Glutathione structure

Mizutani, T. Satoh, K. Nomura, H. Hepatotoxicity of eugenol and related compounds in mice depleted of glutathione structural requirements for toxic potency. Res. Commun. Chem. Pathol. Pharmacol. 1991, 73, 87-95. 

Bernal, which led to the solution of the glutathione structure and her Ph.D. from the University of London. In 1963, she was promoted to Research Management with J. C. Lyons. 

M. Huntley, C. Frederick, D. S. Hamilton, D. J. Creighton, and B. Ganem, Reaction of COTC with glutathione. Structure of the putative glyoxalase inhibition, Org. Lett., 2 (2000) 3143-3144. 

The carbon sulfur bond in LTC4 is formed by the reaction of glutathione (Section 15 13) with leukotriene A4 (LTA4) LTA4 is an epoxide Sug gest a reasonable structure for LTA4... 

FIGURE 6.34 Sheet structures formed from andparallel arrangements of /3-strands, (a) Streptomyces suh i x Xu inhibitor, (b) glutathione reductase domain 3, and (c) the second domain of glyceraldehyde-3-phosphate dehydrogenase represent minimal andparallel /S-sheet domain structures. In each of these cases, an andparallel /S-sheet is largely exposed to solvent on one face and covered by helices and random coils on the other face. (Jane Richardson)... 

This thiol-disulfide interconversion is a key part of numerous biological processes. WeTJ see in Chapter 26, for instance, that disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide "bridges" often form cross-links between q steine amino acid units in the protein chains. Disulfide formation is also involved in the process by which cells protect themselves from oxidative degradation. A cellular component called glutathione removes potentially harmful oxidants and is itself oxidized to glutathione disulfide in the process. Reduction back to the thiol requires the coenzyme flavin adenine dinucleotide (reduced), abbreviated FADH2. 

Glutaric acid, structure of, 753 Glutathione, function of. 668 prostaglandin biosynthesis and, 1070... 

Conjugate In biochemical toxicology, a structure (often an anion) formed by the combination of a xenobiotic (usually a phase I metabolite) with an endogenous component (e.g., glucuronate sulfate or glutathione). 

Soffers AEMF, Ploeman JHTM, Moonen MJH, Wobbes T, van Ommen B, Vervoort J, et al. Regioselectivity and quantitative structure-activity relationships for the conjugation of a series of fluoronitrobenzenes by purified glutathione S -transferase enzymes from rat and man. Chem Res Toxicol 1996 9 638-46. 

Gu Y, Guo J, Pal A, Pan SS, Zimniak P, Singh SV, et al. Crystal structure of human glutathione N-transferase A3-3 and mechanistic implications for its high steroid isomerase activity. Biochemistry 2004 43 15673-9. 

Le Trong I, Stenkamp RE, Ibarra C, Atkins WM, Adman ET. 1.3-A resolution structure of human glutathione N-transferase with N-hexyl glutathione bound reveals possible extended ligandin binding site. Proteins 2002 48 618-27. 

Oakley AJ, Lo Bello M, Battistoni A, Ricci G, Rossjohn J, Villar HO, et al. The structures of human glutathione transferase Pl-1 in complex with glutathione and various inhibitors at high resolution. J Mol Biol 1997 274 84-100. 

SHEEHAN D, MEADE G, FOLEY V M and DOWD 0 A (2001) Structure, function and evolution of glutathione transferases implications for classification of non-mammalian members of an ancient enzyme superfamily , Biochem J, 360 1-16. 

Figure 6.1 Structures of various thiolates discussed in this chapter. Abbreviations CySH = cysteine GSH = glutathione ...

The Na/K ATPase has been extensively purified and characterized, and consists of a catalytic a subunit of around 95 kDa and a glycoprotein 0 subunit of approximately 45 kDa (Skou, 1992). The functional transporter exists as a dimer with each monomer consisting of an a and /3 subunit. Hiatt aal. (1984) have su ested that the non-catalytic jS subunit may be involved in the cottect insertion of the a subunit into the lipid bilayer and, therefore, it is conceivable that a modification of the 0 subunit structure may be reflected by changes in the catalytic activity of the a subunit. Therefore, in studies involving the manipulation of tissue glutathione levels, alterations of intracellular redox state may have an effect on substrate binding at an extracellular site on this ion-translocating protein. 

If cellular redox state, determined by the glutathione status of the heart, plays a role in the modulation of ion transporter activity in cardiac tissue, it is important to identify possible mechanisms by which these effects are mediated. Protein S-,thiolation is a process that was originally used to describe the formation of adducts of proteins with low molecular thiols such as glutathione (Miller etal., 1990). In view of the significant alterations of cardiac glutathione status (GSH and GSSG) and ion-transporter activity during oxidant stress, the process of S-thiolation may be responsible for modifications of protein structure and function. 

Figure 4.14 Diagrammatic representation of (a) oxy-radical>mediated S-thioiation and (b) thiol/disulphide-initiated S-thiolation of protein suiphydryl groups. Under both circumstances mixed disuiphides are formed between glutathione and protein thiois iocated on the ion-translocator protein resulting in an alteration of protein structure and function. Both of these mechanisms are completely reversible by the addition of a suitabie reducing agent, such as reduced glutathione, returning the protein to its native form.

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH provided from the hexose monophosphate pathway. GR, a ubiquitous flavoenzyme, maintains a high value of two for the GSH/GSSG ratio in the red blood cells. l,3-Bis(2-chloroethyl)-nitrosourea (BCNU) selectively inhibits cellular GR. GR is composed of two identical subunits, each of molecular mass 50 kDa (S8). The three-dimensional structure and mechanism of catalysis have been established for human GR (K17). 

To understand the effect of the protein on this modeled reaction mechanism, we selected the first reaction step, H2O2 reduction by a glutathione molecule for further investigations using the ONIOM (QM MM) method [28], The computational setup was similar to the structural study, but the effects of the additional water molecules were added from the active-site model. It is assumed that the reaction coordinate is the same as in the active-site study and no additional reaction pathways were investigated. An important point of the present ONIOM study is the full optimization of QM MM transition states using the novel ONIOM algorithms [9],... 

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