biomolecules
Review

Structures of Toxic Advanced Glycation End-Products Derived
from Glyceraldehyde, A Sugar Metabolite
Akiko Sakai-Sakasai 1,2,† , Kenji Takeda 1,3,† , Hirokazu Suzuki 4 and Masayoshi Takeuchi 1, *,†
1

2

3

4

*
†

Citation: Sakai-Sakasai, A.; Takeda,

Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku,
Uchinada, Kahoku 920-0293, Ishikawa, Japan; asakasai@kanazawa-med.ac.jp (A.S.-S.);
ktakeda@kanazawa-med.ac.jp (K.T.)
General Medicine Center, Kanazawa Medical University Hospital, 1-1 Daigaku, Uchinada,
Kahoku 920-0293, Ishikawa, Japan
Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada,
Kahoku 920-0293, Ishikawa, Japan
Department of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University,
Kanazawa 920-1181, Ishikawa, Japan; h-suzuki@hokuriku-u.ac.jp
Correspondence: takeuchi@kanazawa-med.ac.jp; Tel.: +81-76-218-8456
These authors contributed equally to this work.

Abstract: Advanced glycation end-products (AGEs) have recently been implicated in theonset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced
by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose andfructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate andinduce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following
GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds,
GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, andargpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells.
The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for
AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used
as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations oftreatment efficacy. This review provides an overview of the structures of GA-AGEs.

K.; Suzuki, H.; Takeuchi, M.
Structures of Toxic Advanced
Glycation End-Products Derived from

Keywords: advanced glycation end-products (AGEs); glyceraldehyde (GA); GA-derived AGEs
(GA-AGEs); toxic AGEs (TAGE); lifestyle-related diseases (LSRDs)

Glyceraldehyde, A Sugar Metabolite.
Biomolecules 2024, 14, 202. https://doi.org/10.3390/biom14020202
Academic Editor: Norbert Nass
Received: 12 January 2024
Revised: 1 February 2024
Accepted: 6 February 2024
Published: 8 February 2024

Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Under hyperglycemic conditions, glucose (Glu) reacts with primary amines (the Nterminal or lysine (Lys) side chain) or the guanidine group of the arginine (Arg) side chainof proteins. This process begins with the conversion of reversible Schiff base adducts
to more stable, covalently bound Amadori rearrangement products. Over the course of
several days to weeks, these Amadori products undergo further dehydration, condensation, fragmentation, rearrangement, and oxidation reactions to form irreversibly boundmoieties known as advanced glycation end-products (AGEs) [1–4]. AGEs exogenously or
endogenously accumulate in the body [5–7]. Various AGEs are produced in these reactions,with the different types formed being dependent on the reducing sugars and carbonylcompounds involved [8–17]. The rate of glycation also differs according to the types ofsugars involved, with glyceraldehyde (GA), a tricarbohydrate and intermediate of Glu
and fructose (Fru) metabolism, being faster in glycation reactions than Glu/Fru [18–21].
GA-derived AGEs (GA-AGEs) are highly cytotoxic [22,23].
In our recent studies, we showed that intracellularly accumulated GA-AGEs contributed to the onset/progression of lifestyle-related diseases (LSRDs) by triggering cell

Biomolecules 2024, 14, 202. https://doi.org/10.3390/biom14020202

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In our recent studies, we showed that intracellularly accumulated GA-AGEs contributed to the onset/progression of lifestyle-related diseases (LSRDs) by triggering cell damage [24–36].
Elevated
intracellularlevelslevelsof GA-AGEs
havehavealso also
beenbeen
implicatedin thedamage[24–36].
Elevated
intracellularof GA-AGEs
implicatedinpathogenesisofmetabolicsyndrome(MetS),
non-alcoholicsteatohepatitis(NASH),
cardithe pathogenesis of metabolic syndrome (MetS), non-alcoholic steatohepatitis (NASH),
ovascular diseases(CVD),
diabetes
mellitus(DM)
anditsitscomplications,cardiovasculardiseases(CVD),
diabetes
mellitus(DM)
andcomplications,somesomecancer
cancertypes,
and
Alzheimer’s
disease(AD)[22,23,37–39].
Althoughthemechanisms
types, and Alzheimer’s disease (AD) [22,23,37–39]. Although the mechanismsby
by which
which
GA-AGEs exert
exert their
their toxic
toxic eﬀects
GA-AGEs
effects andand thethe specificspecific structures
structures responsible
responsible have
have notnotyetyetbeenbeen
elucidated, previous
previous studies
studies have
have demonstrated
elucidated,demonstrated thatthat anan antibody
antibody targetingtargetingGA-AGEs
GA-AGEscancaneﬀectively
attenuate
AGE-induced
neurotoxicity
in
the
serum
of
patients
withdiabetic
effectively attenuate AGE-induced neurotoxicity in the serum of patients with diabetic
nephropathy with
with hemodialysis
hemodialysis (DN-HD)
nephropathy(DN-HD) [40].
[40]. However,
However, this
this protective
protective eﬀect
effect was
was notnotobserved
whenantibodies
targeting
other
types
of
AGEs
were
used.
Therefore,AGE
observed when antibodies targeting other types of AGEs were used. Therefore,strucAGEtures containing
epitopes
recognizedby theantibodysolelyappearto be
structurescontaining
epitopes
recognizedby anti-GA-AGE
the anti-GA-AGE
antibodysolelyappeartotoxic,
arecalledtoxic
AGEs(TAGE),
andaredistinct
from
other
GA-AGEs,
includingtribe toxic, are called toxic AGEs (TAGE), and are distinct from other GA-AGEs, including
osidines [41],triosidines[41],GA-derived
GA-derivedpyridinium
pyridiniumcompounds
compounds(GLAP)(GLAP)[42],[42],pyrrolopyridinium
pyrrolopyridiniumLys
Lys
dimers derived
derived fromfrom GAGA (PPGs)
dimers(PPGs) [43],[43], methylglyoxal
methylglyoxal (MGO)-derived(MGO)-derivedhydroimidazolone
hydroimidazolone11(MG-H1) [44],[44], andand argpyrimidine
argpyrimidine (ArgP)(ArgP) [45].
[45].
(MG-H1)This
review
providesanoverviewofstructures
involved
the formationofThis review provides an overview of thethe
structures
involvedin theinformationof AGEs,
AGEs,
particularlyfor
GA-AGEs.
particularly for GA-AGEs.

