A Fluoro Analogue of the Menadione Derivative 6-[2‘-(3‘-Methyl)-1‘,4‘-naphthoquinolyl]hexanoic Acid Is a Suicide Substrate of Glutathione Reductase. Crystal Structure of the Alkylated Human Enzyme†

2006 ◽  
Vol 128 (33) ◽  
pp. 10784-10794 ◽  
Author(s):  
Holger Bauer ◽  
Karin Fritz-Wolf ◽  
Andreas Winzer ◽  
Sebastian Kühner ◽  
Susan Little ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutathione Reductase ◽  
Hexanoic Acid ◽  
Human Enzyme ◽  
Suicide Substrate

scholarly journals 2-[1-(4-Bromophenyl)-2-nitroethyl]hexanoic acid

2014 ◽  
Vol 70 (5) ◽  
pp. o518-o518
Author(s):  
Yanpeng Zhang ◽  
Can Zhang ◽  
Ai-Bao Xia
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bond ◽  
Carboxylic Acid ◽  
Nitro Group ◽  
Benzene Ring ◽  
Acid Group ◽  
Hexanoic Acid ◽  
Dihedral Angles ◽  
Carboxylic Acid Group

In the crystal structure of the title compoud, C14H18BrNO4, molecules are linked by a strong O—H...O hydrogen bond and weaker C—H...O interactions. The benzene ring makes dihedral angles of 3.67 (3) and 72.63 (3)° with the carboxylic acid group and the nitro group, respectively.

scholarly journals Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization

2004 ◽  
Vol 279 (19) ◽  
pp. 20480-20489 ◽  
Author(s):  
Kallol Ray ◽  
Christina S. Hines ◽  
Jerry Coll-Rodriguez ◽  
David W. Rodgers
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Nuclear Import ◽  
Bioactive Peptides ◽  
Protein Protein Interaction ◽  
Human Enzyme ◽  
Deep Channel ◽  
Thimet Oligopeptidase ◽  
Degree Of Order ◽  
Insight Into

Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-Å resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599-611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.

scholarly journals Structural studies on leukotriene A4 hydrolases reveal their catalytic mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C413-C413
Author(s):  
Mahmudul Hasan ◽  
Agnes Rinaldo-Matthis ◽  
Marjolein Thunnissen
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Active Site ◽  
Epoxide Hydrolase ◽  
Aminopeptidase Activity ◽  
Molecular Architecture ◽  
Inhibitor Binding ◽  
Induced Fit ◽  
Human Enzyme ◽  
Leukotriene A4

Vertebrate leukotriene A4 hydrolases are zinc metalloenzymes with an epoxide hydrolase and aminopeptidase activity belonging to the M1 family of aminopeptidases. Bestatin, an amino peptidase inhibitor, can inhibit both the activities. The human enzyme produces LTB4, a powerful mediator of inflammation and is implicated in a wide variety of rheumatoid diseases. The yeast homolog scLTA4H contains only a rudimentary epoxide hydrolase activity. Both the structure of the human enzyme and recently the structure of scLTA4H and have been solved to investigate the molecular architecture of the active site both with and without inhibitor Bestatin. The structure of scLTA4H shows large domain movements creating an open active site. In the human enzyme the LTA4 binding side is a narrow hydrophobic channel. Upon inhibitor a domain shifts occurs and the final binding pocket is formed. The fact that scLTA4H displays this induced fit is an interesting observation. Many members of the M1 family seem to display a certain degree of induced fit, a feature, which however, has never been observed for humLTA4H. Our recent solution SAXS studies show that humLTA4H does not make any conformational changes upon inhibitor binding which is consistent with our previous speculation that it functions by a lock and key mechanism rather than induced fit and is better suited to supply the protective and precise environment for hydrolysis of LTA4 into LTB4. On the other hand Xenopus LTA4H shows conformational change in the higher/wide angular region ( >1 nm-1) and decrease in Porod volume of approximately 20 nm3 but no change in Rg or Dmax was observed. It is also observed that like in crystal structure Xenopus LTA4H forms dimer in solution. Similarly scLTA4H forms dimer in solution, which is unlike the crystal structure, and also make conformational changes upon inhibitor binding. Taken together, Xenopus and scLTA4H makes more compact form, with decrease in flexibility, to perform it's catalytic action.

scholarly journals Crystal structure of glutamate dehydrogenase 2, a positively selected novel human enzyme involved in brain biology and cancer pathophysiology

2021 ◽  
Author(s):  
Christina Dimovasili ◽  
Vasiliki E. Fadouloglou ◽  
Aikaterini Kefala ◽  
Mary Providaki ◽  
Dina Kotsifaki ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutamate Dehydrogenase ◽  
Human Enzyme

scholarly journals The crystal structure of Escherichia coli purine nucleoside phosphorylase: a comparison with the human enzyme reveals a conserved topology

