1GRH

INHIBITION OF HUMAN GLUTATHIONE REDUCTASE BY THE NITROSOUREA DRUGS 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA AND 1-(2-CHLOROETHYL)-3-(2-HYDROXYETHYL)-1-NITROSOUREA

Summary for 1GRH

• Entry DOI: 10.2210/pdb1grh/pdb
• Related: 1GRG
• Descriptor: GLUTATHIONE REDUCTASE, PHOSPHATE ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: oxidoreductase, flavoenzyme
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm: P00390
• Total number of polymer chains: 1
• Total formula weight: 52562.83

Authors

Karplus, P.A.,Schulz, G.E. (deposition date: 1992-12-15, release date: 1994-01-31, Last modification date: 2024-06-05)

Primary citation

Karplus, P.A.,Krauth-Siegel, R.L.,Schirmer, R.H.,Schulz, G.E.
Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis.
Eur.J.Biochem., 171:193-198, 1988

PubMed Abstract: Glutathione reductase from human erythrocytes was inhibited by incubation with the drugs 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HeCNU) under quasi-physiological conditions. For reference purposes, iodoacetamide was used for inactivating alkylation of the enzyme. In each case the modified glutathione reductase was crystallized and its structure determined. These analyses showed that in all experiments the enzyme had reacted at the distal sulfur, that is at the thiol of Cys-58, and virtually nowhere else in the visible structure. The electron density of the HeCNU derivative at 0.3 nm resolution is consistent with a 2-hydroxyethyl group. This alkyl moiety has recently been identified by chemical analysis [Schirmer, R. H., Schöllhammer, T., Eisenbrand, G. and Krauth-Siegel, R. L. (1987) Free Radical Res. Commun. 3, 3-12]. The 0.2 nm resolution electron-density map of the BCNU-derivatized enzyme cannot be explained by a 2-hydroxyethyl group. Instead the modification appears as a carbamoyl moiety containing at least five non-hydrogen atoms. In this derivative the distal cysteine is forced into an unusual conformation.

PubMed: 3338461
DOI: 10.1111/j.1432-1033.1988.tb13775.x

Experimental method

X-RAY DIFFRACTION (3 Å)