2.
Are Produced
Produced inin thethe Human
Human Body
Body
2. Routes by Which Various AGEs Are
We
sugars,We previously
previouslydemonstrated
demonstratedthat
thatAGEsAGEswere
wereproduced
producednot
notonly
onlyfrom
fromreducing
reducing
sugsuch
as
Glu,
Fru,
and
GA,
but
also
from
carbonylcompounds,
includingglycolaldehydears, such as Glu, Fru, and GA, but also from carbonyl compounds, including glycolalde(Glycol),glyoxal(GO), (GO),MGO,MGO,and 3-deoxyglucosone[12,14,16].
We alsoAGEhyde (Glycol),glyoxaland 3-deoxyglucosone[12,14,16].
Wedeveloped
also developed
antibodies
that specificallyrecognize
sevensevendistinct
AGEAGE
classesamong
circulating
proAGE antibodies
that specificallyrecognize
distinctclassesamong
circulatingteins
andandpeptidesin serumcollected
fromfrom
DN-HD.
Basedon our
we proposed
proteins
peptidesin serumcollected
DN-HD.
Basedon findings,
our findings,
we propathways
for thefor
inthe
vivo
of distinct
AGEAGE
classes
by glycation,
as as
shown
in
posed pathways
in formationvivo formationof distinct
classes
by glycation,
shown
Figure1. 1.
in Figure

Figure 1.
1. Routes by which advanced
Figureadvanced glycation
glycation end-products
end-products (AGEs)(AGEs)areare produced
producedinin thethe human
human
body.
HFCS:
high-fructose
cornsyrup;
HbA1c:
hemoglobin
A1c;
Glu-AGEs:
glucose-derived
AGEs;
body. HFCS: high-fructose corn syrup; HbA1c: hemoglobin A1c; Glu-AGEs: glucose-derived
GA-AGEs:
glyceraldehyde-derived
AGEs;
Fru-AGEs:
fructose-derived
AGEs;
Glycol-AGEs:
glyAGEs; GA-AGEs: glyceraldehyde-derived AGEs; Fru-AGEs: fructose-derived AGEs; Glycol-AGEs:
colaldehyde-derived AGEs; GO-AGEs: glyoxal-derived AGEs; MGO-AGEs: methylglyoxal-derived
glycolaldehyde-derived AGEs; GO-AGEs: glyoxal-derived AGEs; MGO-AGEs: methylglyoxalAGEs; 3-DG-AGEs: 3-deoxyglucosone-derived AGEs; GA: glyceraldehyde; P-NH2: free amino residerived
due of a AGEs;
protein.3-DG-AGEs: 3-deoxyglucosone-derived AGEs; GA: glyceraldehyde; P-NH2 : freeamino residue of a protein.

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Marked variations have been reported in the structures of AGEs in vivo and theirproduction is known to be dependent on a number of complex reactions, including dehydration,oxidation,condensation,and rearrangements;
therefore,
theirabundant
forMarked
variations
have been reported
in the structuresof AGEsin vivoand their
mationis
expected.
However,thestructuresof
only
approximately
30
types
of
AGEs
have
production is known to be dependent on a number of complex reactions, including dehybeen elucidated
tocondensation,
date [46–51], andof highly cytotoxic
AGEs
undration,oxidation,and those
rearrangements;
therefore,
theircurrently
abundantremain
formation
known.
These
AGEs
are
classified
into
four
groupsaccordingtotheirchemicalcharacteris expected. However, the structures of only approximately 30 types of AGEs have been
istics:elucidated
to date [46–51], and those of highly cytotoxic AGEs currently remain unknown.
These
AGEs are classified
into four groups
accordingto theirchemical characteristics:
1. Fluorescentand cross-linked
products(i.e., PPGs,
pentosidine,crossline, and vespelysine); and cross-linked products (i.e., PPGs, pentosidine, crossline, and vespelysine);
1.
Fluorescent
2. Fluorescent
Fluorescent andand non-cross-linked
non-cross-linked products
products (i.e.,(i.e., ArgP);
ArgP);
2.
3.
Non-fluorescentandcross-linked
products(i.e.,MGO-Lys-dimer, GO-Lys-dimer,
GO-Lys-dimer,3.
and glucosepane);
4. Non-fluorescent and non-cross-linked products (i.e., trihydroxy-triosidine,
trihydroxy-triosidine, GLAP,
GLAP,
4.
MG-H1, Nεε-(carboxyethyl)Lys,-(carboxyethyl)Lys, N
Nεε-(carboxymethyl)Lys-(carboxymethyl)Lys(CML),(CML),andandpyrraline).
pyrraline).
3.
3. Generation
Generation of
of GA
GA
GA
is
a
very
potentGA is a very potent glycating
glycating agent
agent thatthat isis produced
produced byby thethe pathways
pathways responsible
responsiblefor
for
sugar
fructolysis,
glycolysis,
andandthe polyol
pathway[38], andsugarmetabolism,
metabolism,including
includingfructolysis,
glycolysis,
the polyol
pathway[38],plays
andanimportantrole in role
the generationof GA-AGEs(Figure(Figure
2).
plays
an importantin the generationof GA-AGEs
2).

