Interaction pattern of histidine, carnosine and histamine with methylglyoxal and other carbonyl compounds

Article abstract of DOI:10.1016/j.foodchem.2021.129884

The ability of histidine to scavenge sugar-derived 1,2-dicarbonyl compounds was investigated using aqueous methanolic model systems containing histidine or histamine in the presence of glucose, methylglyoxal, or glyoxal. The samples were prepared either a

Full text of DOI:10.1016/j.foodchem.2021.129884

Food Chemistry 358 (2021) 129884
Contents lists available at ScienceDirect
Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem
Interaction pattern of histidine, carnosine and histamine with
methylglyoxal and other carbonyl compounds
*
Raheleh Ghassem Zadeh, Varoujan Yaylayan
McGill University, Department of Food Science and Agricultural Cshemistry, 21111 Lakeshore, Ste. Anne de Bellevue, Quebec, Canada
A R T I C L E I N F O
A B S T R A C T
Keywords:
Histidine
Histamine
The ability of histidine to scavenge sugar-derived 1,2-dicarbonyl compounds was investigated using aqueous
methanolic model systems containing histidine or histamine in the presence of glucose, methylglyoxal, or
◦
glyoxal. The samples were prepared either at room temperature (RT) or at 150 C and analyzed using ESI-qTOF-
1
,2-Dicarbonyl compounds
13
MS/MS and isotope labeling technique. Replacing glucose with [U-
6
C ]glucose allowed the identification of
1
3
[
6
U- C ]Glucose
glucose carbon atoms incorporated in the products. Various sugar-generated carbonyl compounds ranging in size
from C1 to C6 were captured by histidine or histamine. The majority of the fragments incorporated were either
C3 or C2 units originating from glyoxal (C2) or methylglyoxal (C3). The ESI-qTOF-MS/MS analysis indicated that
Methylglyoxal
Glyoxal
PhIP
Scavenging activity
Isotope labeling technique
ESI-qTOF-MS/MS
histamine could react with either of the two carbonyl carbons of methylglyoxal utilizing the -amino group and/
α
or the imidazolium moiety. Furthermore, when histidine was added to 2-amino-1-methyl-6-phenylimidazo(4,5-
b)pyridine (PhIP) generating model system, it completely suppressed the formation of PhIP due to scavenging of
phenylacetaldehyde.
1
. Introduction
of the reactive glycating agents via both primary amino moiety and
imidazolium group (Hobart et al., 2004). Furthermore, in vivo and in
Numerous scavenging agents such as pyridoxamine (Booth et al.,
996), creatine (L o¨ bner et al., 2015), flavonoids (Proch a´ zkov a´ et al.,
011), and aminoguanidine (Hirsch et al., 1992) have been proposed in
vitro investigations demonstrated the ability of carnosine to reduce
Advanced glycation end products (AGE) generation via reaction with
reducing sugars or other reactive species (such as lipid peroxidation
intermediates) (Freund et al., 2018). The reaction between lipid per-
1
2
the past to mitigate the harmful effects of thermally generated reactive
1
2
,2-dicarbonyl species formed during food processing (Hellwig et al.,
018). Recently, we have introduced the concept of in situ generation of
oxidation products, in particular,
α βnsaturated aldehydes such as
malondialdehyde (MDA), acrolein or 4-hydroxynonenal (HNE), and
histidine or histidine-containing dipeptides have been also investigated
(Guiotto et al., 2005; Vistoli et al., 2017; Xie et al., 2013). In addition,
the reactivity of histidine with reducing sugars was also studied under
the food processing conditions (Gi & Baltes, 1995, 1993a, 1993b, 2005)
and various volatile reaction products such as 2-acetyl- and 2-propionyl-
pyrido[3,4-d]imidazole derivatives were identified in the model systems
and in food products, using GC/MS analysis (Gi & Baltes, 1995, 1993b,
2005). Similar to tryptophan, these studies have confirmed the ability of
the initial Schiff base formed between histidine and carbonyl com-
pounds to undergo Pictet-Spengler type reaction and subsequently form
volatile pyrido[3,4-d]imidazole derivatives. However, the nature of
non-volatile reaction products generated at high temperatures when
histidine derivatives were reacted with carbohydrate-derived carbonyl
compounds such as methylglyoxal has not been identified. Considering
carbonyl scavenging agents during thermal processing of food from
selected amino acids such as tryptophan (Ghassem Zadeh & Yaylayan,
2
019). The main scavenging agent generated from thermal degradation
of tryptophan was identified to be indole. Indole was shown to undergo
electrophilic aromatic substitution type reactions with carbonyl com-
pounds at positions 2 and 3 and, hence scavenge more than one mole of
carbonyl compound per mole of indole. It was further demonstrated that
indole was able to trap the reactive 1,2-dicarbonyl compounds at room
temperature as well as at higher temperatures of food processing (Zadeh
&
Yaylayan, 2020a, 2020b). Histidine, on the other hand, has been
shown to be an efficient anti-crosslinking agent along with carnosine (a
◦
histidine-containing dipeptide) when incubated at 37 C for 2 days in the
presence of glyceraldehyde. Electrophoretic analysis showed a greater
protective role of histidine than carnosine through its scavenging ability
*
Corresponding author.
E-mail address: Varoujan.yaylayan@mcgill.ca (V. Yaylayan).
https://doi.org/10.1016/j.foodchem.2021.129884
Received 18 January 2021; Received in revised form 18 March 2021; Accepted 27 March 2021
Available online 20 April 2021
0
308-8146/© 2021 Elsevier Ltd. All rights reserved.

