Mutational substitution of residues implicated by crystal structure in binding the substrate glutathione to human glutathione S-transferase π

Manoharan, T.; Gulick, Andrew M.; Reinemer, Peter; Dirr, Heini W.; Huber, Robert; Fahl, William E.

doi:10.1016/0022-2836(92)90949-k

Cited by 54 publications

(27 citation statements)

References 13 publications

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“…et al, 1992; Wang et al, 1992). Replacement of amino acid residues in motif I, including the conserved glutamine, has resulted in loss of enzymatic activity and impairment of GSH binding (Kong et al, 1992;Manoharan et al, 1992). The results of mu- tagenesis of the conserved aspartic acid in motif I1 have been somewhat contradictory because one study has reported GST inactivation (Wang et al ., 1992).…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

et al. 1994

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Using computer methods for multiple alignment, sequence motif search, and tertiary structure modeling, we show that eukaryotic translation elongation factor ly (EFly) contains an N-terminal domain related to class 0 glutathione S-transferases (GST). GST-like proteins related to class 8 comprise a large group including, in addition to typical GSTs and EFly, stress-induced proteins from bacteria and plants, bacterial reductive dehalogenases and P-etherases, and several uncharacterized proteins. These proteins share 2 conserved sequence motifs with GSTs of other classes (a, p, and K). Tertiary structure modeling showed that in spite of the relatively low sequence similarity, the GST-related domain of EFly is likely to form a fold very similar to that in the known structures of class a , p , and ?r GSTs. One of the conserved motifs is implicated in glutathione binding, whereas the other motif probably is involved in maintaining the proper conformation of the GST domain. We predict that the GSTlike domain in EFly is enzymatically active and that to exhibit GST activity, EFly has to form homodimers. The GST activity may be involved in the regulation of the assembly of multisubunit complexes containing EFl and aminoacyl-tRNA synthetases by shifting the balance between glutathione, disulfide glutathione, thiol groups of cysteines, and protein disulfide bonds. The GST domain is a widespread, conserved enzymatic module that may be covalently or noncovalently complexed with other proteins. Regulation of protein assembly and folding may be 1 of the functions of GST.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

et al. 1994

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“…9). At equilibrium, three variations are possible for the position of the hydrogen bond between the active site Tyr and the thiol group of gluta- The catalytic role of Tyr has been investigated by sitedirected mutagenesis in which the Tyr was replaced with Phe [58][59][60][61][62][63][64]1271, His, Thr, or Val [63]. These substitutions are not tolerated and result in mutants with severely impaired catalytic activities but with near wild-type-like glutathione binding affinities.…”

