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Jesper Z. Haeggström - One of the best experts on this subject based on the ideXlab platform.
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A remarkable activity of human Leukotriene A4 Hydrolase (LTA4H) toward unnatural amino acids
Amino Acids, 2014Co-Authors: Anna Byzia, Guy S Salvesen, Jesper Z. Haeggström, Marcin DragAbstract:Leukotriene A4 Hydrolase (LTA4H––EC 3.3.2.6) is a bifunctional zinc metalloenzyme, which processes LTA4 through an epoxide Hydrolase activity and is also able to trim one amino acid at a time from N-terminal peptidic substrates via its aminopeptidase activity. In this report, we have utilized a library of 130 individual proteinogenic and unnatural amino acid fluorogenic substrates to determine the aminopeptidase specificity of this enzyme. We have found that the best proteinogenic amino acid recognized by LTA4H is arginine. However, we have also observed several unnatural amino acids, which were significantly better in terms of cleavage rate (k cat/K m values). Among them, the benzyl ester of aspartic acid exhibited a k cat/K m value that was more than two orders of magnitude higher (1.75 × 105 M−1 s−1) as compared to l-Arg (1.5 × 103 M−1 s−1). This information can be used for design of potent inhibitors of this enzyme, but may also suggest yet undiscovered functions or specificities of LTA4H.
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product formation controlled by substrate dynamics in Leukotriene A4 Hydrolase
Biochimica et Biophysica Acta, 2014Co-Authors: Alena Stsiapanava, Fredrik Tholander, Marjolein M. G. M. Thunnissen, Ramakrishnan B. Kumar, Abdul Aziz Qureshi, Damian Niegowski, Jesper Z. Haeggström, Mahmudul Hasan, Agnes RinaldomatthisAbstract:Leukotriene A4 Hydrolase/aminopeptidase (LTA4H) (EC 3.3.2.6) is a bifunctional zinc metalloenzyme with both an epoxide Hydrolase and an aminopeptidase activity. LTA4H from the African claw toad, Xenopus laevis (xlLTA4H) has been shown to, unlike the human enzyme, convert LTA4 to two enzymatic metabolites, LTB4 and another biologically active product Δ(6)-trans-Δ(8)-cis-LTB4 (5(S),12R-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid). In order to study the molecular aspect of the formation of this product we have characterized the structure and function of xlLTA4H. We solved the structure of xlLTA4H to a resolution of 2.3A. It is a dimeric structure where each monomer has three domains with the active site in between the domains, similar as to the human structure. An important difference between the human and amphibian enzyme is the phenylalanine to tyrosine exchange at position 375. Our studies show that mutating F375 in xlLTA4H to tyrosine abolishes the formation of the LTB4 isomeric product Δ(6)-trans-Δ(8)-cis-LTB4. In an attempt to understand how one amino acid exchange leads to a new product profile as seen in the xlLTA4H, we performed a conformer analysis of the triene part of the substrate LTA4. Our results show that the Boltzmann distribution of substrate conformers correlates with the observed distribution of products. We suggest that the observed difference in product profile between the human and the xlLTA4H arises from different level of discrimination between substrate LTA4 conformers.
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Product formation controlled by substrate dynamics in Leukotriene A4 Hydrolase.
Biochimica et Biophysica Acta, 2013Co-Authors: Alena Stsiapanava, Fredrik Tholander, Marjolein M. G. M. Thunnissen, Ramakrishnan B. Kumar, Abdul Aziz Qureshi, Damian Niegowski, Jesper Z. Haeggström, Mahmudul Hasan, Agnes Rinaldo-matthisAbstract:Leukotriene A4 Hydrolase/aminopeptidase (LTA4H) (EC 3.3.2.6) is a bifunctional zinc metalloenzyme with both an epoxide Hydrolase and an aminopeptidase activity. LTA4H from the African claw toad, Xenopus laevis (xlLTA4H) has been shown to, unlike the human enzyme, convert LTA4 to two enzymatic metabolites, LTB4 and another biologically active product Δ(6)-trans-Δ(8)-cis-LTB4 (5(S),12R-dihydroxy-6,10-trans-8,14-cis-eicosatetraenoic acid). In order to study the molecular aspect of the formation of this product we have characterized the structure and function of xlLTA4H. We solved the structure of xlLTA4H to a resolution of 2.3A. It is a dimeric structure where each monomer has three domains with the active site in between the domains, similar as to the human structure. An important difference between the human and amphibian enzyme is the phenylalanine to tyrosine exchange at position 375. Our studies show that mutating F375 in xlLTA4H to tyrosine abolishes the formation of the LTB4 isomeric product Δ(6)-trans-Δ(8)-cis-LTB4. In an attempt to understand how one amino acid exchange leads to a new product profile as seen in the xlLTA4H, we performed a conformer analysis of the triene part of the substrate LTA4. Our results show that the Boltzmann distribution of substrate conformers correlates with the observed distribution of products. We suggest that the observed difference in product profile between the human and the xlLTA4H arises from different level of discrimination between substrate LTA4 conformers. (Less)
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The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits Leukotriene A4 Hydrolase (LTA4H), and shifts macrophage phenotype
