Food allergies and food-induced anaphylaxis: role of cofactors

Shin, Meeyong The Korean Pediatric Society 2021 Clinical and Experimental Pediatrics (CEP) Vol.64 No.8

Food allergies and food-induced anaphylaxis are important health problems. Several cofactors modulating the onset of anaphylaxis have been identified. In the presence of cofactors, allergic reactions may be induced at lower doses of food allergens and/or become severe. Exercise and concomitant infections are well-documented cofactors of anaphylaxis in children. Other factors such as consumption of nonsteroidal anti-inflammatory drugs, alcohol ingestion, and stress have been reported. Cofactors reportedly play a role in approximately 30% of anaphylactic reactions in adults and 14%-18.3% in children. Food-dependent exercise-induced anaphylaxis (FDEIA) is the best-studied model of cofactor-induced anaphylaxis. Wheat-dependent exercise-induced anaphylaxis, the most common FDEIA condition, has been studied the most. The mechanisms of action of cofactors have not yet been fully identified. This review aims to educate clinicians on recent developments in the role of cofactors and highlight the importance of recognizing cofactors in food allergies and food-induced anaphylaxis.

Characterization and Cofactor Binding Mechanism of a Novel NAD(P)H-Dependent Aldehyde Reductase from Klebsiella pneumoniae DSM2026

( Cheng Wei Ma ),( Le Zhang ),( Jian Ying Dai ),( Zhi Long Xiu ) 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.12

During the fermentative production of 1,3-propanediol under high substrate concentrations, accumulation of intracellular 3-hydroxypropionaldehyde will cause premature cessation of cell growth and glycerol consumption. Discovery of oxidoreductases that can convert 3- hydroxypropionaldehyde to 1,3-propanediol using NADPH as cofactor could serve as a solution to this problem. In this paper, the yqhD gene from Klebsiella pneumoniae DSM2026, which was found encoding an aldehyde reductase (KpAR), was cloned and characterized. KpAR showed broad substrate specificity under physiological direction, whereas no catalytic activity was detected in the oxidation direction, and both NADPH and NADH can be utilized as cofactors. The cofactor binding mechanism was then investigated employing homology modeling and molecular dynamics simulations. Hydrogen-bond analysis showed that the hydrogen-bond interactions between KpAR and NADPH are much stronger than that for NADH. Free-energy decomposition dedicated that residues Gly37 to Val41 contribute most to the cofactor preference through polar interactions. In conclusion, this work provides a novel aldehyde reductase that has potential applications in the development of novel genetically engineered strains in the 1,3-propanediol industry, and gives a better understanding of the mechanisms involved in cofactor binding.

The Cofactors Role on Chemical Mechanism of Recombinant Acetohydroxy Acid Synthase from Tobacco

김정목,김정림,김영태,최정도,윤문영 대한화학회 2004 Bulletin of the Korean Chemical Society Vol.25 No.5

Acetohydroxy acid synthase (AHAS) is one of several enzymes that require thiamine diphosphate and a divalent cation as essential cofactors. The active site contains several conserved ionizable groups and all of these appear to be important as judged by the fact that mutation diminishes or abolishes catalytic activity. Recently, we have shown [Yoon, M.-Y., Hwang, J.-H., Choi, M.-K., Baek, D.-K., Kim, J., Kim, Y.-T., Choi, J.-D. FEBS Letters 555 (2003), 185-191] that the activity is pH-dependent due to changes in Vmax and V/$K_m$. Data were consistent with a mechanism in which substrate was selectively catalyzed by the enzyme with an unprotonated base having a pK 6.48, and a protonated group having a pK of 8.25 for catalysis. Here, we have in detail studied the pH dependence of the kinetic parameters of the cofactors (ThDP, FAD, Mg2+) in order to obtain information about the chemical mechanism in the active site. The Vmax of kinetic parameters for all cofactors was pH-dependent on the basic side. The pK of ThDP, FAD and Mg2+ was 9.5, 9.3 and 10.1, respectively. The V/$K_m$ of kinetic parameters for all cofactors was pH-dependent on the acidic and on the basic side. The pK of ThDP, FAD and Mg2+ was 6.2-6.4 on the acidic side and 9.0-9.1 on the basic side. The well-conserved histidine mutant (H392) did not affect the pH-dependence of the kinetic parameters. The data are discussed in terms of the acid-base chemical mechanism.