Figure 2.
2. Routes
throughsugar
metabolicpathways.
G-6-P:
FigureRoutes bybywhichwhichGA
GAand
andMGOMGOarearegenerated
generatedthroughsugar
metabolicpathways.
Gglucose-6-phosphate;
F-6-P:
fructose-6-phosphate;
F-1,6-BP:fructose-1,6-bisphosphate;
F-1-P:
fruc6-P: glucose-6-phosphate; F-6-P: fructose-6-phosphate; F-1,6-BP: fructose-1,6-bisphosphate; F-1-P:
tose-1-phosphate; AR: aldose reductase; SDH: sorbitol dehydrogenase; FK: fructokinase; GAPDH:
fructose-1-phosphate; AR: aldose reductase; SDH: sorbitol dehydrogenase; FK: fructokinase; GAPDH:
GA-3-phosphate dehydrogenase; GLO: glyoxalase; GLAP: GA-derived pyridinium compounds;
GA-3-phosphate dehydrogenase; GLO: glyoxalase; GLAP: GA-derived pyridinium compounds;
PPGs: pyrrolopyridinium Lys dimers derived from GA; MG-H1: MGO-derived hydroimidazolone
PPGs:pyrrolopyridinium
Lys dimers
1; ArgP:
argpyrimidine; TAGE:
toxic derived
AGEs. from GA; MG-H1: MGO-derived hydroimidazolone 1;
ArgP: argpyrimidine; TAGE: toxic AGEs.

3.1. Fructolysis
Fructolysis
3.1.
Fruisisaacommon
commonsugar
sugarinindiets
dietsand
andisisthethemainmain
component
high-Fru
cornsyrup.
Fru
componentof ofhigh-Fru
cornsyrup.
It isItismetabolized
in
cells
via
two
pathways:(1)
Phosphorylationbyhexokinase,whichmetabolized in cells via two pathways: (1) Phosphorylation by hexokinase, which is presentis
present
in However,all cells. However,hexokinase
exhibits
a strong forpreference
for is
Glu,
which
in
all cells.
hexokinase
exhibits a strong
preference
Glu, which
present
at isapresent at a ofconcentrationof 5approximately
5 mM
and,
thus, is inhibitora strong
concentration
approximately
mM in blood and,thus,inis blooda strong
competitiveof Fru phosphorylation. (2) Fructokinase (FK) in the liver, particularly after a meal. Fru
is phosphorylated by a specific FK in the liver to form Fru-1-phosphate (F-1-P), which

Biomolecules 2024, 14, 202

4 of 15is then cleaved by aldolase B [52,53]. The products of Fru metabolism in the liver are
dihydroxyacetone-phosphate (DHA-P) and GA.
3.2. Glycolysis
Glycolysis is a fundamental metabolic pathway for the conversion of Glu to pyruvate.
GA-3-phosphate (GA-3-P) is a key intermediate of this pathway and a substrate of GA-3-P
dehydrogenase (GAPDH). Together with a reduction in GAPDH activity, the metabolismof GA-3-P decreases and GA-3-P accumulates intracellularly. GA-3-P metabolism shifts toanother route and the amount of GA increases, which promotes the formation of GA-AGEs.
As shown in Figure 2, GA-3-P is an intermediate of this pathway, undergoes enzymatic
reduction by GAPDH, and eventually forms pyruvate. Some GA-3-P is also spontaneously
degraded to GA, which reacts non-enzymatically with proteins to create GA-AGEs. GAAGEs have been implicated in diseases related to hyperglycemia [54,55].
3.3. Polyol Pathway
In healthy individuals, Glu is converted to GA-3-P by GAPDH and is maintained at
low levels [56]. Aldose reductase (AR) catalyzes the reduction of Glu to sorbitol, whichis then converted to Fru by sorbitol dehydrogenase. AR has a low affinity for Glu and,thus, this pathway is not very active under normal Glu homeostasis. However, under
hyperglycemic conditions, Glu concentrations are elevated in insulin-independent tissues,
such as red blood cells, the brain and nerve tissues, the lens, and the kidneys, which
enhances the activity of the polyol pathway [57,58]. Fru may also be metabolized to GA
through fructolysis by FK and aldolase B.
Therefore, changes in the regulation of sugar metabolic pathways may induce anincrease in GA levels and, thus, the accumulation of GA-AGEs, resulting in cytotoxicity [23].
4. Generation of MGO
MGO is a highly reactive dicarbonyl compound that is formed as a byproduct ofglycolysis, in which the intermediate triosephosphates, DHA-P and GA-3-P, spontaneously
degrade to generate MGO (Figure 2) [59]. Approximately 0.05–0.1% of the triosephosphates
in glycolysis are degraded to MGO [60]. MGO may contribute to the production of AGEs
through selective reactions with the Arg and Lys side chains on proteins. MGO is an
Arg-directed glycating agent that mainly forms MG-H1 [61,62] and ArgP [63,64]. MGO is
metabolized by multiple pathways to prevent its accumulation to abnormally high levels.
The glyoxalase (GLO) system, comprising GLO 1 and 2, is the primary metabolic pathway
for MGO, converting it to D-lactate [65–68].
5. Structures of GA-AGEs
To date, the following GA-AGE structures have been detected: triosidines [41], GLAP [42],PPGs [43], MG-H1 [44], and ArgP [45] (Figures 1 and 2). Trihydroxy-triosidine, GLAP,
and PPGs were identified in the Lys residues and MG-H1 and ArgP in the Arg residues
of proteins. Even though the cytotoxicity of GA-AGEs has been examined, few studies
have attempted to identify GA-AGEs using a proteome-wide analysis. Senavirathna et al.
reported that Lys residues were significantly more likely to form GA-AGEs than Arg
residues, which will be important for the future development of novel strategies to preventand treat GA-AGE-dependent diseases [69]. This finding also has important implications
for the prevention and treatment of LSRDs.
5.1. Structures of GA-AGEs with Lys Modifications
The roles of the highly reactive triose sugar GA in protein cross-linking and Lys/Arg
modifications during the Maillard reaction have been investigated. However, the structurally distinct GA-AGEs involved in LSRDs currently remain unknown. The modificationof proteins by GA may generate a number of different GA-AGEs, including trihydroxytriosidine, GLAP, PPGs, MG-H1, and Arg P (Figure 3).

