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Non-Enzymatic Glycosylation and Deglycating Enzymes

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DOI: 10.2478/V10133-010-0066-7

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Non-Enzymatic Glycosylation and Deglycating

Enzymes

E. A. Popova, R. S. Mironova & M. K. Odjakova

To cite this article: E. A. Popova, R. S. Mironova & M. K. Odjakova (2010) Non-Enzymatic

Glycosylation and Deglycating Enzymes, Biotechnology & Biotechnological Equipment, 24:3,
1928-1935, DOI: 10.2478/V10133-010-0066-7

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 REVIEW DOI: 10.2478/V10133-010-0066-7 E&EB

Non-enzymatic glycosylation and deglycating enzymes

E. A. Popova1, R. S. Mironova2, M. K. Odjakova1
1
Sofia University, Department of Biochemistry, Sofia, Bulgaria
2
Institute of Molecular Biology, Bulgarian Academy of Science, Sofia, Bulgaria
Correspondence to: M. Odjakova
E-mail: modjakova@biofac.uni-sofia.bg

ABSTRACT
Biological amines react with reducing sugars to form a heterogeneous group of compounds, called advanced glycation end
products, a process known as the Maillard reaction. Glycation of proteins starts with formation of Shiff’s base, which rearrange
into Amadori product. The Amadori products then undergo a series of chemical modifications to form advanced glycation end
products (AGEs). Many advanced glycation end products are capable of forming cross-links between proteins and many of them
are fluorophores. The formation of AGEs is an irreversible process and glycation is a major cause of spontaneous damage to
proteins in physiological systems. AGEs accumulate in tissues with age and their rate of accumulation is accelerated in diabetes.
Hyperglycemia in diabetes causes accelerated AGEs formation and has been linked to various diabetic complications like
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nephropathy, retinopathy, angiopathy, and neuropathy.

Nature has several defense mechanisms to protect tissues from AGEs accumulation. Among them are amadoriases, which can
remove the Amadori product and interrupt the glycation cascade in the early steps of the Maillard reaction. To date three classes
of deglycating enzymes were found-fructosamine oxidases, fructosamine-3-kinases, and fructoselysine 6-phosphate deglycase.
These enzymes are known to occur in mammalian, fungal and other eukaryotic and prokaryotic cells.

Biotechnol. & Biotechnol. Eq. 2010, 24(3), 1928-1935
Keywords: plant glycation, advanced glycation end products,
Maillard reaction, diabetic complications, amadoriases
The Maillard reaction and glycation
The non-enzymatic reaction of the amino groups of biological
amines with reducing sugars, leading to the formation of
protein-protein cross-links, was first studied by L.C. Maillard
in the early 1900s. Reducing sugars are inherently reactive
towards nucleophilic nitrogen bases in amino acids and
proteins. Glucose is the principal free sugar in vivo and is
the least reactive among other reducing sugars. Nevertheless,
glucose can react with free α or ε-amino groups of amino acids,
peptides or proteins to form Shiff’s base, which is unstable
and rearrange to form ketoamine products called Amadori
products. The rearrangement of the Shiff base to the Amadori
product is believed to occur via an intermediate, open chain
enol form (Fig.1).
Fig. 1. Formation of Shiff base and the Amadori rearrangement (61)
1928
The formation of Shiff bases is relatively fast and highly
reversible, whereas the formation of Amadori products is
faster than the reverse reaction, so that with time the Amadori
products tend to accumulate on proteins and other biological
amines. Early stage glycation of proteins by glucose leads to
the formation of fructosyl-lysine (FL, Amadori product), which
degrades slowly in the time course of the Maillard reaction.
The Amadori rearrangement of a lysine-glucose Shiff base is
thought to be facilitated if there is a histidine or another lysine
amino group about 5Å far from the amino group on which the
Shiff base has been formed (1).
The Amadori products can undergo multiple self-
rearrangements to produce intermediates with highly
reactive carbonyl groups (7). These compounds are known
as α-dicarbonyls and include products like glyoxal (GO),
methylglyoxal (MGO), and 3-deoxyglucosone (3-DG). 3-DG
is formed by non-oxidative rearrangement and hydrolysis
of the Amadori product and by fructose-3-phosphate, an
intermediate of the polyol pathway. MGO may be produced
from autooxidation of carbohydrates, decomposition of
triose phosphates and lipid peroxidation. Fructose-phosphate
fragmentation, lipid peroxidation and oxidative fragmentation
of the Schiff base lead to formation of GO. Moreover, GO,
MGO and 3-DG can also be formed by glucose degradation in
vitro (55) (Fig. 2).
Glyoxal and methylglyoxal react with proteins to
form chemically stable advanced glycation end products
(AGEs) very rapidly in contrast to FL. Addition of 1 μM 14C
methylglyoxal to human plasma ex vivo and incubation at
Biotechnol. & Biotechnol. Eq. 24/2010/3
 370C results in irreversible binding of methylglyoxal to plasma
proteins within 24 h (56).
Fluorescent AGE cross-links are useful markers of AGE
formation but they are thought to account for only one percent
or less of the total cross-linking structures formed while the
major AGE structures responsible for protein-protein cross-
links in vivo are non-fluorescent (Fig. 4).