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
the crucial role of these carbonyl moieties in vivo and in vitro, under-
standing the chemical pathways through which histidine can scavenge
these reactive precursors during the processing of foods may provide
promising insight into their application strategies.
was prepared and tested for its ability to generate PhIP the most abun-
dant carcinogenic heterocyclic amines in cooked meat. To confirm the
scavenging efficacy of histidine towards phenylacetaldehyde, an
important precursor of PhIP; histidine or histamine were added to the
above reaction mixture before heating and analyzed for the presence of
PhIP and for the formation of histamine-phenylacetaldehyde adducts.
Furthermore, phenylalanine was replaced with [3-13C]phenylalanine in
the PhIP generating model system and subsequently analyzed using
qTOF-MS/MS after heating in water/methanol at 220C for 2 h. All
samples were analyzed in at least two replicates.
2
. Experimental procedures
2
.1. Materials & reagents
L-carnosine (99%), L-histidine (98%), histamine (97%), methyl-
glyoxal (40% MG solution in water) (≥97%), glyoxal trimeric dihydrate
(
GO) (≥97%), methanol (99%) and D-glucose (Glc) were purchased from
2.4. Electrospray ionization/ quadrupole time of flight/ mass
spectrometric analysis (ESI/qTOF/MS)
1
3
Sigma-Aldrich chemical company (Milwaukee, WI). The [U-
6
C ]D-
glucose (99%) and [3-13C]L-phenylalanine (99%) were purchased from
Cambridge Isotope Laboratories (Tewksbury, MA, USA). 2-Amino-1-
methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was obtained from Tor-
onto Research Chemicals Inc. (Toronto, Ontario, Canada). Reactions
were performed in sealed stainless-steel reactors heated in a commercial
toaster oven (1200 Watts).
The samples were diluted in methanol (90% v/v) before analyzing by
ESI/qTOF/MS. The system used was a Bruker Maxis Impact quadrupole
time-of-flight mass spectrometer (Bruker Daltonics, Bremen, Germany)
operating in positive ion mode. Calibration of the instrument was car-
ried out by using sodium formate clusters. The diluted samples were
infused continuously into the detector. The acquisition parameters for
electrospray interface were the following: nebulizer pressure, 0.6 Bar;
2
.2. Preparation of model systems
◦
drying gas, 4.0 l/min, 180 C; capillary voltage, 4500 V. Scan range was
done from m/z 50 to 800. The data were analyzed by Bruker Compass
Data Analysis software version 4.2. Tandem mass spectrometry (MS/
MS) was carried out in multiple reaction monitoring mode (MRM) using
L-carnosine (9.4 mg), L-Histidine (6.5 mg), or histamine (4.5 mg)
were dissolved in methanol/water (50:50), subsequently, the 1,2-dicar-
bonyl compound was added to the solution and mixed. Model systems
5
, 10 and 20 eV collision energies for the ions studied.
(
see Table 1) prepared at 1:1 M ratio or 1:2 M ratio with excess 1,2-dicar-
bonyl in methanol/water (50:50) solution, and either heated at 150 C for
.5 h in stainless-steel reactors or were kept in closed glass vials at RT for
a week. Similarly, model systems consist of histidine or histamine with
]glucose were prepared in methanol/water at 1:1 M
2
.5. Structural identification
1
glucose and [U-13
Evidence for the proposed structures were provided through high
C
6
resolution ESI/qTOF/MS analysis of their elemental composition, MS/
MS analysis and where possible isotopic-labeling studies.
ratio and heated at 150 C for 1.5 h in a stainless-steel reactor. In addi-
tion, either histidine or histamine was dissolved in methanol/water
(
50:50), then phenylacetaldehyde at 1:1 and 1:2 M ratio was added to
3
. Results and discussion
the solution, mixed, and heated in the reactor at 150 C for 1.5 h. The
reaction mixtures were subsequently analyzed by ESI-qTOF-MS/MS
analysis. All samples were prepared and analyzed in two replicates.
Although histidine is one of the most reactive amino acids (Gazzani
&
Cuzzoni, 1984), surprisingly, it is also one of the least studied in the
context of the Maillard reaction. Histamine, which can be thermally
generated from histidine during food processing, is even less studied in
terms of its scavenging potential towards 1,2-dicarbonyl compounds.
Recently, glucose has been used to scavenge histamine to reduce its
toxicity in food (Jiang et al., 2017). Histamine can undergo Pictet-
Spengler type reaction with carbonyl compounds to form imidazopyr-
idines (Habermehl & Ecsy, 1976) and react with malondialdehyde under
physiological conditions (Li et al., 2005). The main volatile products of
the Pictet-Spengler reaction with glucose were later confirmed to be 2-
acetyl- and 2-propionyl-pyrido[3,4-d]imidazole type adducts (Gi &
Baltes, 1995, 2005). Histidine and histidine-containing peptides can be
considered as suitable candidates for in situ generation of histamine to
prevent the accumulation of harmful 1,2-dicarbonyl compounds during
food processing. To identify the reaction products of histidine with
Maillard generated carbonyl intermediates, various model systems (see
Table 1) consisting of carnosine, histidine, or histamine and glucose
2
.3. Scavenging of phenylacetaldehyde by histidine or histamine in the
PhIP generating model system
A PhIP generating model system consisting of creatinine/serine/
phenylalanine (Ghassem Zadeh & Yaylayan, 2019) in a 1:1:1 M ratio
Table 1
a
Composition of the model systems.