Structure ◽  
1997 ◽  
Vol 5 (10) ◽  
pp. 1373-1383 ◽  
Author(s):  
Chen Mao ◽  
William J Cook ◽  
Min Zhou ◽  
George W Koszalka ◽  
Thomas A Krenitsky ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Escherichia Coli ◽  
Purine Nucleoside Phosphorylase ◽  
Purine Nucleoside ◽  
Nucleoside Phosphorylase ◽  
Human Enzyme

scholarly journals Structure of uridine diphosphateN-acetylglucosamine pyrophosphorylase fromEntamoeba histolytica

2015 ◽  
Vol 71 (5) ◽  
pp. 560-565
Author(s):  
Thomas E. Edwards ◽  
Anna S. Gardberg ◽  
Isabelle Q. H. Phan ◽  
Yang Zhang ◽  
Bart L. Staker ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Trypanosoma Brucei ◽  
Protein Glycosylation ◽  
The Other ◽  
Uridine Diphosphate ◽  
Allosteric Inhibitors ◽  
Amoebic Dysentery ◽  
Cell Wall Biogenesis ◽  
Human Enzyme ◽  
N Terminus

Uridine diphosphateN-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final step in the synthesis of UDP-GlcNAc, which is involved in cell-wall biogenesis in plants and fungi and in protein glycosylation. Small-molecule inhibitors have been developed against UAP fromTrypanosoma bruceithat target an allosteric pocket to provide selectivity over the human enzyme. A 1.8 Å resolution crystal structure was determined of UAP fromEntamoeba histolytica, an anaerobic parasitic protozoan that causes amoebic dysentery. AlthoughE. histolyticaUAP exhibits the same three-domain global architecture as other UAPs, it appears to lack three α-helices at the N-terminus and contains two amino acids in the allosteric pocket that make it appear more like the enzyme from the human host than that from the other parasiteT. brucei. Thus, allosteric inhibitors ofT. bruceiUAP are unlikely to targetEntamoebaUAPs.

scholarly journals Crystal Structure of the Antioxidant Enzyme Glutathione Reductase Inactivated by Peroxynitrite

2001 ◽  
Vol 277 (4) ◽  
pp. 2779-2784 ◽  
Author(s):  
Savvas N. Savvides ◽  
Michael Scheiwein ◽  
Catharina C. Böhme ◽  
Gavin E. Arteel ◽  
P. Andrew Karplus ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutathione Reductase ◽  
Antioxidant Enzyme

scholarly journals Novel insights into eukaryotic γ-glutamyltranspeptidase 1 from the crystal structure of the glutamate-bound human enzyme.

2014 ◽  
Vol 289 (16) ◽  
pp. 11569-11569
Author(s):  
Matthew B. West ◽  
Yunyu Chen ◽  
Stephanie Wickham ◽  
Ann Heroux ◽  
Kyle Cahill ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Human Enzyme

scholarly journals Structure of Cystathionine β-Synthase from Toxoplasma gondii, a key enzyme in its H2S production machinery

2021 ◽  
Author(s):  
◽  
Carmen Fernández-Rodríguez ◽  
Iker Oyenarte ◽  
Carolina Conter ◽  
Irene González-Recio ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hydrogen Sulfide ◽  
Toxoplasma Gondii ◽  
Causative Agent ◽  
Redox Homeostasis ◽  
Signal Transducer ◽  
Human Enzyme ◽  
Transsulfuration Pathway ◽  
Key Enzyme ◽  
H2s Production

ABSTRACTCystathionine β-synthase (CBS), the pivotal enzyme of the reverse transsulfuration pathway, catalyzes the pyridoxal-5’-phosphate-dependent condensation of serine with homocysteine to form cystathionine. Additionally, CBS performs alternative reactions that use homocysteine and cysteine as substrates leading to the endogenous biosynthesis of hydrogen sulfide (H2S), an important signal transducer in many physiological and pathological processes. Toxoplasma gondii, the causative agent of toxoplasmosis, encodes a functional CBS (TgCBS) that contrary to human CBS, is not allosterically regulated by S-adenosylmethionine and can use both, Ser and O-acetylserine (OAS) as substrates. TgCBS is also strongly implicated in the production of H2S, and thus involved in redox homeostasis of the parasite. Here, we report its crystal structure, the first CBS from a protozoan described so far. Our data reveals a basal-like fold that unexpectedly differs from the active conformations found in other organisms, but structurally similar to the pathogenic activated mutant D444N of the human enzyme.

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