Can Glycation Reduce Food Allergenicity? - American Chemical Society

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Can Glycation Reduce Food Allergenicity? Qinchun Rao, Xingyi Jiang, Yida Li, Mustafa Samiwala, and Theodore P. Labuza J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b00660 • Publication Date (Web): 16 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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Journal of Agricultural and Food Chemistry

Can Glycation Reduce Food Allergenicity?

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Qinchun Rao,*,† Xingyi Jiang,* Yida Li,# Mustafa Samiwala,* and Theodore P. Labuza#

6 7

*

8

Florida 32306, USA

9

#

10

Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee,

Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota 55108,

USA

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†

Corresponding Author. Tel: +1 850-644-8215. Fax: +1 850-645-5000. Email: [email protected]

1 ACS Paragon Plus Environment


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Abstract

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As a naturally occurring reaction during food processing, glycation, also known as non-

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enzymatic browning or Maillard reaction, can improve food protein physiochemical properties

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and functionality. In this perspective, three aspects of glycation (terminology confusion between

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glycation and glycosylation, its current application, and its impact on immunoreactivity) are

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elaborated. Overall, the immunoreactivity of glycated proteins may decrease, remain unchanged,

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or even increase after food glycation. Also, it should be noted that the effect of glycation on the

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immunoglobulin (Ig)E- or IgG-binding capacity of allergens do not necessarily and correctly

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predict the allergenicity of the glycated protein in the allergic patient population.

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Keywords: glycation, Maillard reaction, allergenicity, immunoreactivity


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Introduction Currently, there is no approved treatment for food allergy which can only be managed by

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strict dietary avoidance and treatment of symptoms.1 To identify an unknown food allergy, the

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recommended method is in vivo clinical diagnostic tests such as skin prick test and oral food

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challenges, which usually take place after the allergenic symptoms have occurred.2 However,

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these in vivo tests are inconvenient, expensive, and time-consuming. More seriously, these

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diagnostic tests may induce severe and potential life-threatening allergic reactions in patients.2

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To reduce the risk of food allergy, the U.S. food manufacturers have been required to

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label food allergens or ingredients derived from eight major allergenic foods (i.e., egg, milk,

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peanut, tree nuts, fish, shellfish, soy, and wheat) since 2006.3 To better comply with the food

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regulations, in general, the food industry can use two prevention strategies. First, different food

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processing techniques have the potential to reduce the allergenicity of food products, which has

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been reviewed comprehensively.4 Protein glycation is one of these food-processing techniques.

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Second, many immunoglobulin (Ig)E- or IgG-based analytical methods have been used to study

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the effect of different processing techniques on the immunoreactivity of allergenic proteins and

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to detect those undeclared allergenic residues in foods. In this perspective, three aspects of

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glycation (terminology confusion between glycation and glycosylation, its current application,

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and its impact on immunoreactivity) are elaborated.

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Terminology Confusion of Food Protein Glycation Historically, the definition of glycation has been revised at least three times by the

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International Union of Pure and Applied Chemistry (IUPAC) and the International Union of

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Biochemistry (IUB) Joint Commission on Biochemical Nomenclature (JCBN). In 1985, the term



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“glycation” was suggested for “all reactions that link a sugar to a protein or peptide, whether or

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not catalyzed by an enzyme.”5 In 1986, the second half of this statement was revised to “whether

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or not they form a glycosyl bond.”6 In order to distinguish protein glycation from protein

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glycosylation (i.e., the enzymatic-directed protein-carbohydrate interactions),7 its World Wide

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Web version from JCBN has been reworded by Dr. Gerard P. Moss (current Chairman of JCBN)

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to “all such reactions that link a sugar to a protein or peptide,” in which the term “such reactions”

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means non-enzymatic reactions.8 It has been reported that although both glycation and

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glycosylation are not random reactions, glycation is less specific than glycosylation.9

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Despite they are two completely different concepts, the term “glycosylation” has been

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misused in many peer-reviewed studies of various glycated food proteins such as whey proteins10

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and codfish parvalbumin.11 In addition, many research articles complex this term by defining it

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as “non-enzymatic glycosylation”12 and “Maillard-type protein-polysaccharide conjugation.”13

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Overall, this inappropriate terminology usage should be avoided in related research in the future.

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Accuracy and consistency in the use of scientific terms would not only help avoid

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misunderstanding but also improve interdisciplinary communication.