Unlabeled Model systems
Isotopic labeled counterparts containing
Model systems
b
13
b
Carnosine/methylglyoxal (1:1) & (1:2)
b&d
Histidine/[U-
Histamine/[U-
C
13
6
]Glc (1:1)
b
Histidine/methylglyoxal (1:2)
C
6
]Glc (1:1)
13
b&d
Histamine/methylglyoxal (1:2)
Creatinine/serine/[ C-3]phenylalanine/
c
histidine (1:1:1:1)
b
13
Carnosine/GO (1:1)
Creatinine/serine/[ C-3]phenylalanine/
c
histamine (1:1:1:1)
◦
b&d
(Glc), methylglyoxal (MG), or glyoxal (GO) were heated at 150 C in
Histidine/GO (1:1)
b&d
Histamine/GO (1:1)
aqueous methanolic solutions in sealed stainless-steel reactors or were
mixed at room temperature and kept for a week before analysis via ESI-
qTOF-MS/MS. In these model systems, histamine was identified as the
major scavenging agent (see Fig. 1) with minor contributions from intact
histidine, 4-vinyl-1H-imidazole (the deamination product of histamine),
and 2-(1H-imidazol-4-yl)acetaldehyde (the Strecker aldehyde of histi-
dine) (see Fig. S1).
b
Histidine/Glc (1:1)
b
Histamine/Glc (1:1)
b
Histidine/paraformaldehyde (1:1)
b
Histamine/paraformaldehyde (1:1)
Histidine/phenylacetaldehyde (1:1) &
b
(
1:2)
b
Histamine/phenylacetaldehyde (1:1)
Creatinine/serine/phenylalanine
c
(
1:1:1)
Creatinine/serine/phenylalanine/
c
histidine (1:1:1:1)
Creatinine/serine/phenylalanine/
c
histamine (1:1:1:1)
2

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
Fig. 1. Proposed scope of interaction between histamine and 1,2-dicarbonyl compounds where R or R
1
= H, Alkyl. Only one isomer out of many is shown.
3
.1. Proposed scope of the interaction of histamine with glyoxal and
imidazole ring. In addition, the initial mono-substituted adduct (Type A)
was able to undergo further carbonyl–amine reaction with histamine
and form Schiff base adducts to generate 1,2-bis((2-(1H-imidazol-4-yl)
ethyl)amino) type derivatives (Type D) (see Table S5 for related exam-
ples) or undergo Pictet-Spengler type condensation (Table S5).
Furthermore, adducts of types A, B, C and D can further capture addi-
tional carbonyl compounds such as formaldehyde through carbonyl–-
amine reaction at the imidazole ring (see Tables S4 & S5).
methylglyoxal, based on profiling of its reaction products with glucose and
1
3
[
U-
C
6
]glucose
Glucose and [U-13
6
C ]glucose were initially reacted with histidine
and histamine to identify adducts incorporating labeled glucose carbon
atoms for the purpose of profiling the number and diversity of the ad-
ducts formed (see Tables 2 & S1) and predict the 1,2-dicarbonyl pre-
cursors involved in their formation based on the number of carbon
atoms incorporated from glucose. The data in Table 2 indicated that
The proposed histamine derivatives depicted in Fig. 1 were based on
the combined results obtained from studies using model systems con-
different sugar-generated carbonyl or
α
-dicarbonyl fragments ranging
taining glucose, [U-13
6
C ]glucose, glyoxal, methylglyoxal and histamine
in size from C1 to C6 carbons were captured by histidine or histamine.
The majority of the fragments incorporated were either C3 or C2 units.
Utilization of model systems containing histidine or histamine and
glyoxal (C2) or methylglyoxal (C3) could provide further evidence for
their structures if the matching adducts can be identified in these mix-
tures. Furthermore, a survey of the data depicted in Table 2 indicated
that the main reactive moiety in all the above model systems (see
Table 1) was histamine, generated either through decarboxylation of
histidine or hydrolysis of carnosine followed by decarboxylation of the
generated histidine. Histamine was able to produce, in the presence of
excess carbonyl compounds, mono- and di-substituted derivatives
designated as adduct types A, B, and C shown in Fig. 1 (see also
Tables S2, S3 & S4 for corresponding examples). Since the primary
amino group of histamine is more reactive compared to the imidazole
moiety, we propose that the initially formed mono-substituted adduct of
type A, mainly centered at this position rather than at the imidazole
moiety. Reaction with a second mole of carbonyl compound to form di-
substituted adducts of types B and C could occur at the less reactive
via isotopic labeling technique and MS/MS analysis as described in
detail below. In general, methylglyoxal generated adducts of types A, B,
C & D with histamine, whereas glyoxal generated mainly type D adducts
and some type B.
3
.2. Methylglyoxal (MG)
The analysis of the data from the reaction mixture of histidine and/or
histamine with methylglyoxal indicated the formation of not only mono
+
+
substituted adducts of histamine at [M + H] 184.1075 and [M + H]
1
66.0969 (Type A) but also di-substituted derivatives (Types B or C) (see
Fig. 2 and Tables S2 to S4). According to Fig. 2, the high-resolution MS
+
data showed the generation of enediol type adduct at [M + H]
+
2
56.1291 (Type B) and Schiff base type adduct at [M + H] 220.1081
when histidine and/or histamine reacted with MG. Similar enediol type
adducts were also observed with Strecker aldehyde and vinyl-imidazole
+
(
see Fig. S1). The di-substituted adduct observed at [M + H] 256.1291
was also converted into various derivatives by loss of water or through
3

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
Table 2
Table 2 (continued)
Elemental composition of the adducts with observed label incorporation in
Ion
Elemental
Error
(ppm)
intensity)
Model system
1
3
13
[
U-
6
C ]-glucose and [ C-3]phenylalanine containing model systems.