The FASEB Journal, 2013Co-Authors: Min Zhu, Jesper Z. Haeggström, Nikita A. Vlasenko, Bin Deng, Nicos A. PetasisAbstract:Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) is the first identified maresin. Here, we investigate formation, stereochemistry, and precursor role of 13,14-epoxy-docosahexaenoic acid, an intermediate in MaR1 biosynthesis. The 14-lipoxygenation of DHA by human macrophage 12-lipoxygenase (hm12-LOX) gave 14-hydro(peroxy)-docosahexaenoic acid (14-HpDHA), as well as several dihydroxy-docosahexaenoic acids, implicating an epoxide intermediate formation by this enzyme. Using a stereo-controlled synthesis, enantiomerically pure 13S,14S-epoxy-docosa-4Z,7Z,9E,11E,16Z,19Z-hexaenoic acid (13S,14S-epoxy-DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13S,14S-epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13S,14S-epoxide inhibited Leukotriene B4 (LTB4) formation by human Leukotriene A4 Hydrolase (LTA4H) ∼40% (P
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Structure-based dissection of the active site chemistry of Leukotriene A4 Hydrolase: implications for m1 aminopeptidases and inhibitor design.
Chemistry & Biology, 2008Co-Authors: Fredrik Tholander, Marjolein M. G. M. Thunnissen, Ayumo Muroya, Bernard-pierre Roques, Marie-claude Fournie-zaluski, Jesper Z. HaeggströmAbstract:M1 aminopeptidases comprise a large family of biologically important zinc enzymes. We show that peptide turnover by the M1 prototype, Leukotriene A4 Hydrolase/aminopeptidase, involves a shift in substrate position associated with exchange of zinc coordinating groups, while maintaining the overall coordination geometry. The transition state is stabilized by residues conserved among M1 members and in the final reaction step, Glu-296 of the canonical zinc binding HEXXH motif shuffles a proton from the hydrolytic water to the leaving group. Tripeptide substrates bind along the conserved GXMEN motif, precisely occupying the distance between Glu-271 and Arg-563, whereas the Arg specificity is governed by a narrow S1 pocket capped with Asp-375. Our data provide detailed insights to the active site chemistry of M1 aminopeptidases and will aid in the development of novel enzyme inhibitors.
Zigang Dong - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2884: Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2011Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:Considerable attention has focused on the anticancer effects of red wine. Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a well-known polyphenolic compound found in red wine and recognized as a key substance for cancer chemoprevention. Leukotriene A4 Hydrolase (LTA4H) is a bi-functional zinc enzyme that is regarded as a relevant target in certain types of human cancers. Our data indicate that knockdown of LTA4H decreased production of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of MIA PaCa-2 pancreatic cancer cells. An in silico prediction using a shape-similarity approach suggested that LTA4H might be a potential target of resveratrol. Results showed that resveratrol directly bound to LTA4H in vitro and ex vivo and suppressed proliferation and anchorage-independent growth by inhibiting LTA4H activity in MIA PaCa-2 cells. Importantly, resveratrol exerted stronger inhibitory effects compared to bestatin, a well-known inhibitor of LTA4H activity. The inhibitory effects of resveratrol were reduced in MIA PaCa-2 cells transfected with sh-LTA4H compared with sh-mock transfected cells. Notably, in an in vivo xenograft mouse model, resveratrol suppressed MIA PaCa-2 tumor formation by inhibiting LTA4H activity. These findings suggest that LTA4H is a novel target for the preventive and/or therapeutic effects of resveratrol on pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2011-2884
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Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2010Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy- trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied Leukotriene A4 Hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR .
Chul-ho Jeong - One of the best experts on this subject based on the ideXlab platform.
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Leukotriene A4 Hydrolase: an emerging target of natural products for cancer chemoprevention and chemotherapy
Annals of the New York Academy of Sciences, 2018Co-Authors: Tam Thuy Lu Vo, Won-jun Jang, Chul-ho JeongAbstract:: Cancer is the second leading cause of death worldwide and has become a global burden. It has long been known that inflammation is related to cancer, as inflammatory components have been identified in the tumor microenvironment and support tumor progression. Among the key inflammatory mediators, Leukotrienes were found to be involved in cancer development. In particular, Leukotriene B4, which is converted from Leukotriene A4 by Leukotriene A4 Hydrolase (LTA4H), has been implicated in several types of cancer. In addition, LTA4H has attracted attention because of purported roles in inflammation and cancer development. Herein, we review the history of LTA4H, its emerging roles in cancer development, and the development of LTA4H inhibitors in cancer prevention and therapy.