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Application of Glycation and Its Impact on Food Protein Immunoreactivity Food protein glycation, also known as non-enzymatic browning or Maillard reaction, is a

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chemical reaction between an available amino group (usually from proteins) and a carbonyl-

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containing moiety (reducing sugar). A reversible Schiff base is initially formed between a

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reducing sugar and the amino group. The Schiff base undergoes an intramolecular rearrangement

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to form the Amadori products.14 As a naturally occurring reaction during food processing, it has

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been reported that glycation can improve food protein physiochemical properties and


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functionality including solubility, emulsifying and foaming properties, antimicrobial activity, and

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thermal stability.13, 15 Although the glycated food proteins have received much attention in recent

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years, to the best of our knowledge, the commercial glycated food products are still not available.

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Currently, all research and development of food glycation technology are only at the

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laboratory scale. In general, the lab-scale glycation can be classified into two methods: the dry

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method and the wet method. In the dry method, the glycated proteins can be produced during

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storage of the freeze-dried powders of protein-sugar mixtures under an elevated temperature and

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a given relative humidity (Table 1). In the wet method, the glycated proteins can be lyophilized

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after storage of the liquid mixture of protein and reducing sugar under elevated temperature

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(Table 1).

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It is noted that many in vitro (Table 1) and in vivo (Table 2) studies have shown that the

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immunoreactivity of glycated proteins may decrease, remain unchanged, or even increase after

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food glycation. This indicates that protein glycation has the ability to generate new epitopes

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(linear or conformational) and/or change the conformation of existing epitopes recognized by

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IgE and/or IgG antibodies. For example, it has been reported that the conformational change in

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epitopes on glycated hen egg ovalbumin decreased the IgE-binding capacity, simultaneously,

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increased the in vitro immunoreactivity of IgG.16

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The effect of glycation on the protein immunoreactivity is also dependent on a number of

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factors mainly including sources of protein and sugar,17 protein-to-sugar ratio,18 and processing

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conditions (dry or wet methods, temperature, and incubation time).19 For example, the increase

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in the glycation incubation time could not guarantee the reduction of immunoreactivity.18 It

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should be noted that there are few studies being conducted to compare the yield efficiency and

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the immunoreactivity difference between two preparation methods (dry and wet) using the same



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protein. It has been reported that the antigenicity of the wet-heated soy protein isolate (SPI)

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decreased much greater than that of the dry-heated SPI.20 However, this might be caused by the

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difference in the processing conditions and the protein-to-sugar ratios between these two

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methods.

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In addition, there are two major challenges in the study of the effect of glycation on food protein immunoreactivity. First, a simple and effective quantitative analysis method to measure

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the yield of the glycated proteins is needed. Currently, the glycated proteins are mainly

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illustrated by the smearing effect using sodium dodecyl sulfate-polyacrylamide gel

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electrophoresis (SDS-PAGE) due to the change in protein molecular weight (Tables 1 and 2).

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However, the smearing effect may be generated by protein aggregation during glycation. Also,

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although glycation can be indirectly confirmed by the measurement of browning products at 420

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nm,18 it should be noted that this Maillard-induced color change can be developed due to the

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trace amount of the inherent reducing sugar.21

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Second, in vivo studies of food protein glycation are limited (Table 2). Most published

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studies are in vitro (Table 1). However, the effect of food protein glycation on the IgE- or IgG-

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binding capacity of allergens do not necessarily and correctly predict the allergenicity of the

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glycated protein in the allergic patient population. More importantly, as mentioned by the

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European Food Safety Authority (EFSA) recently, “most studies available report on the IgE-

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binding capacity of processed foods rather than on their allergenicity, whereas systematic

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investigations on the effects of food processing on allergenicity under controlled conditions are

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scarce.”22

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Acknowledgements


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This study was supported in part by the Midwest Dairy Association and by the National Institute of Food and Agriculture, U.S. Department of Agriculture (2017-70001-25984).