composition
(
Ion
Elemental
Error
Model system
+
[
M + H]
composition
(ppm)
2
24.1149
(
intensity)
+
[M +
C8H11N O
4.2(0.2%)
3.6(0.3%)
Histidine/MG
Histamine/Glc
13
[
M + H]
54.0970
C
C
C
C
7
H
7
H
5
H
5
H
12
11
12
11
N
3
N
3
N
3
N
3
O
4.1(3.6%)
4.7(3.5%)
2.8(5.1%)
3.9(8.9%)
Histidine/MG
Histamine/MG
Histamine/Glc
2
2
13
+
H] 167.0814
C
5
H
11
N
2
O
2
C
3
1
NaO
+
+
13
[M + H]
Histamine/U C6-Glc
[
M + Na]
76.0796
M +
O C
2
1
3
13
170.0915
1
NaO
C
2
6
Histamine/ U C -Glc
+
[
M + Na]
C
8
H
10
N
2
NaO
3
6.6(0.4%)
4.3(0.1%)
1.3(2.2%)
Histidine/MG
Histidine/Glc
Histamine/Glc
[
+
205.0579
2 3
C8H10KN O
H] 156.1043
+
13
[
M + K]
5 10 2 3 3
C H N NaO C
[
M +
1
3
+
221.0338
Histidine/U C6-Glc
13
Na] 178.086
+
+
[M + Na]
Histamine/U C6-Glc
[
M + H]
40.0815
M +
C
C
C
C
6
H
6
H
5
H
5
H
10
N
3
O
6.5(0.6%)
5.7(3.6%)
1.7(1.3%)
2.9(1.4%)
Histidine/MG
Histamine/MG
Histamine/Glc
2
08.069
1
9
N
3
NaO
1
3
[M +
C14H17N6
4.2(53%)
1.3
Histamine/MG
Histamine/Glc
13
10
9
N O C
3
+
13
6
+
13
13
H] 269.1503
C10H17
N
C4
Na] 162.0645
N
3
NaO
C
6
Histamine/ U C -Glc
+
M + H]+
[M + H]
(10.1%)
Histamine/U C6-Glc
[
2
73.1647
1
41.0855
+
[
M + H]
C
14
H
15
N
N
6
6.9(4%)
1.8
Histamine/MG
[
M +
1
3
+
267.1342
C10H15
6
C4
Histamine/Glc
13
Na] 163.0672
M +
+
[
M + H]
(17.3%)
6
Histamine/U C -Glc
[
[
[
C
C
6
H
H
8
N
3
13
4.9(1.2%)
1.1(1.3%)
Histidine/MG
Histamine/MG
Histamine/Glc
+
271.1488
H] 122.0713
5
N
8 3
C
+
M + H]+
[M + H]
301.1761
[M + Na]
323.1589
C15H21N O
6.6(1.6%)
1.7(1.7%)
0.9(4.6%)
0.8(3.2%)
Histamine/MG
[
6
1
3
C15H20N NaO
Histamine/Glc
13
1
23.0751
Histamine/U
C
6
-Glc
-Glc
6
+
13
+
C10H21N O
C
5
Histamine/U C6-Glc
M + H]
C
C
7
H
H
10
10
N
3
1
3
5.1(1.9%)
1.3(4.2%)
Histamine/MG
Histamine/Glc
13
6
C10H20N NaO 3C5
1
3
1
36.0868
5
N
C
2
6
+
+
[M + H]
06.1945
[
M + H]
38.094
M +
Histamine/U
C
6
3
1
+
[
M + Na]
328.1766
M +
C
C
C
C
8
H
8
H
8
H
5
H
14
13
N
N
3
O
2
4.6(0.6%)
5.5
Histidine/MG
Histamine/MG
Histamine/Glc
+
H] 184.1075
3
NaO
2
[
C
11
H
20
3
N O
5
2.8(3.3%)
2.7
Histidine/MG
Histamine/MG
Histamine/Glc
[
M +
13KN
3
O
2
13
(0.95%)
0.5(0.1%)
8.4(1.2%)
+
+
13
H] 274.1394
3 5
C11H19N NaO
Na] 206.0905
14
N
3
O
2
C
3
Histamine/U
C
6
-Glc
[
M +
C
11
H
19KN
3
O
5
(15.1%)
0.9(1%)
1.5(5.8%)
1.2
[
M +
+
+
13
13
Na] 296.1207
C5H20N O
3
5
C
6
3
Histamine/U C6-Glc
K] 222.0646
1
M + H]+
[M +
C5H19N NaO C6
[
3
5
+
13
K] 312.0949
C
5
3 5 6
H19KN O C
1
87.1171
+
[
M + H]
(27.2%)
0.9(2.1%)
[
M +
C
C
C
C
8
H
8
H
8
H
5
H
12
11
N
N
3
O
6.2(0.6%)
10.2
Histidine/MG
Histamine/MG
Histidine/Glc
Histamine/Glc
+
280.1600
H] 166.0969
3
NaO
[
M +
[
M +
11KN
3
O
13
(0.4%)
+
+
Na] 302.142
Na] 188.0780
12
N
3
O
C
3
8.9(1.6%)
2.4(0.4%)
1
3
[M +
[
M +
6
Histidine/U C -Glc
13
+
+
K] 318.1165
K] 204.0558
Histamine/U
C
6
-Glc
M + H]+
[M +
C13H19N6
6.1(0.4%)
0.8(0.5%)
7.7(2.5%)
5.03
Histamine/MG
Histidine/Glc
Histamine/Glc
[
+
H] 259.1654
C
C
13
H
H
18
6
N Na
1
69.1077
[
M +
13
18KN
6
[
[
M +
C
C
10
H
12
N
3
O
6.5(0.7%)
3.1(0.8%)
Histidine/MG
Histamine/MG
Histamine/Glc
+
13
13
6
+
13
Na] 281.1489
C10H18N Na C3
Histidine/U C -Glc
H] 190.0968
5
H
12
3
N O
C
5
6
1
3
M + H]+
[M +
(1.4%)
Histamine/U C6-Glc
[
+
1
3
K] 297.1253
1
95.1142
Histamine/U
C
6
-Glc
-Glc
[
M +
+
+
Na] 284.1577
M + H]
C
C
C
11
H
18
17
N
N
3
O
4
2.5(1%)
Histamine/MG
Histamine/Glc
13
[
M +
C
7
H
12
N
3
O
2
5.7(1.6%)
4.4(2.3%)
4.5(0.2%)
3.3(0.6%)
6.2(0.7%)
Histidine/GO
Histamine/GO
Histamine/Glc
2
56.1291
11
H
3
NaO
4
3.6(0.7%)
2.5(1.4%)
+
+
13
H] 170.0920
3 2
C7H11N NaO
[
M + Na]
5
H
18
3
N O
4
C
6
Histamine/U
C
6
[
M +
7 11 3 2
C H N KO
13
2
78.1114
+
13
+
Na] 192.0752
C5H N O C2
Histamine/U C6-Glc
[
M + H]
12
3
2
+
13
2
[
M + K]
C
5
H
11
N
3
NaO
C
2
2
62.1504
2
08.0479
+
+
[M + H]
72.0991
[
M + H]
C
C
C
C
11
H
H
16
15
N
N
3
O
3
7.7(2%)
Histidine/MG
Histamine/MG
Histamine/Glc
1
2
38.1174
11
3
NaO
3
1.4(0.2%)
3.1(3.3%)
3.7(0.4%)
+
+
+
13
[M +
[
M + Na]
60.1008
5
H
16
15
3
N O
3 6
C
+
1
3
3
13
Na] 194.0804
2
5
H
3
N NaO
C
6
Histamine/U
C
6
-Glc
+
+
[M + H]
C12H19N O
7.1(0.3%)
2.9
Histamine/GO
Histamine/Glc
13
[
M + H]
44.1386
6
2
63.1602
12
C10H19N O
18 6
C H N NaO
2
+
13
[M + Na]
6
C
2
(10.5%)
1.7(0.5%)
9.4(0.8%)
Histamine/U C6-Glc
[
M + Na]
1
3
2
85.1448
C
10
H
18
6
N NaO
C
2
2
66.1203
+
+
[M + H]
65.1683
[
[
M + H]
C
C
C
11
H
14
13
N
N
3
O
2
5.3(2.8%)
2.3(3.3%)
0.5(0.2%)
Histidine/MG
Histamine/MG
Histamine/Glc
2
2
20.1081
11
H
3
NaO
2
13
2
[M +
[
M + Na]
42.0904
5
H
13
3
N NaO
C
6
+
1
3
Na] 287.148
2
Histamine/U
C
6
-Glc
+
[
[
M + H]
C
12
H
17
N
6
8.3(0.4%)
4.1(1.9%)
2.9(0.3%)
Histamine/GO
Histidine/Glc
Histamine/Glc
[
M +
+
245.1497
6
C12H16N Na
Na] 248.1108
+
13
+
[M + Na]
6
C10H16N Na C2
M + H]
18.0912
C
C
C
C
11
H
11
H
11
H
12
11
N
N
3
O
2
8.2(1.2%)
2.9(2.3%)
7.6(0.2%)
8.1(0.2%)
Histidine/MG
1
3
2
67.1339
6
Histidine/U C -Glc
2
3
NaO
2
Histamine/MG
Histamine/Glc
13
1
3
[
M +
6
Histamine/U C -Glc
[
M +
11KN
3
13
O
2
+
+
Na] 269.1409
Na] 240.0742
5
H
12
3
N O
2
C
6
Histamine/U
C
6
-Glc
M +
C
14
H
19
6
N O
2
2.9(2%)
Histidine/GO
Histamine/GO
continued on next page)
[
M +
+
+
H] 303.1560
C14H18N NaO
2
1.4(1.4%)
K] 256.0469
6
(
4

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
+
Table 2 (continued)
pattern. The di-substituted adduct at [M + H] 256.1291 was observed
+
to undergo dehydration reactions to generate ions at [M + H] 238.1183
Ion
Elemental
Error
Model system
+
composition
(ppm)
(C11
H
16
N
3
O
3; 3.6 ppm) and its sodiated counterpart at [M + Na]
+
(
intensity)
260.1008 (C11
H
15
3
N NaO
;
0.4 ppm) and [M
+
H] 220.1072
3
[
M +
C
C
14
H
H
18KN
6
O
2
4.7(1.5%)
3.1(1.6%)
Histidine/Glc
Histamine/Glc
11 14 3 2
(C H N O ; 6.4 ppm) as shown in Fig. 2. Figs. S4, S5, and S6 show the
+
13
Na] 325.1391
10
18
N
6
2 4
NaO C
1
3
proposed MS/MS fragmentations of these ions generated at 10 eV
collision energy, supporting the proposed structures.
