Maillard reaction

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The Maillard reaction is responsible for 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 amino acid and a reducing sugar, usually requiring heat, but in practise it is way more complex than that. The Maillard reaction and lipid peroxidation both include a whole network of different reactions that 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). 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.[1]

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[2]) and nucleotides, forming advanced glycation end-products (AGEs). 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 (or as bound in peptides or proteins) 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).

  • Asparagine may readily form acrylamide.
  • Aspartic acid may also form acrylamide.[3]
  • Arginine and histidine may yield Maillard reaction products with anti-oxidant properties.[4]
  • Glutamine readily forms heterocyclic amines (HCAs), but may also yield 3-butenamide.[5]
  • Glutamic acid may readily form HCAs or HMF (a melanoid intermediate), acrylamide (with glucose or fructose)[6] or 2-Pyrrolidinone.[7]
  • 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[8](a melanoid), or with 1-DG forming several products.[9]
  • beta-Alanine may yield acrylamide through the acrylic acid pathway.[10]
  • Lysine may readily form pent-4-en-1-amine or CEL, or react with furfural to form furpipate[11](a melanoid)
  • Glycine may form HCAs, or with pyruvic acid to form 3-amino-4,5-dimethylfuran-2,3-dione[12], with methylglyoxal to from DMHF at low pH[13], with ribose to form 2-acetylfuran [14], or other [a melanoidins (in reaction with glucose[15] or xylose[16]).
  • Cysteine may form 5-hydroxy-3-mercapto-2-pentanone in reaction with thiamine and xylose[17], or DMHF (a melanoid intermediate), in reaction with methylglyoxal at high pH[18], or acrylamide (in reaction with ammonia, after conversion into pyruvic acid > acrylic acid).[19]
  • Threonine may form furan or 2-methylfuran (melanoidins), with degraded hexoses.[20]
  • Serine may form furan with degraded hexoses[21] or acrylamide (in reaction with ammonia, after conversion into pyruvic acid > acrylic acid).[22]
  • Carnosine may form acrylamide through the acrylic acid pathway [23], but by reacting with acrolein[24] (an aldehyde) it may prevent formation of other (cross-linking) AGEs[25]

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.[26] Depending on the level of phosphate, the route of AGE formation may shift.[27] Unsaturated fatty acids also accelerate AGE/ALE formation.[28]

  • 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.[29]
  • Glucose-6-phosphate Compared to glucose, generates more melanoidins, 'stabilizing' deoxyosones (1-DG and 3-DG; highly reactive intermediates).[30]

Inhibitors

  • Dietary restriction, by inhibiting glycoxidation rate[31] reduces oxidative stress by AGEs.[32] Caloric restriction reduces levels of CML and pentosidine in collagen[33], but also negatively affects wound healing.[34]
  • Antioxidants in general inhibit AGE formation[35] by reducing lipidperoxidation, though a degradation product of vitamin C (L-threose) may also yield AGEs (formyl threosyl pyrrole).[36] Reactive oxygen species (counteracted by antioxidants) accelerate some of the effects of AGEs [37].
  • Vitamin E substantially inhibits CML formation [38], or hardly.[39] Vitamin E levels correlate with endogenous secretory receptors in defending against plaque formation induced by AGEs.[40]
  • Nicotinamide (vitamin B3) inhibits AGE formation.[41]
  • Thiols / Mercaptans (sulfhydryl compounds) in general inhibit AGE formation. Examples are: Glutathione, cysteine and co-enzyme-A.
  • Glutathione; Acetylcysteine (inhibits CML formation[42]) 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.[43] Reactive intermediates such as GO, MGO, PGO and 3-DG, however, inhibit glutathione peroxidase (GPx) activity, by irreversively modifying arginine residues in GPx.[44]
  • Enzymes; Fructosyl amine oxidase enzymes have the ability to deglycate Amadori products (Maillard intermediates) [45], 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).[46] and by the metabolism of alpha-oxoaldehydes by the glutathione-dependent enzyme glyoxalase I, aldo-keto reductases [47], superoxide dismutase and catalase.[48] These enzymatic activities are part of the enzymatic defence against glycation.
  • Vitamin B6 (Pyridoxal 5'-phosphate; PLP); PLP and pyridoxal are the most effective lipid glycation inhibitors.[49] Pyridoxamine, pyridoxine, pyridoxal and their 5'-phosphates are precursors for the active form of vitamin B6 (Pyridoxal 5'-phosphate; PLP). Vitamin B6 (in mg/100g) in raw foods: 0.82 in wild Atlantic salmon (farmed: 0.60); 0.55 in wild Coho salmon (farmed: 0.66); 0.54 in walnuts; 0.44 in King mackerel; 0.40 in wild Chinook salmon, Atlantic and Spanish mackerel; 0.29 in California avocadoes; 0.17 in wild Sockeye salmon; 0.08 in Florida avocadoes.[50]
  • Pyridoxamine acts on various pathways in the glycation process. It inhibits the formation of AGEs and the chemical modification of protein by ALEs during lipid peroxidation reactions. Pyridoxamine chelates the metals crucial to the redox reaction.[51] Pyridoxamine traps and cleaves alpha-dicarbonyls (intermediates in glycoxidation and lipoxidation reactions).[52] 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.[53] Pyridoxamine also traps reactive oxyen species (ROS)[54] 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.[55] 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.[56]
  • Alpha-lipoic acid (ALA) inhibits AGEs formation [57] by inhibiting lipid peroxidation.[58] ALA is endogenously derived from caprylic acid (octanoic acid; endogenously synthesized), present in coconut oil (7.6%), palm kernel oil (4.8%) and sheep milk (0.12%).
  • Taurine inhibits AGE formation by inhibiting lipid peroxidation[59] and reducing serum glucose (by increasing glucose utilization).[60]
  • 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.[61] 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.[62]
  • Oleanolic acid (in garlic) inhibits pentosidine and CML formation.[63]
  • Ursolic acid (in apples (particularly the peel), prunes, basil, rosemary, lavender, oregano, thyme) inhibits CML formation.[64]