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Abstract 2884: Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2011Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:Considerable attention has focused on the anticancer effects of red wine. Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a well-known polyphenolic compound found in red wine and recognized as a key substance for cancer chemoprevention. Leukotriene A4 Hydrolase (LTA4H) is a bi-functional zinc enzyme that is regarded as a relevant target in certain types of human cancers. Our data indicate that knockdown of LTA4H decreased production of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of MIA PaCa-2 pancreatic cancer cells. An in silico prediction using a shape-similarity approach suggested that LTA4H might be a potential target of resveratrol. Results showed that resveratrol directly bound to LTA4H in vitro and ex vivo and suppressed proliferation and anchorage-independent growth by inhibiting LTA4H activity in MIA PaCa-2 cells. Importantly, resveratrol exerted stronger inhibitory effects compared to bestatin, a well-known inhibitor of LTA4H activity. The inhibitory effects of resveratrol were reduced in MIA PaCa-2 cells transfected with sh-LTA4H compared with sh-mock transfected cells. Notably, in an in vivo xenograft mouse model, resveratrol suppressed MIA PaCa-2 tumor formation by inhibiting LTA4H activity. These findings suggest that LTA4H is a novel target for the preventive and/or therapeutic effects of resveratrol on pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2011-2884
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Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2010Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy- trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied Leukotriene A4 Hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR .
Naomi Oi - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2884: Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2011Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:Considerable attention has focused on the anticancer effects of red wine. Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a well-known polyphenolic compound found in red wine and recognized as a key substance for cancer chemoprevention. Leukotriene A4 Hydrolase (LTA4H) is a bi-functional zinc enzyme that is regarded as a relevant target in certain types of human cancers. Our data indicate that knockdown of LTA4H decreased production of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of MIA PaCa-2 pancreatic cancer cells. An in silico prediction using a shape-similarity approach suggested that LTA4H might be a potential target of resveratrol. Results showed that resveratrol directly bound to LTA4H in vitro and ex vivo and suppressed proliferation and anchorage-independent growth by inhibiting LTA4H activity in MIA PaCa-2 cells. Importantly, resveratrol exerted stronger inhibitory effects compared to bestatin, a well-known inhibitor of LTA4H activity. The inhibitory effects of resveratrol were reduced in MIA PaCa-2 cells transfected with sh-LTA4H compared with sh-mock transfected cells. Notably, in an in vivo xenograft mouse model, resveratrol suppressed MIA PaCa-2 tumor formation by inhibiting LTA4H activity. These findings suggest that LTA4H is a novel target for the preventive and/or therapeutic effects of resveratrol on pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2011-2884
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Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2010Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy- trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied Leukotriene A4 Hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR .
Angelo Pugliese - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2884: Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2011Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:Considerable attention has focused on the anticancer effects of red wine. Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a well-known polyphenolic compound found in red wine and recognized as a key substance for cancer chemoprevention. Leukotriene A4 Hydrolase (LTA4H) is a bi-functional zinc enzyme that is regarded as a relevant target in certain types of human cancers. Our data indicate that knockdown of LTA4H decreased production of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of MIA PaCa-2 pancreatic cancer cells. An in silico prediction using a shape-similarity approach suggested that LTA4H might be a potential target of resveratrol. Results showed that resveratrol directly bound to LTA4H in vitro and ex vivo and suppressed proliferation and anchorage-independent growth by inhibiting LTA4H activity in MIA PaCa-2 cells. Importantly, resveratrol exerted stronger inhibitory effects compared to bestatin, a well-known inhibitor of LTA4H activity. The inhibitory effects of resveratrol were reduced in MIA PaCa-2 cells transfected with sh-LTA4H compared with sh-mock transfected cells. Notably, in an in vivo xenograft mouse model, resveratrol suppressed MIA PaCa-2 tumor formation by inhibiting LTA4H activity. These findings suggest that LTA4H is a novel target for the preventive and/or therapeutic effects of resveratrol on pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2011-2884
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Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting Leukotriene A4 Hydrolase
Cancer Research, 2010Co-Authors: Naomi Oi, Angelo Pugliese, Chul-ho Jeong, Janos Nadas, Ann M Bode, Zigang DongAbstract:The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy- trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied Leukotriene A4 Hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of Leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR .