Thioredoxin reductase - Two modes of catalysis have evolved

Thioredoxin reductase (EC 1.6.4.5) is a widely distributed flavoprotein tha t catalyzes the NADPH-dependent reduction of thioredoxin. Thioredoxin plays several key roles in maintaining the redox environment of the cell. Like a ll members of the enzyme family that includes lipoamide dehydrogenase, glut athione 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 l ower eukaryotes having a M-r of 35 000, and a protein in higher eukaryotes having a M-r of 55 000. Reducing equivalents are transferred from the apola r flavin binding site to the protein substrate by distinct mechanisms in th e two forms of thioredoxin reductase. In the low M-r enzyme, interconversio n between two conformations occurs twice in each catalytic cycle. After red uction of the disulfide by the flavin, the pyridine nucleotide domain must rotate with respect to the flavin domain in order to expose the nascent dit hiol for reaction with thioredoxin; this motion repositions the pyridine ri ng adjacent to the flavin ring. In the high M-r enzyme, a third redox activ e group shuttles the reducing equivalent from the apolar active site to the protein surface. This group is a second redox active disulfide in thioredo xin reductase from Plasmodium falciparum and a selenenylsulfide in the mamm alian enzyme. P. falciparum is the major causative agent of malaria and it is hoped that the chemical difference between the two high M-r forms may be exploited for drug design.