Section: An Evolutionarily Conserved G-site Tyrosine and The Activatimentioning

confidence: 99%

X‐ray crystal structures of cytosolic glutathione S‐transferases

Dirr

Reinemer

Huber

1994

European Journal of Biochemistry

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416

321

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Crystal structures of cytosolic glutathione S-transferases (EC 2.5.1.18), complexed with glutathione or its analogues, are reviewed. The atomic models define protein architectural relationships between the different gene classes in the superfamily, and reveal the molecular basis for substrate binding at the two adjacent subsites of the active site. Considerable progress has been made in understanding the mechanism whereby the thiol group of glutathione is destabilized (lowering its pK,) at the active site, a rate-enhancement strategy shared by the soluble glutathione S-transferases. Portrait of a superfamily of detoxification enzymesMany sophisticated defense strategies have evolved in organisms enabling them to deal with the constant threat by a broad spectrum of both foreign and endogenous cytotoxic and genotoxic compounds [1]. Enzyme systems that transact the chemical detoxification and elimination processes of these structurally diverse molecules, many of which are highly non-polar, can be divided into three major but interrelated groups; phase I enzymes, such as the cytochrome P450 superfamily, activate chemicals by forming reactive functional groups (e.g. epoxides) in them; phase I1 enzymes deactivate these reactive chemicals by appending a hydrophilic moiety (e.g. glutathionyl, glucuronyl, or sulphuryl) to the functional group ; phase Ill enzymes mediate the cellular elimination of the inactive and water-soluble products.The superfamily of glutathione S-transferases (EC 2.5.1.18) represents an integral part of the phase I1 detoxification mechanism. These intracellular proteins are found in most aerobic eukaryotes and prokaryotes, and protect cells against chemical-induced toxicity and stress by catalyzing the S-conjugation between the thiol group of glutathione and an electrophilic moiety in the hydrophobic and toxic sub- GST, glutathione S-transferase; pGSTP1-1, hGSTAl-1, rGSTM1-1 etc., acronyms for the glutathione S-transferases (GST), the prefix indicating the species (p, porcine; h, human ; r, rat; b, bovine; m, mouse; rb, rabbit; c, chicken; gp, guinea pig) while P, A, and M indicate gene class pi, alpha and mu, respectively ; 1-1 indicates a dimer of two type-1 subunits; GSH, reduced glutathione; P1, P2 etc. and G1, G2 etc., designate peptide functional groups in glutathione and the corresponding G-site ligands of the glutathione S-transferases, respectively; G-site, glutatbione-binding site; H-site, hydrophobic electrophile-binding site.Enzyme. Glutathione S-transferase (EC 2.5.1.1 8).strate. Glutathione S-transferases are perhaps the single most important family of enzymes involved in the metabolism of alkylating compounds [2]. The resultant glutathione S-conjugates can be exported from animal cells by putative membrane ATP-dependent pump systems [3] after which they are metabolized via the mercapturate pathway and eventually eliminated. An extraordinary feature of the glutathione S-transferase superfamily is the occurrence of multiple enzyme forms that, according to sequence similarities and subc...

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“…of alpha (Stenberg et al, 1991) and pi (Kolm et al, 1992;Manoharan et al, 1992) GSTs have established the essential role of a conserved N-terminal active-site tyrosine residue. This tyrosine's hydroxyl group is implicated in the deprotonation of the glutathione thiol group to generate a more reactive thiolate nucleophile .…”

mentioning

confidence: 99%

MIF proteins are theta‐class glutathione S‐transferase homologs

1993

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MIF proteins are mammalian polypeptides of approximately 13,000 molecular weight. This class includes human macrophage migration inhibitory factor (MIF), a rat liver protein that has glutathione S-transferase (GST) activity (TRANSMIF), and the mouse delayed early response gene 6 (DER6) protein. MIF proteins were previously linked to GSTs by demonstrating transferase activity and observing N-terminal sequence homology with a mu-class GST (Blocki, EA., Schlievert, P.M., & Wackett, L.P., 1992, Nature360, 269-270). In this study, MIF proteins are shown to be structurally related to the theta class of GSTs. This is established in three ways. First, unique primary sequence patterns are developed for each of the GST gene classes. The patterns identify the three MIF proteins as theta-like transferase homologs. Second, pattern analysis indicates that GST members of the theta class contain a serine residue in place of the N-terminal tyrosine that is implicated in glutathione deprotonation and activation in GSTs of known structure (Liu, S., et al., 1992, J. Biol. Chem. 267, 4296-4299). The MIF proteins contain a threonine at this position. Third, polyclonal antibodies raised against recombinant human MIF crossreact on Western blots with rat theta GST but not with alpha and mu GSTs. That MIF proteins have glutathionebinding ability may provide a common structural key toward understanding the varied functions of this widely distributed emerging gene family. Because theta is thought to be the most ancient evolutionary GST class, MIF proteins may have diverged early in evolution but retained a glutathione-binding domain.

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Mutational substitution of residues implicated by crystal structure in binding the substrate glutathione to human glutathione S-transferase π

Cited by 54 publications

References 13 publications

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

X‐ray crystal structures of cytosolic glutathione S‐transferases

MIF proteins are theta‐class glutathione S‐transferase homologs

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