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structurally distinct GA-AGEs involved in LSRDs currently remain unknown. The modification of proteins by GA may generate a number of diﬀerent GA-AGEs, including trihy5 of 15
droxy-triosidine, GLAP, PPGs, MG-H1, and Arg P (Figure 3).

Figure 3. Structures ofGA-derived pyridinium;pyridinium; PPG:of glyceraldehyde
glyceraldehyde (GA)-derived(GA)-derived AGEs. GLAP: GA-derived
pyrrolopyridinium Lys
Lys dimer
dimer derived
derived fromfrom GA;
GA;MG-H1:
MG-H1: MGO-derived
MGO-derived hydroimidazolone
hydroimidazolone1.
1.
pyrrolopyridinium

5.1.1.
Triosidines
5.1.1. Triosidinesαα -acetyl-L-Arg and isolated
Tessier
Tessier et
et al.
al. incubatedincubated GA
GAwith
withNNα-acetyl-L-Lys-acetyl-L-Lys andand N
Nα-acetyl-L-Arg
and isolated
four
four new
new Maillard
Maillard reaction
reaction pyridinium
pyridinium compounds
compounds named
named triosidines
triosidines [41].
[41]. Lys
Lys adducts
adductsaretrihydroxy-triosidine,
Lys-hydroxy-triosidine,andtriosidine-carbaldehyde,
thethelatterofare trihydroxy-triosidine, Lys-hydroxy-triosidine, and triosidine-carbaldehyde,
latterwhich
is labile.
TheTheLys-Arg
adductis Arg-hydroxy-triosidine.
Triosidines
are a are
novel
class
of whichis labile.
Lys-Arg
adductis Arg-hydroxy-triosidine.
Triosidinesa novel
of
AGEs
that
are
expected
to
offer
novel
insights
ofbiomedical
importancefor
disordersofclass of AGEs that are expected to oﬀer novel insights of biomedical importance for disortriose
metabolism
andthebiophysical
and
toxic
effectsoftriose-based
diseases.
ders of triose metabolism and the biophysical and toxic eﬀects of triose-based diseases.
5.1.2. GLAP
5.1.2. GLAP
GLAP is formed from GA with Nα -acetyl-L-Lys [42]. Since GLAP is not formed
from GANα-acetyl-L-Lys[42]. Since
GLAP
is not formed
from
fromGLAP
MGO,isit formed
has potential
as awith
specific
marker of reduced
GAPDH
activity
in metabolic
MGO,
it
has
potentialasaspecific
markerof
reduced
GAPDH
activityinmetabolicdisdiseases, such as diabetic complications. Although GLAP, which is formed by GA-relatedeases, suchwas
as identified
diabetic complications.
Althoughand
GLAP,
whichcollagenis formed
by GA-related
glycation,in the plasma proteinstail tendonof streptozotocinglycation,
was
identified
intheplasmaproteins
andtailtendoncollagenof
streptozotocininduced diabetic rats [70], it remains unclear whether circulating GLAP levels may be
inducedratsof[70],it remains
unclearwhether
circulatinglevelsbeused
as a diabetic
biomarker
vascularinjury indiabetic
patients.
Usui et al.GLAP
revealed
thatmay
GLAP
used
as
a
biomarker
ofvascularinjuryindiabetic
patients.
Usui
et
al.
revealedthat
GLAP
derived from GA induced oxidative stress in HL-60 cells [71]. GLAP also exerted toxic
derivedinfrom
inducedoxidative
stressinhibitedin HL-60bycells[71]. GLAP also
exertedtoxic
effects
PC12GA
neuronal
cells,
which werean anti-receptor
for AGEs(RAGE)
eﬀects in PC12
neuronal
cells,
which were that
inhibited
an anti-receptor
for AGEs(RAGE)
antibody[72]. Matsui
et al.
demonstrated
GLAPbyinteractedwith RAGE
and induced
antibody[72].
Matsuietal.
demonstrated
that
GLAP
interacted
with
RAGE
and
inducedthe production of reactive oxygen species (ROS) in endothelial cells (ECs) [73]. However,the precise
productionof reactive
oxygenspeciesin endothelial
cells (ECs)[73]. However,thestructural
moieties
requiredfor(ROS)the toxic
effects of GLAP
via RAGE
have nottheprecisestructural
moieties
required
for
the
toxic
eﬀects
of
GLAP
via
RAGE
have notyet been fully elucidated.
yet been fully elucidated.
5.1.3. PPGs
The pyridinium-type AGEs trihydroxy-triosidine and GLAP have been identified as
GA-AGEs; however, their pathological effects are yet to be clarified. The Maillard reaction
between Nα -acetyl-L-Lys and GA was recently examined under physiological conditions

