DIFFERENTIAL SUSCEPTIBILITY OF FILARIAL AND HUMAN ERYTHROCYTE GLUTATHIONE-REDUCTASE TO INHIBITION BY THE TRIVALENT ORGANIC ARSENICAL MELARSEN OXIDE

被引:15
作者
MULLER, S
WALTER, RD
FAIRLAMB, AH
机构
[1] BERNHARD NOCHT INST TROP MED,D-20359 HAMBURG,GERMANY
[2] UNIV LONDON LONDON SCH HYG & TROP MED,LONDON WC1E 7HT,ENGLAND
基金
英国惠康基金;
关键词
FILARIASIS; CHEMOTHERAPY; GLUTATHIONE REDUCTASE; ARSENICAL DRUG;
D O I
10.1016/0166-6851(94)00053-P
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The glutathione reductases (GR) from two cattle filariae (Setaria digitata and Onchocerca gutturosa) have been isolated and their properties have been compared to those of human erythrocyte GR. In general, the enzymes appear to be very similar with respect to substrate-specificity for glutathione disulfide and NADPH, molecular mass (97 kDa vs. 98 kDa) and oligomeric organisation (subunit size of 51 kDa vs. 50 kDa). However, studies on the inhibition of the enzymes by the trivalent melaminophenyl arsenical melarsen oxide revealed that the human GR is less susceptible to inhibition by the arsenical than the filarial enzymes. Further, it was found that the mechanism of inactivation differs for the host and filarial enzymes. The human enzyme is inhibited by melarsen oxide in a competitive manner with a K-i of 23.7 mu M, whereas the filarial GRs are inhibited in two stages: an immediate partial inactivation followed by a time-dependent stage with saturable pseudo-first-order kinetics. K-i values for the S. digitata and O. gutturosa GRs are 38.3 mu M and 4.5 mu M, respectively, with maximum second-stage inactivation rates of 1.0 X 10(-4) s(-1) and 24.3 X 10(-4) s(-1), respectively. These differences between host and parasite enzyme might reflect differences in the primary and secondary structure of the proteins which might be exploitable for the design of new specific macrofilaricidal drugs.
引用
收藏
页码:211 / 219
页数:9
相关论文
共 21 条
[1]   STRUCTURE OF TRYPANOTHIONE REDUCTASE FROM CRITHIDIA-FASCICULATA AT 2.6 ANGSTROM RESOLUTION - ENZYME-NADP INTERACTIONS AT 2.8 ANGSTROM RESOLUTION [J].
BAILEY, S ;
FAIRLAMB, AH ;
HUNTER, WN .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1994, 50 :139-154
[2]   EFFECT OF ARSENICAL DRUGS ON GLUTATHIONE METABOLISM OF LITOMOSOIDES-CARINII [J].
BHARGAVA, KK ;
LETRANG, N ;
CERAMI, A ;
EATON, JW .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 1983, 9 (01) :29-35
[3]   FLUOROMETRIC ASSAY OF PROTEINS IN NANOGRAM RANGE [J].
BOHLEN, P ;
STEIN, S ;
DAIRMAN, W ;
UDENFRIEND, S .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1973, 155 (01) :213-220
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]   MECHANISM OF INHIBITION OF TRYPANOTHIONE REDUCTASE AND GLUTATHIONE-REDUCTASE BY TRIVALENT ORGANIC ARSENICALS [J].
CUNNINGHAM, ML ;
ZVELEBIL, MJJM ;
FAIRLAMB, AH .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1994, 221 (01) :285-295
[6]   THE ANTHELMINTIC ACTIVITY OF A NOVEL ORGANIC ARSENICAL, R7/45, UPON BRUGIA-PAHANGI IN MERIONES-UNGUICULATUS [J].
DENHAM, DA ;
MIDWINTER, ITC ;
FRIEDHEIM, EAH .
JOURNAL OF HELMINTHOLOGY, 1990, 64 (02) :100-104
[7]   HUMAN TRYPANOSOMIASIS IN THE IVORY-COAST - THERAPY AND PROBLEMS [J].
DOUA, F ;
YAPO, FB .
ACTA TROPICA, 1993, 54 (3-4) :163-168
[8]   ACTIVE-SITE OF TRYPANOTHIONE REDUCTASE - A TARGET FOR RATIONAL DRUG DESIGN [J].
HUNTER, WN ;
BAILEY, S ;
HABASH, J ;
HARROP, SJ ;
HELLIWELL, JR ;
ABOAGYEKWARTENG, T ;
SMITH, K ;
FAIRLAMB, AH .
JOURNAL OF MOLECULAR BIOLOGY, 1992, 227 (01) :322-333
[9]   REFINED STRUCTURE OF GLUTATHIONE-REDUCTASE AT 1.54 A RESOLUTION [J].
KARPLUS, PA ;
SCHULZ, GE .
JOURNAL OF MOLECULAR BIOLOGY, 1987, 195 (03) :701-729
[10]  
KARPLUS PA, 1993, CHEM BIOCH FLAVOENZY, V3, P213