Fig. 2. Formation of glyoxal, methylglyoxal, 3-deoxyglucosone, and glucosone

in glucose degradation (55)
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Some of the advanced products of glycation are

fluorophores and therefore fluorescent spectroscopy is widely
used to estimate formation of AGEs. This phenomenon is
called “Maillard type fluorescence” and can be detected under
370 nm excitation and 440 nm emission. The structures of
many fluorescent AGEs including cross-line, pentosidine,
vesperlysine A, B, and C and the Maillard reaction product
X, have already been identified (Fig. 3). Many proteins
including hemoglobin, lens crystalline, collagen, myelin (6)
and β2-microglobulin (31) have been found associated with
fluorescent advanced glycation products.

Fig. 4. Non-fluorescent AGE cross-links

Fructosamine-derived lysine-arginine cross-link

glucosepan is to date the major cross-link known to accumulate
in human collagen in aging and diabetes (51). GO and MGO
can react with lysine residues in proteins to form bis (lysyl)
imidazolium cross-links GOLD and MOLD (3).

Fig. 3. Fluorescent AGE cross-links formed under physiological conditions

The fluorescent AGE crosslink pentosidine can be formed

by reaction of lysine and arginine with glucose, ribose,
ascorbic acid, and 3-deoxyglucosone. Calabrese et al. (2007)
demonstrated a significant increase in both urinary and plasma
levels of pentosidine in patients suffering from type 2 diabetes
complicated by nephropathy as compared to control subjects Fig. 5. Pathway for the formation of pyrraline- 3) from peptide-bound lysine-
(18). 1) and 3-deoxyglucosulose- 2) (44)
Biotechnol. & Biotechnol. Eq. 24/2010/3 1929
 Besides the cross-linking AGEs, a number of non cross-
linking AGE structures are formed under physiological
conditions. Pyrraline is one of the few AGEs that have been
quantified in foods. Protein-bound pyrraline is formed from the
ε-amino group of lysine and 3-deoxyglucosone (Fig. 5).
Important AGEs formed in vivo are hydroimidazolones
derived from arginine residues modified by GO and MG
(G-H1 and MG-H1), which have a relatively short half-
live under physiological conditions (2-6 weeks) with a
concentration depending on the balance between formation
and decomposition rates.
The degradation of proteins damaged by glycation also
leads to the formation of glycation free adducts, like Nε-
carboxymethyl-lysine (CML), which increases in diabetes (4).
Furthermore, CML seems to be formed from both carbohydrate
and lipid sources (58).
Diet is a major environmental source of proinflammatory
AGEs. During industrial food processing and home cooking
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as well as during long-term food storage AGE formation is
of particular importance for the nutritional quality of food
proteins. The pre-formed AGEs are absorbed by the body
during digestion with about 30% efficiency. As noted by
Vlassara, industrial processing makes food flavorful and
colorful but does also contribute to significant production
and accumulation of AGEs (63). Bobalova et al. (2010)
demonstrated that glycation of heat stable barley albumin Z,
one of the most important proteins in beer, is detectable at the
second day of malting (13).
Bread and meat seem to be a great contributor to the
formation and accumulation of AGEs (9). Vegetarian food also
contributes to the accumulation of AGEs in the body, especially
fruits rich on fructose that readily reacts with proteins.
Evidence from animal studies suggests that restriction of food
intake is an effective tool for extending lifespan and preventing
chronic diseases. Monica Negrean et al. (2007) reported that in
type 2 diabetic patients a high AGE diet over 6 week caused
a significant increase in serum AGE markers of inflammation
such as C-reactive protein (CRP), tumor necrosis factor α
(TNF-α) and in markers of endothelial dysfunction (vascular
cell adhesion molecule 1), whereas a low-AGE diet led to
suppression of all these markers (46).
Role of AGEs in aging and diabetic compilations
Glycation is a slow process under physiological conditions,
giving rise to lysine- and arginine-derived glycation adducts in
extracellular and cellular proteins (57). Inside cells, the impact
of glycation is countered by the high turnover rate and short
half-life of most proteins. However, long-lived extracellular
proteins, such as lens crystallines produced by fibre cells,
accumulate glycation products, whereby the extent of protein
glycation in fiber cells may be up to 10-fold higher compared
to proteins with high turnover (5).
AGEs play an important role in the structural and
functional alterations of proteins in aging and diabetes (15).
1930
Chronic hyperglycemia in diabetes causes non-enzymatic
glycation of free amino-groups of proteins and leads to various
complications like nephropathy, retinopathy, neuropathy and
angiopathy. Several pathological conditions, such as diabetes,
Alzheimer’s disease, and atherosclerosis have been associated
with damages, induced by oxidation stress, carbonyl stress,
glycation and UV-irradiation. These pathophysiological
conditions are characterized by enhanced formation of AGEs
in blood and tissues (50). Patients with diabetes have less
favourable outcomes from myocardial infarction (26) and after
coronary interventions (8, 28). Increasing evidence suggests
that impaired glycemic homeostasis in diabetics has a direct
influence on the propagation of atherosclerotic plaques (16).
High glucose concentration in diabetes leads, via diverse
mechanisms (the polyol pathway, hexosamine pathway,
and AGE pathway), to increased production of free radical
intermediates (14, 17, 52). H2O2 is a highly reactive oxygen
species, which is overproduced in diabetics. Recently, L.
Holmquist et al. (2007) demonstrated that H2O2 can be
regarded as a true first messenger, which travels between cells
and activates specific signaling molecules (33). In such a way,
H2O2 activates transcription factors like Nuclear Factor NF-κB
and subsequent expression of NF-κB-regulated cytokines or
nitric oxide synthase (48).
The level of glycated albumin is also elevated in diabetics
and glycated serum albumin has been reported to be a better
indicator of glycemic status than HbA1c (76). AGE-modified
albumin exhibits atherogenic effects in various cell types (e.g.
endothelial, mesanglial, mesothelial, monocyte-macrophage,
and vascular smooth muscle cells). Endothelioma and umbilical
vein endothelial cells respond to Amadori-modified albumin
with enhanced nitric oxide synthase activity and NO-dependent
apoptosis (7). Glycated albumin also stimulates adhesion of
monocytes to endothelial cells through enhanced transcription
of the cell surface adhesion molecules E-selectin, vascular cell
adhesion molecule-1 (VCAM-1), and intercellular adhesion
molecule-1 (ICAM-1) leading to endothelial cell activation at
atherosclerosis-prone vascular sites (22). Lin Lu et al. (2007)
demonstrated that increased serum levels of glycated albumin,
TNF-α, and CRP are associated with the presence and severity
of cardiovascular diseases and renal impairment in patients
with type 2 diabetes (41).
Lipids may also be modified by AGEs (10). AGE
modifications of low density lipoproteins (LDL) can occur
both on amino groups of the apoprotein component and on
aminolipid components such as phosphatidylethanolamine.
Non-enzymatic glycation of Apolipoprotein B (Apo B)
in LDL is considered to be a proatherogenic modification
contributory to the increased susceptibility of diabetic patients
to atherosclerotic disease. AGE formation on the apoprotein
component can lead to cross-linking of LDL to the collagen
layer of the blood vessel wall thus leading to accelerated
development of atherosclerosis (60). Moreover, high-density
lipoproteins are expected, when subjected to glycation, to
Biotechnol. & Biotechnol. Eq. 24/2010/3
 lose their anti-inflammatory and cytoprotective properties,
which are suggested to play important protective role in the
propagation of atherosclerosis and also in neurodegenerative
diseases (40).
Retinopathy and cataract
More than 60% of diabetic patients would have some degree
of retinopathy 20 years after the onset of diabetes. The earliest
histopathological hallmark of diabetic retinopathy is loss of
pericytes, which are implicated in the maintenance of capillary
tone. Retinal pericytes accumulate AGEs during diabetes,
which induce growth retardation and apoptotic cell death
and also exert an immediate toxicity to cultured pericytes
(70). AGEs act on pericytes, stimulating vascular endothelial
growth factor (VEGF) expression (70). VEGF is known as
vascular permeability factor, and is thought a pivotal factor
in the pathogenesis of proliferative diabetic retinopathy. The
thickening of basement membrane and increased deposition
of extracellular matrix components may contribute to the
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development of abnormal retinal hemodynamics (2).
Advanced glycation end products induced by
hyperglycemia contribute to cataract formation, which is
a leading cause of blindness. Cataracts are aggregates that
result from dysfunctional protein interactions. Glycation leads
to protein cross-linking, which may act as a nucleation site,
leading to further aggregation. Hong Yan et al. (2006) reported
that advanced glycation cross-linking cause a decrease in
chaperon function of α-crystalline and the inactivation of
enzymes (74). Oxidative stress due to enhanced free radical
production in diabetics is also considered to be associated with
cataract and macular degeneration (59). Moreover, the levels
of glutathione, advanced oxidation products, and superoxide
dismutase activity in a diabetic senile cataract group are
significantly increased compared to the control (non-diabetic)
group (75).
Neuropathy
Diabetes mellitus is a major cause of peripheral neuropathy,
manifested as distal symmetrical polyneuropathy (62).
Basement membrane thickening and pericyte degeneration
have been observed in diabetic neuropathy. An interaction
between AGE-modified myelin and macrophages may initiate