The Cofactors Role on Chemical Mechanism of Recombinant Acetohydroxy Acid Synthase from Tobacco

Kim, Joung-Mok,Kim, Jung-Rim,Kim, Young-Tae,Choi, Jung-Do,Yoon, Moon-Young Korean Chemical Society 2004 Bulletin of the Korean Chemical Society Vol.25 No.5

Acetohydroxy acid synthase (AHAS) is one of several enzymes that require thiamine diphosphate and a divalent cation as essential cofactors. The active site contains several conserved ionizable groups and all of these appear to be important as judged by the fact that mutation diminishes or abolishes catalytic activity. Recently, we have shown [Yoon, M.-Y., Hwang, J.-H., Choi, M.-K., Baek, D.-K., Kim, J., Kim, Y.-T., Choi, J.-D. FEBS Letters 555 (2003), 185-191] that the activity is pH-dependent due to changes in $V_{max}$ and V/$K_m$. Data were consistent with a mechanism in which substrate was selectively catalyzed by the enzyme with an unprotonated base having a pK 6.48, and a protonated group having a pK of 8.25 for catalysis. Here, we have in detail studied the pH dependence of the kinetic parameters of the cofactors (ThDP, FAD, $Mg^{2+}$) in order to obtain information about the chemical mechanism in the active site. The $V_{max}$ of kinetic parameters for all cofactors was pH-dependent on the basic side. The pK of ThDP, FAD and $Mg^{2+}$ was 9.5, 9.3 and 10.1, respectively. The V/$K_m$ of kinetic parameters for all cofactors was pH-dependent on the acidic and on the basic side. The pK of ThDP, FAD and $Mg^{2+}$ was 6.2-6.4 on the acidic side and 9.0-9.1 on the basic side. The well-conserved histidine mutant (H392) did not affect the pH-dependence of the kinetic parameters. The data are discussed in terms of the acid-base chemical mechanism.

Refolding of horseradish peroxidase is enhanced in presence of metal cofactors and ionic liquids

Bae, Sang‐,Woo,Eom, Doyoung,Mai, Ngoc Lan,Koo, Yoon‐,Mo WILEY‐VCH Verlag 2016 Biotechnology journal Vol.11 No.4

<P><B>Abstract</B></P><P>The effects of various refolding additives, including metal cofactors, organic co‐solvents, and ionic liquids, on the refolding of horseradish peroxidase (HRP), a well‐known hemoprotein containing four disulfide bonds and two different types of metal centers, a ferrous ion‐containing heme group and two calcium atoms, which provide a stabilizing effect on protein structure and function, were investigated. Both metal cofactors (Ca<SUP>2+</SUP> and hemin) and ionic liquids have positive impact on the refolding of HRP. For instance, the HRP refolding yield remarkably increased by over 3‐fold upon addition of hemin and calcium chloride to the refolding buffer as compared to that in the conventional urea‐containing refolding buffer. Moreover, the addition of ionic liquids [EMIM][Cl] to the hemin and calcium cofactor‐containing refolding buffer further enhanced the HRP refolding yield up to 80% as compared to 12% in conventional refolding buffer at relatively high initial protein concentration (5 mg/ml). These results indicated that refolding method utilizing metal cofactors and ionic liquids could enhance the yield and efficiency for metalloprotein.</P>

Development of Saccharomyces cerevisiae Reductase YOL151W Mutants Suitable for Chiral Alcohol Synthesis Using an NADH Cofactor Regeneration System

ShinAhYoon,JihyeJung,SeongsoonPark,HyungKwounKim 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.2