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and the main products identified were PPG1 and PPG2, which are fluorescent AGEs inwhich pyrrolopyridine ring structures cross-link two Lys molecules [43]. Based on thesefindings, a mechanism was proposed for the generation of PPG1 and PPG2 in vitro via
a unique reaction to expand the skeleton as an alternative to the typical route for theformation of Schiff bases.
5.2. Structures of GA-AGEs with Arg Modifications
Although the majority of AGEs are formed from the Lys/Arg residues of proteins, thestructures of GA-AGEs produced from Arg residues remain unclear.
5.2.1. MG-H1
Usui et al. isolated and identified GA-AGEs formed from GA and Nα -acetyl-L-Arg.
A major product was identified as MG-H1 [44]. They isolated and identified MG-H1,
which was generated in the presence of Lys/Arg residues, and suggested that MG-H1 wasformed through both GA-related and MGO-related pathways. MG-H1 has potential as
an indicator of damage to GA- and MGO-related enzymes, such as GAPDH and GLO.
Rabbani et al. recently reported a relationship between serum MG-H1 levels and thestage of chronic kidney disease [74]. Zhang et al. also showed that plasma MG-H1 levels
were associated with impaired cognitive performance in Chinese community-dwelling
middle-aged and elderly subjects [75]. However, further studies are needed to clarify the
relationship between blood MG-H1 levels and LSRDs.
5.2.2. ArgP
Three major GA-AGEs were formed from a mixture of Nα -acetyl-L-Lys, Nα -acetyl-LArg, and GA. Two of these compounds were GLAP and MG-H1, as previously reported,
while the other was identified as ArgP. Although ArgP is a modified product of Arg residues,
it did not form from GA with Arg residues [45]. The co-existence of Lys residues is necessary
for the formation of ArgP, which is considered to be derived from MGO; however, a numberof pathways are involved in the formation of ArgP. ArgP may be generated by both MGO
and GA and, thus, has potential as a marker of both MGO-/GA-related glycation.
6. Structures of TAGE
GA is one of the most potent precursors of GA-AGEs because it causes the nonenzymatic glycation of proteins, resulting in irreversible TAGE production. The formationof TAGE mainly occurs intracellularly through glycation reactions between GA and intracellular proteins, which produce TAGE molecules of different sizes and properties. Althougha more detailed understanding of the mechanisms underlying TAGE toxicity is needed, previous studies have indicated that it is due to oxidative stress-induced damage [26,39], theloss of protein functions as a result of glycation modifications [39], and TAGE aggregation
and accumulation [30].
6.1. Proposed TAGE Structures
TAGE were prepared by a model system, involving a reaction between egg lysozyme
and GA, and samples were separated by sodium dodecyl sulfate polyacrylamide gelelectrophoresis. After their migration, the separated proteins were transferred to PVDF
membranes and an anti-TAGE antibody recognized dimer/trimer bands (intermolecular
protein cross-links) and monomer bands (intramolecular protein cross-links) [unpublisheddata]. Two compounds with GA-derived 1,4-dihydropyrazine rings emitting AGE-specificfluorescence and forming intra/intermolecular cross-links have been proposed as candidate
TAGE structures (Figure 4) [76].

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fluorescence and forming intra/intermolecular cross-links have been proposed as candi7 of 15
date TAGE structures (Figure 4) [76].

Figure4. 4.
Proposedstructuresof TAGE.
(A): 1,4-Di(5-amino-5-carboxypentyl)-2,5-dihydroxyFigure
Proposedstructuresof TAGE.
(A): 1,4-Di(5-amino-5-carboxypentyl)-2,5-dihydroxymethyl1,4-dihydropyrazine;(B): 1,4-di(5-amino-5-carboxypentyl)-5-(5-amino-5-carboxy-pentylaminomemethyl-1,4-dihydropyrazine;(B): 1,4-di(5-amino-5-carboxypentyl)-5-(5-amino-5-carboxy-pentythyl)-2-hydroxymethyl-1,4-dihydropyrazine.
laminomethyl)-2-hydroxymethyl-1,4-dihydropyrazine.