segmental demyelination.
AGEs play a role in abnormal aggregation in Alzheimer’s
disease (AD). A threefold increase in content of AGEs is reported
in the brains of AD patients compared with age-matched
controls (42). Increased levels of AGEs are also observed in
olfractory bulbs, which are early targets of AD (42). Moreover,
Gomes et al. (2005) reported the involvement of AGEs in the
pathogenesis of familiar amyloidotic polyneuropathy (32).
Nephropathy
In diabetic nephropathy the tiny glomerular capillaries are
affected and kidney’s filtration ability is reduced. It has been
shown that CML and pentosidine accumulate in expanded
Biotechnol. & Biotechnol. Eq. 24/2010/3
mesangial and nodular lesions in diabetic nephropathy (54).
AGEs induce apoptotic cell death and vascular endothelial
growth factor (VEGF) expression in cultured mesangial cells
(71), which support glomerular filtration. Oxidative stress has
been suggested to play a main role in the pathogenesis of type
2 diabetes. As a consequence of the increased oxidative status
AGEs accumulation is accelerated by reactive oxygen species
(ROS). AGEs in turn, through the formation of glycated
proteins are also able to produce ROS. During these reactions
compounds with a carbonyl or dicarbonyl moieties are formed
(23). Moreover, there is a significant positive linear correlation
between protein carbonyls and heat shock protein 60 (Hsp60)
expression levels in lymphocytes confirming the importance of
the heat shock response in the oxidative stress (18).
Glycation in plants
A model system for studying the process of aging in plants
is potato (Solanum tuberosum) seed-tubers. Aging beyond
about 8 months leads to changes in growth potential (35),
oxidative stress (36), and decreased protein content (37).
Long-term aging of potato seed-tubers resulted in a loss of
patatin (an antioxidant) and a cystein-proteinase inhibitor,
potato multicystatin (PMC) (38). Oxidation and glycation
have been identified as non-enzymatic mechanisms that affect
the structure and function of proteins and render them more
susceptible to proteolysis during aging process (27). Eckardt
et al. (1995) found that carbonyl content and susceptibility of
Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase)
to proteolysis increased during oxidative stress. Reducing
sugars increase during aging and this is an ideal environment
for protein glycation and loss of enzyme activity. Moreover
glycation of purified cucumber (Cucumis sativus L.) Rubisco
by ascorbic acid leads to decrease in activity of Rubisco and
increases protease susceptibility (72).
Sugar hydrolysis and lipid peroxidation have been shown
to contribute to non-enzymatic modifications of proteins
during seed storage. Mature seeds of many species contain
only trace amounts of reducing sugars, but sugar composition
profile could change during storage (11). Murthy et al. (2000)
demonstrated that the content of glucose and lipid peroxidation
products in seed axes of mungbean significantly increased
during seed storage. Moreover, accumulation of Amadori
products was correlated to lipid peroxidation, whereas the
accumulation of AGE was correlated to sugar hydrolysis (43).
The glycation of many proteins also alters antigenicity of
affected proteins. It has been shown that advanced stages of
the Maillard reaction can lead to protein cross-links creating
novel epitopes, which can bind IgE antibodies and, in this
way, enhance the allergenicity of the protein (49). However,
glycation has been proposed as a way to mask the allergenicity
of soy protein (66). Van de Lagemaat et al. (2007) found that in
vitro antigenicity of soy protein was reduced by glycation with
both fructose and fructooligosaccharides (39).
1931
 Natural defence mechanisms against AGEs 3-phosphates. The later are unstable and spontaneously
formation decompose into inorganic phosphate and 3-deoxyglucosone
There are several defence mechanisms for protection of tissues while regenerating the free lysine residue (Fig. 7).
from carbonyl stress and accumulation of AGEs. Human
serum albumin through its reduced Cys-34 is able to scavenge
hydroxyl radicals. Oxidation of Cys-34 leads to formation of
sulfenic acid, which is further oxidized to sulfinic acid (19).
Glyoxalase 1, certain aldehyde reductases and dehydrogenase
isozymes detoxify reactive carbonyl species like GO, MGO,
and 3-DG. Glutathione (γ-glutamyl-cysteinyl-glycine) is an
important defense factor against oxidative stress. Dietary
supply of glutathione has been shown to prevent diabetic
complications such as nephropathy and neuropathy (47).
Hong Yan et al. (2008) reported that carnosine (a dipeptide,
Fig. 6. Role of oxidases in degradation of the Amadori product (67)
highly concentrated in muscle and brain tissues) inhibits
the formation of AGEs in diabetic rats (73). Taurine, which
is normally found at high concentrations intracellularly in
most animal tissues, reduces the production of AGEs and
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prevents animal collagen from abnormalities, caused by high-