[
M +
6
Histidine/U C -Glc
13
+
K] 341.1144
Histamine/U
C
6
-Glc
[
M +
Furthermore, the analysis of the data also indicated that the mono-
+
+
Na] 329.1534
substituted derivative observed at [M + H] 166.0969 (C
8 12 3
H N O)
+
[
M + H]
C
C
12
H
H
13
12
N
N
6
C
12
1
H
12
N
6
Na
4.4(0.3%)
2.3(0.1%)
7.8(0.2%)
Histamine/Glc
13
was able to capture the second molecule of histamine and subsequently
3
2
41.1191
10
6
Na
C
2
Histamine/U
C
6
-Glc
+
+
produce an ion at [M + H] 277.1763 (Type D) consistent with the
[
M + Na]
63.1015
2
elemental composition of C13
H
21
N
6
O as shown in Fig. 2. The imidazole
+
[
M +
ring moiety in [M + H] 277.1763 seemed to be able to scavenge
+
Na] 265.1109
reactive carbonyl compounds such as formaldehyde and after dehy-
+
[
[
[
M + H]
C
C
13
H
H
15
15
N
N
6
1
6
5.7
Histamine/GO
Histamine/Glc
13
+
3
dration and oxidation steps generates a very intense peak at [M + H]
2
55.1340
10
C
3
(19.9%)
0.06
+
17 6
269.1503 (C14H N ; 4.2 ppm). This peak was the most intense peak
[
M + H]
58.1459
M +
Histamine/U
C
C
C
6
-Glc
6
-Glc
6
-Glc
2
(0.5%)
3.6
observed in the reaction mixture of methylglyoxal and histamine at
C
C
12
H
H
16
16
N
N
6
NaO
NaO
Histamine/GO
Histamine/Glc
◦
1
50 C and at RT conditions. This ion was also identified in the hista-
+
13
Na] 283.1286
10
6
C
C
2
(17.3%)
4.5(1.6%)
13
mine/glucose model system and incorporated, as expected 4 × C from
1
3
[
M +
Histamine/U
1
3
+
+
[U-
C
6
]glucose and generated the labeled ion at [M + H] 273.1647
Na] 285.1338
(C10[1 C]
3
+
M + H]
C
C
C
C
12
H
12
H
10
H
10
H
19
18
19
18
N
6
N
6
N
6
N
6
O
4.7(0.6%)
3.1
Histamine/GO
Histamine/Glc
13
4 17 6
H N ; 1.3 ppm) (see Tables 2 & S5). Furthermore, MS/MS
2
63.1606
NaO
13
fragmentation under 20 eV collision energy produced two major frag-
+
[
M + Na]
85.1448
O
C
2
1
(15.6%)
1.7(0.5%)
9.4(0.8%)
Histamine/U
+
ments consistent with the proposed structure; one ion at [M + H]
3
2
NaO
2
+
+
175.0979 and the other at [M + H] 95.0609 (see Fig. 2). On the other
[
M + H]
65.1683
hand, the Strecker aldehyde and 4-vinyl-1H-imidazole were also
2
[
M +
observed to trap 1,2-dicarbonyls via electrophilic aromatic substitution
+
+
Na] 287.148
type reactions generating adducts such as [M + H] 167.0814
[
M +
C
C
C
C
13
H
13
H
12
H
12
H
16
15
16
15
N
N
N
N
3
5.5
Histidine/
+
(
C
8
H
11
N
2
O
2
; 4.2 ppm error), [M + Na] 205.0579 (C
8 10 2 3
H N NaO ; 6.6
+
H] 214.1334
M +
3
1
3
Na
(71.5%)
4.7
Phenylacetaldehyde
Histamine/
+
3
ppm error) or [M + H] 153.0656 (C
7 9 2 2
H N O ; 5.3 ppm error) in the
[
C
+
13
reaction mixtures (see Tables S1 and S2).
.3. Glyoxal (GO)
Na] 236.1153
3
Na
C
(43.1%)
2.2(4.5%)
0.9(0.3%)
Phenylacetaldehyde
Histamine /Labeled
PhIP model reaction
[
M +
+
H] 215.1373
3
[
M +
+
Na] 237.1195
Glyoxal generated mainly type D and some type B adducts as shown
in Fig. 3. Similar to MG, glyoxal was able to undergo carbonyl–amine
type reactions at imidazole and -amino moieties of histamine and
[
M +
C
C
22
H
H
20
20
N
N
3
13
3.3(100%)
2(0.6%)
Histidine/
+
H] 326.1668
20
3
C
2
Phenylacetaldehyde
Histamine/
[
M +
α
+
H] 328.1731
Phenylacetaldehyde
Histamine /Labeled
PhIP model reaction
histidine and subsequently generate mono- or di-substituted derivatives
as shown in Fig. 3. The proposed structure of the mono-substituted
+
adduct at [M + H] 170.0920 (C
7 12 3 2
H N O ; 5.7 ppm) (Type A) was
1
3
further confirmed by observing the incorporation of 2 × C-labelled
+
+
+
oxidation forming ions at [M + H] 238.1174, [M + H] 220.1081, and
carbon atoms in the labelled ion at [M
+
H]
172.0991
+
+
5 2 12 3 2 6
(C [ H N O ; 3.3 ppm) when glucose was replaced with [U- C ]
13C]
13
at [M + H] 218.0912 the oxidized from of the ion at [M + H]
2
20.1081, as shown in Fig. 2 and Table S3. The proposed structures of
glucose in histidine or histamine model systems. Moreover, under the
reaction conditions, the mono-substituted ion was able to scavenge a
these mono and di-substituted adducts were based on the observation of
the same ions in the histamine/glucose model system and incorporation
+
second molecule of glyoxal and produce adducts at [M + H] 228.0970
1
3
+
of three or six carbon atoms from [U-
6
C ]glucose into their structures,
(
C
9
H
14
N
3
O
4
) or [M + Na] 250.0793 (C
9
H
13
N
3
NaO
4
; 4.2 ppm) and in
1
3
+
+
showing the expected
C-labelled ions at [M + H] 262.1504
the case of histidine, an adduct was observed at [M + Na] 294.0689
1
3
+
13
+
(
C
5
[
C]
6
H
18
N
3
O
4
3
), [M + H] 244.1386 (C
5
[
C]
6
H
16
N
3
O
3
), [M + Na]
10 13 3 6
(C H N NaO ; 4.3 ppm) (Type B) (see Table S3). The proposed
+
+
+
2
48.1108 (C
5
[1 C]
6
H
13
N
3
NaO
2
), and [M