The aldo-keto reductases catalyze reduction reactions using various aliphatic and aromatic aldehydes/ketones. Most reductases require NADPH exclusively as their cofactors. However, NADPH is much more expensive and unstable than NADH. In this study, we attempted to change the five amino acid residues that interact with the 2`-phosphate group of the adenosine ribose of NADPH. These residues were selected based on a docking model of the YOL151W reductase and were substituted with other amino acids to develop NADH-utilizing enzymes. Ten mutants were constructed by site-directed mutagenesis and expressed in Escherichia coli. Among them, four mutants showed higher reductase activities than wild-type when using the NADH cofactor. Analysis of the kinetic parameters for the wild type and mutants indicated that the kcat/Km value of the Asn9Glu mutant toward NADH increased 3-fold. A docking model was used to show that the carboxyl group of Glu 9 of the mutant formed an additional hydrogen bond with the 2`-hydroxyl group of adenosine ribose. The Asn9Glu mutant was able to produce (R)-ethyl-4-chloro-3-hydroxyl butanoate rapidly when using the NADH regeneration system.

식물의 냉해에 대한 생체방어기구로서 항산소성 효소의 유도 : (II) $Mn^{+2}$이온에 의한 세포내 SOD의 활성화와 벼 유묘의 내냉성 향상

한창균,김종평,정진,Hahn, Chang-Kyun,Kim, Jong-Pyung,Jung, Jin 한국응용생명화학회 1991 Applied Biological Chemistry (Appl Biol Chem) Vol.34 No.2

벼 유묘에 의 한 $Mn^{+2}$(Mn-SOD의 cofactor)의 흡수는 유묘조직중 SOD 활성을 증가시킴과 아울러 유묘의 냉해저항성을 현저히 향상시키는 결과를 보였으며, SOD 활성 증가정도와 냉해 저 항성 향상정도간에는 정의 상관관계가 있었다. 이에 반하여, Fe-SOD와 Cu/Zn-SOD의 cofactor들인 $Fe^{+3},\;Cu^{+2},$ 및 $Zn^{+2}$의 흡수는 조직내 SOD활성이나 식물의 냉해저항성에 어떤 유의성 있는 영향도 미치지 않았다. 이러한 결과들이 시사하는 바는 아마도 superoxide에 의해 유도되고 $Mn^{+2}$의 존재에 의해 활성화된 Mn-SOD가 (최소한 벼의 경우에는) 저온 스트레스에 대항하는 생체방어 시스템의 중요한 子성분일 것이라는 점이다. 어느정도의 냉해억제효과가 있다고 인정된 Abscisic acid의 처리도 벼 유묘조직의 SOD 활성을 증가시켰다. 이 관찰결과도 식물의 냉해 유발상황 하에서 세포내 SOD가 담당하는 중요한 생체방어 역할을 부각시키는 또 하나의 정보를 제공한 것이다. The uptake of $Mn^{+2}$, a metal cofactor Mn-SOD, by rice seedings resulted in not only a substantial increase in SOD activity in leaf tissues of the plants, but also a significant enhancement of their cold tolerance : the relative extent of the cold tolerance appeared to accord with relative level of the SOD activity. In contrast, $Fe^{+3},\;Cu^{+2}$ and $Zn^{+2}$, which are the cofactors of Fe-SOD and Cu/Zn-SOD, were found to be ineffective for increasing the SOD activity as well as for improving the chilling-resistant capacity of the plants. The results suggest that Mn-SOD, which is most likely induced by its substrate(superoxide) and activated by the presence of $Mn^{+2}$a at high level, is the enzyme acting as an active component of the defense system against low temperature stress in rice plants. In addition, the application of abscisic acid which has been know to protect to some extent certain plants from chilling injury brought about an increase in SOD activity in rice tissues, providing another affirmative information for the crucial role of SOD under the circumstance of cold stress in plants.