fructose diet (45). Furthermore, several thousands of plant-
derived products like epigallocatechin-3-gallate in green tea,
chlorogenic acid and caffeic acid in coffee beans, capsaicin in
hot chili peppers, hisperitin in citrus fruits, rutin and quercetin
in apples and onions, seem to have the potential to delay aging
(12).
Another protection from AGEs accumulation is
accomplished by amadoriases, enzymes which can interrupt
the glycation cascade at early stages. To date, three groups
of enzymes, capable to reverse the Amadori formation were
discovered. The first encompasses oxidases, which were
first reported in Corynebacterium sp. and Aspergillus sp. by Fig. 7. Proposed role of fructosamine kinase in the decomposition of
fructoselysine (53)
Horiuchi et al. (34). These FAD-containing enzymes were
found to deglycate fructosyl amino acids into glucosone Furthermore, Van Shaftingen and co-workers reported
and the primary amine under formation of H2O2 (Fig. 6). By the existence of a mammalian FN3K-RP (FN3K-related
growing Aspergillus sp. on a minimal medium containing protein), which does not phosphorylate fructosamines but
Amadori products as the sole carbon source, two deglycating ribulosamines and psicosamines (20) and a plant ribulosamine/
enzymes were found and cloned from that microorganism
erythrulosamine 3-kinase (29). The plant homologue of FN3K
(68), which were named amadoriase I and II. Fructosyl amine
and FN3K-RP appears to be targeted to the chloroplasts in
oxidases from different sources showed different activities. For
the same enzyme, the activities varied depending on the size many species. Spinach leaves have an approximately 700-fold
and the charge status of the substrate. For example amadoriase higher ribulosamine kinase activity compared with the specific
II from Aspergillus sp. has a preference for anionic substrates activity of FN3K in human erythrocytes (29).
and mutagenesis studies suggested that two arginine residues FN3K is present in many tissues including skeletal muscle
are responsible for that (69). In 2008 Collard et al. identified and heart (24), where the intracellular glucose concentration
the crystal structure of the Aspergillus fructosamine oxidase. is more than 10-fold lower than that in plasma. Fructosamine-
The active site pocket of the enzyme is about 12 Ǻ deep and 6-phosphates, which are more powerful glycating agents
this explains why glycated lysyl residues bound to globular
than glucose result from the reaction of amines with Glu-6-P,
proteins are poor substrates of the enzyme (21).
but they are not substrates for FN3K. Further investigations
A second group of deglycating enzymes was discovered
led to the discovery of magnesium-dependent phosphatase
by Van Shaftingen and co-workers (25) based on earlier NMR
studies by Szwergold et al. (1990). Van Shaftingen and co- (MDP-1) by Van Shaftingen and co-workers, which converts
workers have cloned and fully characterized the enzyme fructosamine-6-phosphates to fructosamines. A phosphatase
fructosamine 3-kinase (25). This enzyme phosphorylates carrying out this reaction was detected in rat tissues and MDP-
with high affinity both low molecular mass and protein bound 1 may act in concert with FN3K to free proteins from the
fructosamines, leading to the formation of fructosamine glycation products derived from Glu-6-P (30).
1932 Biotechnol. & Biotechnol. Eq. 24/2010/3

