scholarly journals Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of bestatin

2000 ◽  
Vol 345 (3) ◽  
pp. 621-625 ◽  
Author(s):  
Martina ANDBERG ◽  
Anders WETTERHOLM ◽  
Juan F. MEDINA ◽  
Jesper Z. HAEGGSTRÖM
Keyword(s):  
Epoxide Hydrolase ◽  
Critical Role ◽  
Tight Binding ◽  
Leukotriene B4 ◽  
Catalytic Residue ◽  
Ic50 Values ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4 ◽  
Structural Determinant

Leukotriene A4 hydrolase is a bifunctional Zn2+-containing enzyme catalysing the formation of the potent chemotaxin leukotriene B4. From an analysis of three mutants of Glu-296 we have found that this catalytic residue is critical for the binding of bestatin, a classical aminopeptidase inhibitor. For bestatin, but not for three other tight-binding inhibitors, the IC50 values for inhibition of the epoxide hydrolase activity decreased in the mutants to 0.7-0.003% of the control. Hence Glu-296 is an important structural determinant for binding of bestatin to leukotriene A4 hydrolase; this conclusion might also apply to other members of the M1 family of metallopeptidases.

scholarly journals Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19

2020 ◽  
Author(s):  
Xiaopeng Tang ◽  
Mingqian Fang ◽  
Juan Zhang ◽  
Zhiyi Liao ◽  
Ruomei Cheng ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Leukotriene B4 ◽  
Spike Protein ◽  
Aminopeptidase Activity ◽  
Healthy Control ◽  
Leukotriene A4 Hydrolase ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Leukotriene A4

Abstract Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that fibrinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent inflammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identified as a fibrinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the first endogenous inhibitor of LTA4H, a pro-inflammatory enzyme catalyzing final and rating limited step in biosynthesis of leukotriene-B4 that is an extremely inflammatory mediator and a target to design superior anti-inflammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and fibrinogen expression in vivo. Collectively, these findings identify the imbalance between inflammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior anti-inflammatory function because it specifically targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H’s aminopeptidase activity.

scholarly journals Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2871
Author(s):  
Suaad A. Audat ◽  
Nizar A. Al-Shar’i ◽  
Buthina A. Al-Oudat ◽  
Amanda Bryant-Friedrich ◽  
Mel F. Bedi ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
3D Structure ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Leukotriene B4 ◽  
Hydrolase Activity ◽  
Lipid Mediator ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4

Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

scholarly journals Leukotriene A4 hydrolase: a critical role of glutamic acid-296 for the binding of bestatin

2000 ◽  
Vol 345 (3) ◽  
pp. 621 ◽  
Author(s):  
Martina ANDBERG ◽  
Anders WETTERHOLM ◽  
Juan F. MEDINA ◽  
Jesper Z. HAEGGSTRÖM
Keyword(s):  
Glutamic Acid ◽  
Critical Role ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4

scholarly journals Critical role of leukotriene B4 receptor signaling in mouse 3T3-L1 preadipocyte differentiation

2013 ◽  
Vol 12 (1) ◽  
Author(s):  
Kae Hirata ◽  
Koichiro Wada ◽  
Yuka Murata ◽  
Atsushi Nakajima ◽  
Takashi Yamashiro ◽  
...  
Keyword(s):  
Critical Role ◽  
Leukotriene B4 ◽  
Receptor Signaling ◽  
Preadipocyte Differentiation ◽  
Leukotriene B4 Receptor

scholarly journals Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export

2022 ◽  
Vol 8 ◽  
Author(s):  
Tinghan Li ◽  
Yibo Wen ◽  
Hangtian Guo ◽  
Tingting Yang ◽  
Haitao Yang ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Rna Binding ◽  
Critical Role ◽  
Tight Binding ◽  
Viral Proteins ◽  
Interferon Signaling ◽  
Binding Groove ◽  
Mrna Binding ◽  
Common Target

The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)–nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1–Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1–Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1–Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1–Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.

Leukotriene A4 Hydrolase: A Key Enzyme in the Biosynthesis of Leukotriene B4

Eicosanoids ◽  
1996 ◽  
pp. 1-12 ◽  
Author(s):  
Anders Wetterholm ◽  
Martina Blomster ◽  
Jesper Z. Haeggström
Keyword(s):  
Leukotriene B4 ◽  
Key Enzyme ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4
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