Intermediates

Sugars that react with amino acids may form Amadori compounds (N-substituted 1-amino-1-deoxyketoses), which are labile Maillard intermediates. Reaction of xylose and glycine at 90 degrees C (pH 6) for 2 h, for example, showed rapid formation of xylulosylglycine. 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%).[65]

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.[66] Particularly alpha-oxoaldehydes such as 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.[67] 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).[68]

  • 2,3-butanedione
  • 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.[69]
  • 3-deoxyglucosone (3-DG; from glucose-glutamic acid) Its levels (and of Pyrraline) are increased in diabetes.[70]
  • 1-deoxyglucosone (1-DG; 1-deoxy-D-erythro-hexo-2,3-diulose, an alpha-dicarbonyl) Its degradation mainly yields lactic acid and glyceric acid[71], but may also yield acetic acid released as sugar fragment.[72]
  • 3-deoxypentosone (3-DP)
  • 3-deoxy-2-hexosulose may react with phenolic compounds.[73]
  • 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).[74]
  • 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.[75] Notably N6-(2,3-dihydroxy-5,6-dioxohexyl)-l-lysinate is formed from lysine, which is highly reactive.[76]
  • 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.[77]
  • Fructoselysine may yield several AGEs, including pentosidine and CML.[78]
  • Glyoxal (GO) forms on autoxidation of glucose, and may yield CML.[79]
  • Methylglyoxal (MGO) is a metabolite of glucose, which readily binds to free (or bound in proteins) arginine, lysine, and cysteine, leading to the formation of Maillard reaction end-products, including advanced glycosylation end-products. MGO is associated with hypertension.[80] Acute hyperglycemia increases MGO levels 1.27-fold, and resulting CML levels by 21%.[81] Serum MGO levels are elevated in diabetes patients. Several commercial beverages contain very high levels of MGO.[82] Ammonolysis of MGO may render formamide, which may react with 2-aminopropanal (from MGO) to give carcinogenic 4- or 5-methylimidazole.[83]
  • Phenylglyoxal (PGO)
  • 5-hydroxy-3-mercapto-2-pentanone from thiamine, cysteine, and xylose.[84]
  • Ketoglutaric acids
  • oxazolidin-5-one from phenylalanine and glycolaldehyde[85]
  • Pyruvic acid

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[86]; AGEs/ALEs are indicators of tissue aging.[87] Good glycemic control limits damage due to AGEs/ALEs.[88] Maillard end-products include heterocyclic amines (HCAs), acrylamides, styrene, melanoidins and many other compounds.

  • 5-methylimidazoline-4-one (MG-H1; non-toxic), from arginine and methylglyoxal.[89]
  • 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[90]
  • glyceraldehyde-derived pyridinium (GLAP; toxic) induces reactive oxygen species (ROS) production in HL-60 cells.[91]
  • Pyrraline is a glucose-derived AGE against which polyclonal and monoclonal antibodies have been raised. Pyrraline is found predominantly in the sclerosed extracellular matrix of glomerular and arteriolar renal tissues from both diabetic and aged nondiabetic individuals.[92] Pyrraline and pentosidine are particularly present in plaques in brain tissue from patients with Alzheimer disease.[93]
  • 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[94], Amadori compounds, 3-deoxyglucosone, and other sugars. Its formation is inhibited by aminoguanidine[95]). Pentosidine is found in plasma proteins and red blood cells.[96] 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.[97] Pentosidine levels correlate with uremia[98][99] and bone and joint disorders.[100] The amount of pentosidine per collagen in human articular cartilage increases linearly with age.[101]
  • Glucosepane is a lysine-arginine protein cross-linking product derived from D-glucose, structurally related to pentosidine. [102] It is the most prevalent cross-linking AGE in human tissue.[103]
  • 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.[104]
  • 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.[105] The latter is inhibited by arginine.[106] (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.[107] 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.[108] CML is readily created from intermediates by heat treatment over 80°C.[109]
  • 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 [110] and are biomarkers for oxidative stress.[111]
  • 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).[112]
  • N(ε)-(4-hydroxy-2-nonenal)lysine (4H2NL, an ALE);
  • Acetamide Amides are derivates of ammonia or (carboxylated) amines. Acetamide is a carcinogenic derived from acetic acid, by dehydrating ammonium acetate[113], or by hydrolysis of acetonitrile[114]. Thermal degradation (>200°C) of chitin also yields acetamide.[115] Chitin is a good inducer for defense mechanisms in plants[116], 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.[117]
  • Chloropropanols 3-monochloropropane-1,2-diol (3-MCPD) is a chloropropanol.
  • 4-hydroxy-trans-2,3-nonenal (HNE) is cytotoxic. Its formation is increased as the result of elevated lipidperoxidation [118], yielding acrolein.[119]