Selective expression of a unique glutathione S-transferase Yb3 gene in rat brain.

Abramovitz, Mark; Listowsky, Irving

doi:10.1016/s0021-9258(18)47634-x

Cited by 89 publications

(5 citation statements)

References 45 publications

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“…Previous studies have offered a glimpse of the regions of polypeptide or residues that might be involved in the architecture of the xenobiotic substrate binding site of u class GSH transferases. Comparisons of the primary structures of u class GSH transferases from rat have led to the conclusion that sequence variations in the polypeptide are grouped in four so-called variable regions (Abramovitz & Listowsky, 1987; Zhang & Armstrong, 1990). variable-sequence regions, the secondary structural elements, and the domain structure of isoenzyme 3-3.…”

Section: Discussionmentioning

confidence: 99%

“…Isoenzymes of the n class GSH transferases share a high degree of sequence similarity (typically about 78% sequence identity), yet exhibit quite different catalytic characteristics. Analyses of the primary structures of the isoenzymes from rats (Abramovitz & Listowsky, 1987; & Armstrong, 1990;Zhang et al, 1992) have revealed two important features of the sequence variability. One is the fact that the sequence differences are clustered in four variable regions.…”

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confidence: 99%

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Structure and Function of the Xenobiotic Substrate Binding Site of a Glutathione S-Transferase as Revealed by X-ray Crystallographic Analysis of Product Complexes with the Diastereomers of 9-(S-Glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene

Ji¹,

Johnson²,

Sesay³

et al. 1994

Biochemistry

119

100

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The three-dimensional structures of isoenzyme 3-3 of glutathione (GSH) transferase complexed with (9R,10R)- and (9S,10S)-9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene [(9R,10R)-2 and (9S,10S)-2], which are the products of the addition of GSH to phenanthrene 9,10-oxide, have been determined at resolutions of 1.9 and 1.8 A, respectively. The structures indicate that the xenobiotic substrate binding site is a hydrophobic cavity defined by the side chains of Y6, W7, V9, and L12 from domain I (the GSH binding domain) and I111, Y115, F208, and S209 in domain II of the protein. All of these residues are located in variable-sequence regions of the primary structure of class mu isoenzymes. Three of the eight residues (V9, I111, and S209) of isoenzyme 3-3 that are in direct van der Waals contact with the dihydrophenanthrenyl portion of the products are mutated (V9I, I111A, and S209A) in the related isoenzyme 4-4. These three residues are implicated in control of the stereoselectivity of the class mu isoenzymes. The hydroxyl group of Y115 is found to be hydrogen-bonded to the 10-hydroxyl group of (9S,10S)-2, a fact suggesting that this residue could act as an electrophile to stabilize the transition state for the addition of GSH to epoxides. The Y115F mutant isoenzyme 3-3 is about 100-fold less efficient than the native enzyme in catalyzing the addition of GSH to phenanthrene 9,10-oxide and about 50-fold less efficient in the Michael addition of GSH to 4-phenyl-3-buten-2-one. The side chain of Y115 is positioned so as to act as a general-acid catalytic group for two types of reactions that would benefit from electrophilic assistance. The results are consistent with the notion that domain II, which harbors most of the variability in primary structure, plays a crucial role in defining the substrate specificity of class mu isoenzymes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Structure and Function of the Xenobiotic Substrate Binding Site of a Glutathione S-Transferase as Revealed by X-ray Crystallographic Analysis of Product Complexes with the Diastereomers of 9-(S-Glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene

Ji¹,

Johnson²,

Sesay³

et al. 1994

Biochemistry

119

100

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“…Figure 1: (A) Sequence identities of the mu class subunit types 3, 4, and 6 from rat. The sequences of the three subunits (Ding et al, 1986; Lai & Tu, 1986; Abramovitz & Listowsky, 1987) were aligned and scanned in one-residue increments with a ten-residue window. The percent identity (log scale) is plotted for each window.…”

Section: Methodsmentioning

confidence: 99%

Modular mutagenesis of exons 1, 2, and 8 of a glutathione S-transferase from the Mu class. Mechanistic and structural consequences for chimeras of isoenzyme 3-3

Zhang

Liu²,

Shan³

et al. 1992

Biochemistry

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Exons 1 and 2 and exon 8 of the mu class GSH transferases from rat encode sequence-variable regions 1 and 4 of mu class isoenzymes, respectively. These two of four variable regions are located at the N- and C-termini of this isoenzyme class and impinge on the active site. In order to assess the influence of these variable regions on the catalytic diversity of the class mu isoenzymes, seven chimeric isoenzymes were constructed by transplantation of the variable regions of the sequence of the type 4 subunit into the corresponding regions of the type 3 subunit. The chimeric isoenzymes exhibit unique catalytic properties. Replacement of all, or part, of variable region 4 of the type 3 subunit with that of the type 4 subunit results in chimeric catalysts with higher turnover numbers in nucleophilic aromatic substitution reactions. Analysis of the crystal structure of isoenzyme 3-3 [Ji, X., Zhang, P., Armstrong, R. N., & Gilliland, G. L. (1992) Biochemistry (preceding paper in this issue)] suggests that interaction of the flexible C-terminal tail with the N-terminal domain helps limit the rate of product release from the active site of isoenzyme 3-3 in this type of reaction. Substitution of all, or part, of the sequence-variable region 1 of subunit 3 with that of subunit 4 results in chimeric isoenzymes that mimic the high stereoselectivity but not the catalytic efficiency of isoenzyme 4-4 toward alpha,beta-unsaturated ketones.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Chimeric Glutathione Transferases. Inspection of the primary sequence information available from cDNA clones (25, [45][46][47][48] of the class µ isoenzymes from rat indicates that there are several variable regions (<70% amino acid identity) in the primary structure connected by highly conserved regions with >90% identity as shown in the schematic of Figure 9. Interesting questions arise as to the importance of these variable regions to the different catalytic properties of individual isoenzymes and to the evolution of catalytic function.…”

Section: Identification Of Essential Catalytic Residuesmentioning

confidence: 99%

Glutathione S-transferases: reaction mechanism, structure, and function

Armstrong

1991

Chem. Res. Toxicol.

349

253

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Selective expression of a unique glutathione S-transferase Yb3 gene in rat brain.

Cited by 89 publications

References 45 publications

Structure and Function of the Xenobiotic Substrate Binding Site of a Glutathione S-Transferase as Revealed by X-ray Crystallographic Analysis of Product Complexes with the Diastereomers of 9-(S-Glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene

Structure and Function of the Xenobiotic Substrate Binding Site of a Glutathione S-Transferase as Revealed by X-ray Crystallographic Analysis of Product Complexes with the Diastereomers of 9-(S-Glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene

Modular mutagenesis of exons 1, 2, and 8 of a glutathione S-transferase from the Mu class. Mechanistic and structural consequences for chimeras of isoenzyme 3-3

Glutathione S-transferases: reaction mechanism, structure, and function

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