Structure, function, and mechanism of cytosolic quinone reductases.
Quinone reductases type 1 (QR1) are FAD-containing enzymes that catalyze the reduction of many quinones, including menadione (Vit K3), to hydroquinones using reducing equivalents provided by NAD(P)H. The reaction proceeds with a ping-pong mechanism in which the NAD(P)H and the substrate occupy alternatively overlapping regions of the same binding site and participate in a double hydride transfer: one from NAD(P)H to the FAD of the enzyme, and one from the FADH(2) of the enzyme to the quinone substrate. The main function of QR1 is probably the detoxification of dietary quinones but it may also contribute to the reduction of vitamin K for its involvement in blood coagulation. In addition, the same reaction that QR1 uses in the detoxification of quinones, activates some compounds making them cytotoxic. Since QR1 is elevated in many tumors, this property has encouraged the development of chemotherapeutic compounds that become cytotoxic after reduction by QR1. The structures of QR1 alone, and in complexes with substrates, inhibitors, and chemotherapeutic prodrugs, combined with biochemical and mechanistic studies have provided invaluable insight into the mechanism of the enzyme as well as suggestions for the improvements of the chemotherapeutic prodrugs. Similar information is beginning to accumulate about another related enzyme, QR2.
Bianchet
Mario A
MA
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, USA.
Erdemli
Sabri Bora
SB
Amzel
L Mario
LM
D001665:Binding Sites; D001779:Blood Coagulation Factors / Q000096:biosynthesis; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry* / Q000502:physiology*; D009249:NADP / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism; D011487:Protein Conformation
D001779:Blood Coagulation Factors; D011355:Prodrugs; D009243:NAD; D009249:NADP; D016660:NAD(P)H Dehydrogenase (Quinone)