+
H]
224.1149
structures of these observed ions at [M + H] 228.0907, [M + Na]
1
3
+
5 6 12 3 2
(C [ C] H N O ) (see Tables 2 and S3). In addition, the MS/MS
2
50.0805, and [M + Na] 294.0689 from histidine were further sub-
analysis provided further structural information on these ions regarding
stantiated via MS/MS analysis under the 10 eV collision energy (see
Figs. S7, S8 and S9). Under MS/MS fragmentations, sodiated ions easily
lost glyoxal moieties (Figs. S8 and S9) relative to protonated species
+
their isomeric nature. MS/MS fragmentation of the ion at [M + H]
1
66.0969 (see Fig. S2) have indicated that some of the fragment ions can
+
be rationalized as arising only from isomer A and others only from
isomer B, indicating both the amino group and the imidazole moiety can
such as [M + H] 228.0907 that underwent more complex fragmenta-
tion patterns (see Fig. S7). All reported MS/MS fragmentations were
consistent with the proposed structures. Moreover, the mono-
scavenge -dicarbonyl compounds. Furthermore, MS/MS analysis also
α
+
indicated that histamine could react with either of the two carbonyl
carbons of MG, for example, the MS/MS analysis (see Fig. S3) of the ion
substituted product observed at [M + H] 170.0920 reacted with a
second mole of histamine (see Fig. 3), subsequently generating an ion at
+
+
+
at [M + H] 256.1291 generated a fragment ion at [M + H] 138.0953
[
M + H] 281.1726 (C12
H
21
N
6
O
2
; 1.2 ppm) which could lose either two
+
that can be rationalized only as originating from an isomer where the
moles of water and form the ion at [M + Na] 267.1339 (C12
16 6
H N Na;
+
nitrogen atom is attached to C-2 atom of MG and the ion at [M + H]
4
.1 ppm) or lose one mole of water and undergo oxidation to produce
+
1
22.0721 can be rationalized only if the attachment was at C-1 as shown
the ion at [M + H] 259.1313 (C12
H
15
N
+
6
O; 4.9 ppm) followed by
Na; 2.3
1
3
in Fig. S3. Both ions incorporated the predicted number of labeled C-
atoms from glucose as indicated. Other fragment ions shown in Fig. S3
supported the proposed structure, and all the proposed MS/MS frag-
ments were consistent with the expected isotope label incorporation
dehydration to generate ion at [M + Na] 263.1015 (C12
12 6
H N
ppm) (Type D) (see Fig. 3 and Tables S1 and S5). Fig. S10 depicts the
+
proposed MS/MS fragmentations of [M + H] 259.1313. Replacing
glucose with [U-13
C ]glucose in the model reactions, confirmed the
6
5

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
N
N
N
N
N
N
-
H O
2
H C
CH2
3
OH
O
O
O
O
H C
3
H C
3
[
M+H]+: 238.1183
[
M+H]+: 220.1072
[
M+Na]+: 260.1008
-
H O
2
NH
N
N
NH
N
-
H O
NH
HO
MG
NH
O
2
N
HO
N
H C
3
OH
O
O
H C
3
H C
3
O
H C
3
[
M+H]+: 184.1075
[
M+H]+: 166.0969
[M+H]+: 256.1291
histamine
N
N
N
N
+
NH
N
O
N
+
N
H2
C
MS/MS
CH2
N
CH2
-
H O; [O]
2
NH
H C
N
3
NH
N
[
M+H]+ 175.0979
HO
H C
3
NH
NH
N
96.7%
H C
3
+
NH
N
[
M+H]+: 277.1763
[M+H]+: 269.1503
H C
2
[
M+H]+ 95.0609
9.7%
8
Fig. 2. Proposed reaction sequence of formation of the major ions identified in histamine/methylglyoxal reaction mixture and the fragment ions observed from [M +
+
H] 269.1503. Only one isomer out of many is shown. Errors associated with calculating elemental formulas were less than 5 ppm in the above structures. (see also
Tables S2-S5).
1
3
incorporation of 2 x C-labelled atoms in the structure of the ions at [M
4. Scavenging of phenylacetaldehyde in PhIP generating model
system
+
+
+
Na] 267.1339 and [M + Na] 263.1015 generating labelled coun-
+
13
terparts at [M + Na] 269.1409 (C10
[
2
C] H
16
N
6
Na; 2.9 ppm) and [M +
Na] 265.1109 (C10[13C]
+
N
6
Na; 7.8 ppm). In addition, the dehy-
To illustrate the potential of histidine to scavenge phenyl-
acetaldehyde, a critical precursor of thermally generated carcinogens, in
particular PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine),
either histidine or histamine were reacted with phenylacetaldehyde in
2
H
12
+
drated ion observed at [M + Na] 267.1339 was able to trap another
+
mole of glyoxal via the imidazole ring and form the ion at [M + Na]
3
25.1391 (C14
H
18
N
6
NaO
2
; 1.4 ppm) (see Figs. 3 and S5). This was
+
◦
verified further by observing labelled ion at [M + Na] 329.1534
an aqueous methanolic solution and heated at 150 C for 1.5 h (see
1
3
13
(
C
10
[
C]
4
H
18
N
6
NaO
2
; 3.1 ppm) through the incorporation of 4 × C-
section 2.2 and Table 1) and analyzed by qTOF-MS/MS, to identify the
specific adducts formed. The analysis of data indicated the formation of
various adducts of types A, B, and C in the reaction mixtures. However,
+
labeled carbon atoms in [M + Na] 325.1391.
