues from both diabetic and aged nondiabetic individuals.[150] Pyrraline and pentosidine are particularly present in plaques in brain tissue from patients with Alzheimer disease.[151]
  • Pentosidine (an imidazo[4,5-b]pyridinium) is often used as a marker for AGE stress. It comprises lysine and arginine, cross-linked by a pentose (isomers of ribose, arabinose, xylose or lyxose, but also by vitamin C[152], Amadori compounds, 3-deoxyglucosone, and other sugars (pentoses as well as hexosesFull Free Article). Its formation is inhibited by aminoguanidine[153]). Pentosidine is found in plasma proteins and red blood cells.[154] Pentosidine level increases from 5 to 75 pmol/mg collagen over lifespan. A 3 to 10 fold increase was noted in subjects with severe end-stage renal disease requiring hemodialysis.[155] Pentosidine levels correlate with uremia[156][157] and bone and joint disorders.[158] The amount of pentosidine per collagen in human articular cartilage increases linearly with age.[159]
  • Glucosepane is a lysine-arginine protein cross-linking product derived from D-glucose, structurally related to pentosidine. [160] It is the most prevalent cross-linking AGE in human tissue.[161]
  • Pent-4-en-1-amine Is considered the lysine-glucose counterpart of acrylamide (instead of asparagine-glucose). In the presence of sugars, lysine, similarly to asparagine and phenylalanine, can undergo carbonyl-assisted decarboxylative deamination reaction to generate pent-4-en-1-amine. Alternatively, decarboxylation of lysine generates cadaverine (1,5-diaminopentane) followed by deamination to form pent-4-en-1-amine.[162]
  • Vesperlysines (AGEs)
  • N(ε)-(carboxyethyl)lysine (CEL, an AGE/ALE); Incubation of bovine serum albumine with glucose yields methylglyoxal (a reactive glucose metabolite), which subsequently (in combination with lysine) yields CEL.[163] The latter is inhibited by arginine.[164] (as arginine also readily reacts with methylglyoxal)
  • N(ε)-(carboxymethyl)lysine (CML, an AGE/ALE); In rats, during the processes of aging, hippocampal microvessels and hippocampal pyramidal neurons accumulate AGES, particularly CML. Further conjugation of CML seems to occur in the microvessels and pyramidal neurons of hippocampus and it brings about deleterious change of endothelial cells and pyramidal neuron death, causing deficiency of recognition and reference memory in rodents during the processes of aging.[165] In rats fed a diet high in polyunsaturated fats, CML and CEL levels increased in the brain, remained unchanged in the kidney, and decreased in the liver.[166] CML is readily created from intermediates by heat treatment over 80°C.[167] CML may be formed through various pathways.Full Free Article
  • N(ε)-(carboxymethyl)hydroxylysine (CMhL). Hydroxylysine (an amino acid) is unique to collagen. The level of CMhL (and that of CML) accumulate with age in long-lived proteins in human tissues [168] and are biomarkers for oxidative stress.[169]
  • N(ε)-(malondialdehyde)lysine (MDL, an ALE); in rats fed high levels of polyunsaturated fats, MDL levels increased in all tissues measured (liver, kidney, brain).[170]
  • N(ε)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine, an ALE; acrolein derived)) may reflect the cumulative burden of oxidative stress over long periods of time[171] and is a biomarker for diabetic retinopathy.[172]
  • N(ε)-(4-hydroxy-2-nonenal)lysine (4H2NL, an ALE);
  • 4-hydroxynonenal-lysine; an ALE.[173]
  • Acetamide Amides are derivates of ammonia or (carboxylated) amines. Acetamide is a carcinogenic derived from acetic acid, by dehydrating ammonium acetate[174], or by hydrolysis of acetonitrile[175]. Thermal degradation (>200°C) of chitin also yields acetamide.[176] Chitin is a good inducer for defense mechanisms in plants[177], and present in fungi, the exoskeletons of crustaceans such as crabs, lobsters and shrimps, in mollusks, and in the internal shells of squid and octopus. Acetamide is also a byproduct of thermochemical treatment of lignocellulosic biomass.[178]
  • Chloropropanols 3-monochloropropane-1,2-diol (3-MCPD) is a chloropropanol.
  • Imidazolones are the reaction products of the guanidino group of arginine with 3-deoxyglucosone (3-DG).[179] Full Free Text
  • 4-hydroxy-trans-2,3-nonenal (HNE) is cytotoxic. Its formation is increased as the result of elevated lipidperoxidation [180], yielding acrolein.[181]
  • 2-ammonio-6-([2-[(4-ammonio-5-oxido-5-oxopentyl)amino]-4,5-dihydro-1H-imidazol-5-ylidene]amino)hexanoate (GODIC) is a cross-linking unit (lysine-arginine) in vivo and in foodstuffs, readily formed from GO or MGO.[182]
  • 2-ammonio-6-([2-[(4-ammonio-5-oxido-5-oxopentyl)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene]amino)hexanoate (MODIC), is a cross-linking unit (lysine-arginine) in vivo and in foodstuffs, readily formed from GO or MGO.[183]
  • (GOLD 3) imidazolium cross-linking unit
  • (MOLD 4) imidazolium cross-linking unit

Author

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Author of this article is Thijs Klompmaker, born in 1966