Fig. 8. Proposed deglycation pathway of fructoselysine in E. coli. (64)
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A third group of deglycating enzymes was reported
by Van Shaftingen and co-workers (64) who found that
fructoselysine can sustain the growth of Escherichia coli.
These findings suggested the existence of a whole set of genes
(a bacterial operon) that controls the uptake and metabolism of
fructoselysine. The pathway responsible for utilization of this
Amadori product in E. coli consists of kinase and deglycase
(Fig. 8).
The kinase belongs to Pfk/ribokinase family and catalyzes
the ATP-dependent phosphorylation of fructoselysine
to fructoselysine-6-phosphate. The deglycase catalyzes
the formation of lysine and glucose-6-phosphate from
fructoselysine 6-phosphate. Moreover, Van Schaftingen and
colleagues (65) described the presence of glucoselysine-6-
phosphate deglycase in Enterococcus faecium.
Summary and future directions
Glycation is a major cause of spontaneous damage to proteins,
giving rise to the presence of lysine- and arginine-derived
glycation adducts in extracellular and cellular proteins. Highly
reactive α-dicarbonyls like MG and GO, formed in the time
course of the Maillard reaction, react readily with proteins,
thus playing an important role in aging and disease processes.
Glycation is increased in diabetes and there is a considerable
body of evidence implicating accumulation of advanced
glycation end products as a main factor in the development
of diabetic complications, atherosclerosis, nephropathy,
Alzheimer’s disease, and the normal aging process. Cell damage
by AGEs comes from cross-linking of structural proteins,
especially long-lived like collagens and lens crystalline, and
metabolic enzymes, affecting their physiological functions.
However, the diet is a main environmental source of AGEs
and “unhealthy” lifestyle seems to be associated with most
chronic diseases. Restrictions in food intake and low-AGE
diet are effective ways for prolonging lifespan and preventing
chronic diseases.
Biotechnol. & Biotechnol. Eq. 24/2010/3
The diabetic complications can be ameliorated by reducing
glycation and numerous natural and synthetic compounds
are being investigated for an eventual therapeutic potential.
Among natural defence mechanisms against glycation
are the enzymes called amadoriases, which catalyze the
decomposition of Amadori products, thus interrupting the
glycation cascade at early stages. These enzymes are known
to occur in mammalian, fungal, plant and prokaryotic cells. To
date, glycation in plants has been scarcely studied. However,
the high levels of ribulosamine kinase activity in plants may
be associated with increased glycation “stress” as compared to
that in mammalian tissues, which makes plants an attractive
model for future investigations on natural defence mechanisms
against glycation.
Acknowledgements
This work is supported by grants from Ministry of Education
and Sciences of Bulgaria (ВУ-Б-203/06) and (TK-B-1602/06).
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