6.2.New
NewConcept
ConceptininLSRDs:
LSRDs:theThe
TAGE
Theory6.2.
TAGE
TheoryAlthoughGA-AGEs
GA-AGEsare
areaastructurally
structurallyheterogeneous
heterogeneousgroup
groupofofmolecules,
molecules,thethespecificspecific
Althoughstructures
responsible
for
their
toxicity
have
yet
to
be
identified.
structures responsible for their toxicity have yet to be identified.
Theneurotoxicity
neurotoxicityofofAGEs
AGEsininthe
theserum
serumofofDN-HD
DN-HDwaswaspreviously
previouslyshown
showntotobebecomcomThepletelysuppressedbyananti-TAGE
antibody,
andthisprotective
effectwasnotachieved
pletely suppressed by an anti-TAGE antibody, and this protective eﬀect was not achieved
whenantibodies
antibodiestargetingtargetingother
othertypes
typesofofAGEsAGEswere
wereused
used [40].
[40]. Therefore,
Therefore,solely
solelyAGE
AGE
whenstructurescontaining
epitopes
recognizedbytheanti-GA-AGE
antibody
appeartobestructures containing epitopes recognized by the anti-GA-AGE antibody appear totoxic.
beSpecific
GA-AGEs
recognizedby thebyanti-TAGE
antibody
are called
TAGE TAGE
and areanddistinct
toxic.
Specific
GA-AGEs
recognized
the anti-TAGE
antibody
are calledarefrom other AGEs and GA-AGEs, such as triosidines, GLAP, PPGs, MG-H1, and ArgP. The
distinct from other AGEs and GA-AGEs, such as triosidines, GLAP, PPGs, MG-H1, andaccumulation of intracellular GA-AGEs has been implicated in the onset/progression of
ArgP. The accumulation of intracellular GA-AGEs has been implicated in the onset/proLSRDs. This discovery has led to the TAGE concept.
gression of LSRDs. This discovery has led to the TAGE concept.
7. Cytotoxicity of TAGE
7. Cytotoxicity of TAGE
Previous studies have suggested the involvement of TAGE accumulation in the pathogenhave
suggested
the involvementof TAGEin the pathesis Previousof NASH,studies
CVD, DMandits complications,some cancer
types,accumulation
and AD [22,23,37–39,55,77].
ogenesis
of
NASH,
CVD,
DM
and
its
complications,somecancertypes,andAD
We recently demonstrated that TAGE were produced by and accumulated in[22,23,37–
many cell
39,55,77].
We recently
demonstrated
that cells,
TAGEleakwere
producedby andaccumulatedintypes [24–36].
Excessive
TAGE damage
intosurroundingcells
and the circumany
types [24–36].
Excessive
TAGE
damageofcells,
leak into surrounding
cells andto
lation,cellinteractwith RAGE,
and theactivation
the TAGE–RAGE
axis contributes
thecirculation,interact
with
RAGE,
and
the
activationoftheTAGE–RAGE
axis
contrib-of
the onset/progression of LSRDs [54,55]. We previously reported the binding affinity
utes
to
the
onset/progressionof
LSRDs[54,55].
We
previously
reportedthebindingaﬃnthe human RAGE protein to TAGE, which were more abundant in the serum of patients
ity
of
the
human
RAGE
protein
to
TAGE,
which
were
more
abundant
in
the
serum
of
with DM than in healthy controls. The dissociation constant of TAGE with RAGE waspatients
with
DM
than
in
healthy
controls.
The
dissociation
constant
of
TAGE
with
RAGE
0.36 µM [78]. In DM, TAGE have been suggested to exert intracellular effects by strongly
was0.36 toµM[78]. In DM, TAGE have been suggested to exert intracellular eﬀects bybinding
RAGE.
strongly binding to RAGE.
7.1. Accumulation of Intracellular TAGE and Cell Damage
7.1.
Accumulationof Intracellular
TAGE
and Cell Damage
7.1.1.
Intracellular
TAGE and Cell
Death

7.1.1. Intracellular
and Cell
Death
Intracellular TAGEGA levels
are increasedby the frequent and excessive intake of sugarsweetened
beverages
and/orprocessed
foods,
are prevalent
in contemporary
daily
Intracellular GA levels are increased by thewhich
frequent
and excessive
intake of sugardiets.
Reactions
betweenelevatedlevelsofGA
andintracellular
proteins
inducethesweetened beverages and/or processed foods, which are prevalent in contemporary daily
production
of
TAGE
[79],
which
exert
cytotoxic
effectsinvariouscell
types,
includinghepadiets. Reactions between elevated levels of GA and intracellular proteins induce the protocytesof[24–27],[28–30],cardiomyocytes[31]
and including
cardiac fibroblasts
ductionTAGE neuroblastoma[79], which exertcells
cytotoxic
eﬀectsin various cell
types,
hepato(CFs)[32],
pancreatic
ductalcells[33],
β-cells[34],
myoblasts[35],
andosteoblasts[36].
cytes [24–27], neuroblastoma cells [28–30], cardiomyocytes [31] and cardiac
fibroblasts
Based
on
these
findings,
TAGE
have
been
suggested
to
play
a
role
in
apoptosis
and/or(CFs) [32], pancreatic ductal cells [33], β-cells [34], myoblasts [35], and osteoblasts [36].
necrosis,whichfindings,
ultimately
lead haveto cellbeen
deathsuggested
and tissuetodamage.
Basedon these
TAGE
play a role in apoptosis and/or
necrosis,whichultimately lead to cell death and tissue damage.
TAGE andHepatocytes
Cell damage caused by the production and accumulation of TAGE has been examinedusing molecular biological methods with established human hepatic parenchymal cell lines(Hep3B and HepG2) and primary cultured hepatocytes. The findings obtained revealed
the following: (i) when GA was added to hepatocytes, the cell viability decreased as
the TAGE levels increased [24,25,27]; (ii) the molecular chaperone Hsc70 [24] and theBiomolecules 2024, 14, 202