The pH Studies of Recombinant Acetohydroxy Acid Synthase from Tobacco

윤문영,최정도,김복환 대한화학회 2003 Bulletin of the Korean Chemical Society Vol.24 No.5

Acetohydroxy acid synthase (AHAS) is one of several enzymes that require thiamine diphosphate and a divalent cation as essential cofactors. The active site contains several conserved ionizable groups and all of these appear to be important as judged by the fact that mutation diminishes or abolishes catalytic activity. Recently, we have shown [Yoon, M.-Y., Hwang, J.-H., Choi, M.-K., Baek, D.-K., Kim, J., Kim, Y.-T., Choi, J.-D. FEBS Letters 555 (2003), 185-191] that the activity is pH-dependent due to changes in Vmax and V/$K_m$. Data were consistent with a mechanism in which substrate was selectively catalyzed by the enzyme with an unprotonated base having a pK 6.48, and a protonated group having a pK of 8.25 for catalysis. Here, we have in detail studied the pH dependence of the kinetic parameters of the cofactors (ThDP, FAD, Mg2+) in order to obtain information about the chemical mechanism in the active site. The Vmax of kinetic parameters for all cofactors was pH-dependent on the basic side. The pK of ThDP, FAD and Mg2+ was 9.5, 9.3 and 10.1, respectively. The V/$K_m$ of kinetic parameters for all cofactors was pH-dependent on the acidic and on the basic side. The pK of ThDP, FAD and Mg2+ was 6.2-6.4 on the acidic side and 9.0-9.1 on the basic side. The well-conserved histidine mutant (H392) did not affect the pH-dependence of the kinetic parameters. The data are discussed in terms of the acid-base chemical mechanism.

Biochemical Analysis of Interaction between Kringle Domains of Plasminogen and Prion Proteins with Q167R Mutation

( Jeongmin Lee ),( Byoung Woo Lee ),( Hae-eun Kang ),( Kevine K. Choe ),( Moosik Kwon ),( Chongsuk Ryou ) 한국미생물 · 생명공학회 2017 Journal of microbiology and biotechnology Vol.27 No.5

The conformational change of cellular prion protein (PrP^C) to its misfolded counterpart, termed PrP^Sc, is mediated by a hypothesized cellular cofactor. This cofactor is believed to interact directly with certain amino acid residues of PrP^C. When these are mutated into cationic amino acid residues, PrPSc formation and prion replication halt in a dominant negative (DN) manner, presumably due to strong binding of the cofactor to mutated PrP^C, designated as DN PrP mutants. Previous studies demonstrated that plasminogen and its kringle domains bind to PrP and accelerate PrP^Sc generation. In this study, in vitro binding analysis of kringle domains of plasminogen to Q167R DN mutant PrP (PrPQ167R) was performed in parallel with the wild type (WT) and Q218K DN mutant PrP (PrPQ218K). The binding affinity of PrPQ167R was higher than that of WT PrP, but lower than that of PrPQ218K. Scatchard analysis further indicated that, like PrPQ218K and WT PrP, PrPQ167R interaction with plasminogen occurred at multiple sites, suggesting cooperativity in this interaction. Competitive binding analysis using L-lysine or L-arginine confirmed the increase of the specificity and binding affinity of the interaction as PrP acquired DN mutations. Circular dichroism spectroscopy demonstrated that the recombinant PrPs used in this study retained the α-helix-rich structure. The α-helix unfolding study revealed similar conformational stability for WT and DN-mutated PrPs. This study provides an additional piece of biochemical evidence concerning the interaction of plasminogen with DN mutant PrPs.

Efficient Production of Phenyllactic Acid by Whole-cell Biocatalysis with Cofactor Regeneration System

이완서,박영태,임성아,염승호,전충,이회석,연영주 한국생물공학회 2021 Biotechnology and Bioprocess Engineering Vol.26 No.3

D-phenyllactic acid is a value added chemical with potential uses in wide areas of industry such as antibiotics, biopolymers, and pharmaceutical syntheses. It can be reduced from phenylpyruvic acid by various 2- hydroxy acid dehydrogenases. In this work, the 2-hydroxy acid dehydrogenase from Oenococcus oeni has been expressed in Escherichia coli whole cell along with formate dehydrogenases from two difference sources, Candida boidinii and Pseudomonas species, for regeneration of NADH cofactor. This could enhance the conversion of the product up to 78%, 3.4-fold increase from the one without cofactor regeneration, demonstrating a possibility of an efficient D-phenyllactic acid production system. Structural analysis by molecular dynamics simulation indicated the flexibility of the enzyme was lowered when the bound substrate was phenylpyruvic acid, compared to the natural substrate, pyruvate. This can be exploited to design 2-hydroxy acid dehydrogenase to increase the flexibility for phenylpyruvic acid, in order to further improve the production of D-phenyllactic acid.