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Table 1. Effect of glycation on the in vitro immunoreactivity of various food proteins Food protein

Reducing sugar

Atlantic cod parvalbumin

Glucose

Bovine β-lactoglobulin

Galactose

1:1

10-kDa dextran

1:2

20-kDa dextran

1:2

Bovine whey protein isolate

Glucose

0.17-7.83:1

Buckwheat Fag e 1

20-kDa arabinogalactan 1.4-kDa xyloglucan Glucose Ribose

1:1

Glucose

Hazelnut Cor a 11

Hen egg ovalbumin

Glucose

Protein: sugar (w/w) 1:5 (molar ratio)

Glycation conditions Temp. Matrix (°C) Liquid 60

Immunoreactivity Time 5-48 h

Powder (RH44%) Powder (RH44%) Powder (RH44%) Powder (RH79%)

40

1d

60

36 h

60

60 h

40-60

24-120 h

60

7d

1:18 1:15

Powder (RH65%) Liquid Liquid

100 100

30 min 30 min

1:2

Powder

37

7d

25:21

Liquid

60 145 60

3d 20 min 0-2 h

1:0.05

Powder (RH65%) Powder (RH65%)

50

48-96 h

50

48-96 h

100

2h

Hen egg ovomucoid

Glucose

1:0.05

Peanut 2S albumins (Ara h 2/6)

Glucose

1:4.5

Liquid


Glycation degree

• Higher molecular weight bands on reducing SDSPAGE • Reduction of lysine content • Highly glycated • Non-aggregated • Maximum level of glycation • Low aggregation • Maximum level of glycation • Low aggregation • Absorbance increase at 420 nm • Decrease in free amino acid content • Broad bands on reducing SDS-PAGE • Weak and diffused protein band on reducing SDSPAGE • Smear bands on reducing SDS-PAGE • Decrease in free amino acid content

• Decrease of free amino acid group • Covalent aggregation on non-reducing SDS-PAGE • Diffuse bands at high molecular weight on nonreducing SDS-PAGE • Decrease in free amino acid content N/A

IgG

↓

IgE

References

↑

11

↑

23

↑ × 18

↓

↓

↓

24

↓ ↓ 19

×

×

↓ ↓ ↑

↓ ↓ ↓

↓

↓

25

↓

↑

25

↓

26

16

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Food protein

Reducing sugar

Scallop tropomyosin

Glucose

Protein: sugar (w/w) 1:540

Ribose Maltose Maltotriose Ribose

1: 450 1:1027 1:1513 1:450

Fructooligosaccharides (FOS)

Squid tropomyosin Soy protein isolate

Immunoreactivity Time 48 h

Glycation degree

IgG

Powder (RH35%)

60

1:1.1

Powder (RH65%)

60

0-19 d

Fructose

1:0.07

60

0-19 d

FOS

1:4-74 (molar ratio) 1:1.3-24 (molar ratio)

Powder (RH65%) Liquid

95

0-5 h

↓

Liquid

95

0-5 h

↓

• Reduction of lysine content • Smear bands on reducing SDS-PAGE • Invisible 7S and 11S fractions on SDS-PAGE • A significant decrease in free amino acid groups • Decrease in free amino acid content

IgE ↑

• Smear bands on SDS-PAGE • Reduction of lysine content

3h 15 d 15 d 3h

Fructose

120 121

Glycation conditions Temp. Matrix (°C) Powder 60 (RH35%)

↑ ↑ × ↓

↓

References 17

27

20

↓

RH: relative humidity; ↑: increase; ↓: decrease; ×: unchanged; N/A: not available; d: day; h: hour; min: minute; w: week; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis



122

Table 2. Effect of glycation on the in vivo allergenicity of hen egg ovalbumin

Reducing Sugar Glucose

Mannose Glucomanna

123

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Glycation conditions Protein:sugar Temp. Matrix (w/w) (°C) 1:4003 Liquid 50

Time

1:4003

Liquid

1:1

Powder (RH65%)

Glycation degree

Mouse model

Allergenicity

6w

• Diffuse bands on reducing SDS-PAGE

C57BL/6J(B6)

↑

50

6w

• Diffuse bands on nonreducing SDS-PAGE

BALB/c

↑

55

72 h

• Higher molecular weight bands on reducing SDS-PAGE • Decrease of free amino acids

BALB/c

↓

RH: relative humidity; ↑: increase; ↓: decrease; h: hour; w: week


Explanation

• Scavenger receptor class A type-1 and type-2 targets glycated OVA to the MHC class Ⅱ loading pathway in myeloid dendritic cell • Glycation enhanced the activation of OVA-specific CD4+ T cells • Glycan structure (pyraline-OVA) can bind to scavenger receptor class A, which enhanced the activation of OVAspecific CD4+ T cells • Regulation of dendritic cells differentiation and T-cell activation • Reduction of type-1 and type-2 immune response

References 28

29

30

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References

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Can Glycation Reduce Food Allergenicity? - American Chemical Society

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