8 of 15

apoptosis execution factor caspase-3 [25] were identified as proteins that undergo TAGE
modifications; (iii) ROS production was associated with the intracellular accumulation of
TAGE, suggesting a mitochondrial abnormality as the cause [26]; (iv) the mRNA levelsof C-reactive protein, a marker of inflammation, significantly increased after the additionof GA [24]. These findings indicate that the production and accumulation of intracellular
TAGE induce cell damage and inflammatory reactions. Therefore, strategies to suppress
the intracellular accumulation of TAGE have potential for the prevention and treatment of
the onset/progression of NASH [39].
TAGE and Neurons
A GA-treated human neuroblastoma (SH-SY5Y) cell extract was obtained by
two-dimensional electrophoresis, detected using the TAGE-specific antibody, and target proteins were identified using a time-of-flight mass spectrometer. One of the target
proteins was β-tubulin, which plays an important role in the formation of microtubules innerve axons. The GA-induced formation of TAGE on β-tubulin may result in the generation of TAGE–β-tubulin aggregates, thereby inhibiting nerve axon elongation [29]. The
phosphorylation of tau, which is present in neurofibrillary tangles, was also observed.
The formation of TAGE–β-tubulin was found to induce similar pathological changes toneurofibrillary tangles in AD, which contribute to the onset/progression of AD. Abnormal
aggregation associated with the production of TAGE–β-tubulin appeared to inhibit thenormal formation of microtubules, thereby suppressing neuronal axon elongation. Furthermore, pyridoxamine (PM), a type of vitamin B6, attenuated the inhibition of nerveaxon elongation by suppressing the formation of TAGE [30]. Therefore, a more detailed
understanding of the production of TAGE–β-tubulin and the mitigating effects of PM will
provide insights into the mechanisms underlying the onset of AD.
TAGE, Cardiomyocytes, and CFs
We previously reported that the intracellular accumulation of TAGE reduced the beatrate of cardiomyocytes and this was accompanied by a decrease in autophagy function andcell death [31]. On the other hand, extracellular TAGE did not directly inhibit cardiomyocyte
beating or induce cardiomyocyte cell death. In our recent study, we immunologically
identified Hsp90β and its high-molecular-weight (HMW) complex as one of the proteinsthat undergo TAGE modifications in cardiomyocytes. We also showed that the protein
levels of LC3-II and the LC3-II/LC3-I ratio decreased with TAGE modifications to Hsp90β[unpublished data]. Based on these findings, TAGE affect the functions of proteins that
regulate autophagy-related pathways, such as those involved in the production of LC3-II.
Furthermore, when CFs were treated with GA, cell death was induced due to the production
and accumulation of intracellular TAGE [32]. However, the addition of TAGE in excess of aphysiological concentration to CFs did not induce cell death. Therefore, we speculate thatthe intracellular accumulation of TAGE induced cell death in CFs and directly suppressed
cardiac repair.
7.1.2. Mechanisms Underlying Intracellular TAGE Degradation
Intracellularly accumulated TAGE have been implicated in the onset and progressionof diseases. The trigger for TAGE accumulation is an elevation in intracellular GA levels.
However, it remains unclear whether there is an endogenous defense system that recognizes
and eliminates TAGE as aberrant intracellular proteins. The findings of our recent study,
which utilized mutated forms of checkpoint kinase 1 (CHK1), a serine-threonine kinase
central to cell cycle checkpoints and the DNA damage response (DDR) [80], strongly
suggest the existence of a cellular pathway that recognizes and degrades TAGE [81].
CHK1, glycation-modified by a GA stimulation, formed HMW complexes that gradually accumulated intracellularly. The loss of CHK1 function due to TAGE modifications
may induce cell death through DNA damage. Furthermore, CHK1 underwent the cleavageof its C-terminal regulatory domain by SPRTN metalloprotease, forming CHK1 cleavage

Biomolecules 2024, 14, 202

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products (CHK1-CPs) comprising the constitutively activated N-terminal kinase domain.
In contrast to the accumulation of intact CHK1 with glycation, CHK1-CPs decreased in atime-dependent manner in response to the GA stimulation, indicating that GA not only
modified CHK1 through glycation, leading to functional impairment, but also contributed
to the degradation of highly active CHK1-CPs, thereby inhibiting the DDR pathway. It
is important to note that in response to the GA stimulation, CHK1-CPs and their mimic(d270WT) were rapidly degraded primarily through the ubiquitin–proteasome pathway.
Furthermore, an inactive mutant variant of d270WT underwent glycation and ubiquitin
modifications more rapidly than d270WT when stimulated with GA. On the other hand,p62, which is involved in selective autophagy, appeared to be one of the components ofthese HMW complexes that escaped degradation [81].
The recognition of structural changes induced by glycation and their ubiquitinationsuggest the presence of specific ubiquitin ligases. Future research needs to focus not only
on the relationship between TAGE formation and diseases, but also on identifying the ubiquitin ligases and degradation pathways triggered by structural changes due to glycation.
Advances in this field will contribute to the development of effective interventions fordiseases related to protein aggregation and AGE accumulation, such as DM, AD, and CVD.
7.1.3. Extracellular TAGE and the TAGE–RAGE Axis
A great variety of precursors and complex mechanisms of AGE formation generatemany chemically diverse AGE molecules that have so far been identified in foods and in
human blood/tissues [82–86]. Most often, processed foods in modern diets are rich insugars and proteins that, during thermal processing, undergo the Maillard reaction, leading
to rapid AGE formation [87–90]. CML, one of the most well-described AGEs, was used as arepresentative for the determination of AGE levels in food products [91].
Glu/Fru metabolic pathways in cells produce GA, which, in turn, generates intracellular TAGE and, ultimately, results in cell death. The extracellular leakage of TAGE
affects the surrounding cells via interactions with RAGE. TAGE accumulation and theup-regulated expression of RAGE are promoted by the frequent and excessive intake of
dietary AGEs [92], resulting in TAGE–RAGE interactions, which produce ROS. ROS havebeen shown to up-regulate RAGE expression and increase the production of TAGE, whichhave been suggested to play a role in the onset/progression of LSRDs [93–96].
Moreover, the interactions between TAGE and RAGE have been shown to elicit oxidative, inflammatory, and thrombogenic responses in ECs [96,97]. We recently focusedon RAS guanyl nucleotide-releasing protein 2 (RASGRP2), a guanine nucleotide exchange
factor that activates small GTPases. We showed that RASGRP2 expressed in human vascular ECs activated RAP1 and R-RAS, which suppressed apoptosis. Furthermore, using theestablished RASGRP2 stable overexpression line, we conducted an analysis with a focus
on TAGE-induced vascular endothelial dysfunction, particularly barrier dysfunction. The
findings obtained revealed that the localization of VE-cadherin and ZO-1 was disrupted
and vascular permeability increased. In addition, RASGRP2 suppressed TAGE-induced
vascular permeability by preventing the disturbance of VE-cadherin localization throughthe activation of RAP1 and R-RAS signals. We suggested that TAGE increased the vascularpermeability by disrupting both adherens and tight junctions through intricate ROS andnon-ROS signaling pathways [98].
Yamagishi’s group recently reported that RAGE-aptamer significantly inhibited thebinding of AGEs, senescent macroprotein derivatives formed at an accelerated rate underDM, to RAGE, and, as a result, the onset/progression of diabetic nephropathy, melanoma
growth and metastasis, and renal injury were attenuated in animal models of chronic
kidney disease [99–103].
These findings indicate the therapeutic potential of targeting the TAGE–RAGE axis toprevent vascular complications in DM.

