Thioredoxin reductase two modes of catalysis have evolved.
Thioredoxin reductase (EC 1.6.4.5) is a widely distributed flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin. Thioredoxin plays several key roles in maintaining the redox environment of the cell. Like all members of the enzyme family that includes lipoamide dehydrogenase, glutathione reductase and mercuric reductase, thioredoxin reductase contains a redox active disulfide adjacent to the flavin ring. Evolution has produced two forms of thioredoxin reductase, a protein in prokaryotes, archaea and lower eukaryotes having a Mr of 35 000, and a protein in higher eukaryotes having a Mr of 55 000. Reducing equivalents are transferred from the apolar flavin binding site to the protein substrate by distinct mechanisms in the two forms of thioredoxin reductase. In the low Mr enzyme, interconversion between two conformations occurs twice in each catalytic cycle. After reduction of the disulfide by the flavin, the pyridine nucleotide domain must rotate with respect to the flavin domain in order to expose the nascent dithiol for reaction with thioredoxin; this motion repositions the pyridine ring adjacent to the flavin ring. In the high Mr enzyme, a third redox active group shuttles the reducing equivalent from the apolar active site to the protein surface. This group is a second redox active disulfide in thioredoxin reductase from Plasmodium falciparum and a selenenylsulfide in the mammalian enzyme. P. falciparum is the major causative agent of malaria and it is hoped that the chemical difference between the two high Mr forms may be exploited for drug design.
Williams
C H
CH
Department of Veterans Affairs Medical Center, Ann Arbor, MI, USA. chaswill@umich.edu
Arscott
L D
LD
Müller
S
S
Lennon
B W
BW
Ludwig
M L
ML
Wang
P F
PF
Veine
D M
DM
Becker
K
K
Schirmer
R H
RH
D000818:Animals; D002384:Catalysis; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry* / Q000378:metabolism*
D013880:Thioredoxin-Disulfide Reductase