+
the ion observed at [M + H] 214.1334 and shown in Fig. 4, was one of
3
.4. Reaction at room temperature
the most intense adducts that was also identified in the reaction mixture
of PhIP generating model system (see section 2.3) when histidine or
histamine were added to the reaction mixture before heating. In this
mixture, the formation of PhIP was confirmed through the observation
Performing the reaction of the model systems at room temperature
(
see section 2.2 & Table 1) demonstrated a similar scavenging activity to
that of high temperature reactions, however, methylglyoxal exhibited
much higher reactivity than glyoxal at room temperature, generating
adducts of types A, B, C, and D.
+
of both protonated and potassiated PhIP ions at [M + H] 225.1128
+
(
C
13
H
13
N
4
; 5.4 ppm error) and [M + K] 263.0717 (C13
4
H12KN ; 6.5 ppm
6

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
N
NH
N
NH
O
NH
O
GO
N
HO
HO
OH
O
[
M+H]+: 228.0970
M+Na]+: 250.0805
Histamine
[
M+H]+: 170.0920
[
NH
NH
NH
N
NH
HO
N
N
N
N
[O]
-H O
2
-
H O
2
NH
NH
N
NH
N
NH
N
HO
NH
HO
N
[
M+H]+: 281.1726
[M+H]+: 259.1292
[
[
M+H]+: 241.1191
M+Na]+: 263.1015
-
2 H O
[O]
2
NH
N
NH
N
N
GO
N
O
HO
N
NH
N
N
N
N
[
M+Na]+: 267.1339
M+H]+: 245.1497
[M+Na]+: 325.1391
[M+H]+: 303.1560
[
Fig. 3. Proposed reaction sequence of formation of the major ions identified in histamine/glyoxal reaction mixture. Only one isomer out of many is shown. Errors
associated with calculating elemental formulas were less than 5 ppm in the above structures. (see also Tables S3 & S5).
error) consistent with the elemental composition of the standard PhIP,
as reported earlier (Ghassem Zadeh and Yaylayan, 2019). The PhIP in-
dicator ions completely disappeared after the addition of histidine or
histamine to the PhIP generating reaction mixture with concomitant
shown in Fig. 4.
5. Conclusion
+
formation of the phenylacetaldehyde adducts including [M + H]
This study depicts the potential of histidine derivatives to scavenge
thermally generated 1,2-dicarbonyl compounds in model Maillard re-
action systems. The isotope labeling data and MS/MS fragmentation
analysis confirmed that histamine could react with either of the two
2
14.1334. The MS/MS analysis of the mono-substituted adduct observed
+
at [M + H] 214.1334 (C13
16 3
H N ) confirmed the formation of two
isomeric structures A and B (see Fig. 4). Histamine was able to capture
phenylacetaldehyde at either imidazole moiety, forming isomer A or at
carbonyl carbons of methylglyoxal utilizing the -amino group and/or
α
the
α
-amino position, generating isomer B as a Schiff base adduct. The
the imidazolium moiety and subsequently form a complex mixture of
isomers. Furthermore, histidine showed potential to capture phenyl-
acetaldehyde under the reaction conditions suppressing the generation
of PhIP in a model system, further emphasizing the importance of the
concept of in situ generation of carbonyl scavenging agents as a prom-
ising strategy to mitigate the accumulation of toxic compounds in food
products.
+
+
fragment ions observed at [M + H] 197.1075 and [M + H] 185.1075
can be originated only from isomer A and fragment ions observed at [M
+
+
+
+
H] 122.0714; [M + H] 120.0808 and [M + H] 95.0603 could be
justified only as arising from isomer B as shown in Fig. 4. The proposed
isomeric structures were further supported through isotope labeling
studies when phenylalanine was replaced with [3-13C]phenylalanine in
the PhIP generating model system and the corresponding labeled ion at
+
13
3
[
M + H] 215.1373 (C12
H
16
N
C; 0.5 ppm) (see Table 2) was observed
CRediT authorship contribution statement
+
in the reaction mixture with the disappearance of the ion at [M + H]
+
2
14.1334. The observed MS/MS fragment ions of [M + H] 215.1373
Raheleh Ghassem Zadeh: Data curation, Formal analysis, Meth-
odology, Validation, Writing - original draft. Varoujan Yaylayan:
were also consistent with the expected isotope incorporation patterns
7

R. Ghassem Zadeh and V. Yaylayan
Food Chemistry 358 (2021) 129884
N
N
N
NH
*
+
N
CH2
CH
+
13
+
[
M+H] 198.1119 (C12
[
C]H13
N
2
5ppm)
C H N
3
6
8
+
+
[M+H] 122.0714 (3.9 ppm)
[
M+H] 197.1075 (C13
H
13
N
2
1.9 ppm)
84.2%
14.2%
-NH3
N
N
H N
2
N
N
N
NH+
NH
CH
2
*
+
*
C H N
2
5
6
+
[
M+H] 95.0603 (6.6 ppm)
1.2%
6
isomer A
isomer B
+
13
[
M+H] 215.1378 (C12
[
C]H16
N
3
0.5 ppm)
1 ppm)
+
[
M+H] 214.1342 (C13
H
16
N
3
N
CH
3
NH
*
N
*
+
13
[
M+H] 186.1113 (C11
[
C]H13N2 0.5 ppm)
(C12H13N2 2 ppm)
7.4%
+
13
[M+H] 121.0841 (C7[ C]H10
N
4.8 ppm)
+
[
M+H] 185.1075
+
[M+H] 120.0808 (C H10N 4.4 ppm)
8
2
1
0%
Fig. 4. MS/MS fragmentations of [M + H]+ 214.1342 (under 10 eV collision energy) generated either in histidine/phenylacetaldehyde or histamine/phenyl-
acetaldehyde. Values in parenthesis represent errors in ppm associated with calculating elemental formulas.
Supervision, Conceptualization, Project administration, Writing - review
editing, Funding acquisition.
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