Biomolecules 2024, 14, 202

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7.2. Involvement of Circulating TAGE in LSRDs
Intracellular TAGE accumulation has been implicated in the pathogenesis of a numberof cellular disorders, and extracellular leakage elevates the circulating TAGE levels [23,37].
We previously reported increases in the serum TAGE levels under oxidative stress and inflammatory/hyperglycemic conditions and showed that they were associated with insulin
resistance, endothelial dysfunction, vascular inflammation, and a decreased number andreduced migratory activity of endothelial progenitor cells (EPCs) in humans [23].
Collectively, our findings indicate the potential of serum TAGE levels as a biomarker
for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment
efficacy [23]. (i) Increased serum TAGE levels were observed not only in DM patients,
but also in non-DM states, and (ii) the serum TAGE levels were significantly higher inpatients with NASH, which is a liver phenotype of MetS, than in healthy subjects and the
non-alcoholic fatty liver group. (iii) Even in healthy subjects, a decrease in the numberof vascular EPCs was observed in the group with high serum TAGE levels, indicating
the potential of TAGE as markers for predicting the progression of arteriosclerosis in the
future. (iv) In healthy subjects administered collagen tripeptide, which inhibits TAGE,
reductions were observed in the serum TAGE levels and the cardio-ankle vascular index
also decreased. In other words, reductions in TAGE levels may restore the elasticity ofblood vessels and prevent arteriosclerosis. (v) Examinations of the relationship between
serum TAGE levels and continued pregnancy rates in patients being treated for infertility
revealed that the continued pregnancy rate was low in groups with high serum TAGE
levels, even at younger ages. Following the administration of water chestnut extract toinfertility-refractory patients and another round of infertility treatment, the serum TAGE
levels were reduced and the birth rate increased. (vi) We also conducted an observational
study on the relationship between serum TAGE levels before the diagnosis of colorectal
cancer (CRC) and mortality, and found that the serum TAGE levels correlated with CRCspecific mortality and all-cause mortality. A strong relationship was observed between
TAGE levels and CRC-specific mortality in patients with distal colon cancer [104]. Therefore,
these findings support a direct relationship between prediagnostic serum TAGE levels in
CRC patients and CRC-specific and all-cause mortality.
Elevated serum TAGE levels may be used in predictions of the onset/progressionof LSRDs, even in healthy subjects with normal blood test results; therefore, the similar
application of circulating TAGE levels is possible. In future studies, high-risk patients may
be identified by measuring their TAGE levels and important information may be obtainedthat will accelerate treatment decision making. A more detailed understanding of serum
TAGE levels will facilitate early predictions of the onset/progression of disease. However,there is no supportive evidence for a relationship between the blood GA-AGE levels anddiseases using anti-triosidine, anti-GLAP, and anti-PPG antibodies. Based on the findings
discussed in this review, specific GA-AGE structures in TAGE may play roles in numerous
types of cell injury both in vitro and in vivo.
8. Conclusions and Perspectives
Based on research performed by our group, we proposed the TAGE theory [22,23,37–39].
Increases in the serum TAGE levels as a result of different types of cell damage may be
used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as
in evaluations of treatment efficacy, including DM and non-DM [23]. Early predictionsof the onset/progression of LSRDs may be achieved based on measurements of serum
TAGE levels, which will contribute to the prevention of LSRDs and extend the healthy
life expectancy.
Among the many categories of AGEs, GA-AGEs are denoted as TAGE due to their inherent toxicity. Notably, anti-TAGE antibodies did not recognize known GA-AGE structurescontaining pyridine rings, such as triosidines, GLAP, and PPGs. In our proposed framework, two compounds featuring GA-derived 1,4-dihydropyridine rings have emerged as
candidates for the structures of TAGE when they undergo dimerization and trimerization,

Biomolecules 2024, 14, 202

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respectively [76]. The anti-TAGE antibody identified dimeric/trimeric bands (representing
intermolecular protein cross-links) and monomeric bands (indicating intramolecular protein cross-links) in the reaction mixture of a lysozyme protein and GA. In consideration of
the diverse array of proteins within cells, each with varying molecular sizes and subcellular
localizations, it is conceivable that higher-order cross-linked TAGE structures may also
be present. Consequently, a more exhaustive and intricate structural analysis of TAGE isimperative for future investigations.
The introduction of the TAGE theory presents a novel research perspective for LSRDs.
Author Contributions: All authors substantially contributed to the preparation of this review (M.T.:
Conceptualization, designed the review, M.T., A.S.-S. and K.T.: original draft preparation, editing,and visualization, H.S.: visualization of chemical structures and review). All authors have read andagreed to the published version of the manuscript.
Funding: This work was supported by JSPS KAKENHI Grant Numbers JP21K11583 (A.S.-S.),
JP20K08410 (K.T.), JP21H04865 (M.T.).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare that they have no known competing financial interests or
personal relationships that may have affected the work reported in this manuscript.

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