2.6.3 Aldo-Keto Reductases (AKR)
The AKRs constitute a large family of enzymes involved in reduction of
various aldehydes and ketones:
H+ + NAD(P)H + O OH
H+ NAD(P)+The reaction is usually in favor of reduction, and these enzymes are distinct
from the ADHs. The enzymes in the group, which is now quite large (Jez et al.,
1997; Penning, 2004), share 40% sequence identity. Substrates include
endobiotics and xenobiotics. The proteins are generally 30–40 kDa in size. The
mechanism is ordered bi-bi, where the cofactor (NAD(P)H) binds first and
leaves last, as with ADH and ALDH. Several crystal structures are now
available. A conserved triad appears to be involved in at least many of these
enzymes, involving Tyr55, Asp50, Lys84, and His1 (17 in the case of AKRlC9)
(Penning, 2004). It is of interest to note that even the ‘‘housekeeping’’ enzymes,
lactic dehydrogenase andD-glyceraldehyde 3-phosphate dehydrogenase are
now classified as members of the superfamily.
Substrates include sugar aldehydes, and some of the enzymes (e.g., aldose
reductase) are targets in the treatment of diabetes and glaucoma. Other substrates
include steroids, prostaglandins, lipid aldehydes (e.g., 4-hydroxynonenal and its
glutathione conjugate), aflatoxin B 1 dialdehyde (Ellis et al., 1993; Guengerich
et al., 2001), the tobacco-specific nitrosamine 4- (methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK), and polycyclic aromatic hydrocarbon (PAH)
dihydrodiols (Flynn and Kubiseski, 1997; Penning, 2004). In most of these
reactions the reaction results in detoxication, but in the latter case activation can
also occur with the formation of O 2 and reactive catechol quinones (Penning,
2004).
Some of the AKR enzymes are inducible. Systems involved include an
osmotic stress system, AP1:fos/jun (where several forms of each of the two
components may be involved), and ARE:Keapl/Nrf2/small Maf. The latter of
these has been clearly shown to respond to oxidative and electrophilic stresses,
and the responses can be considered part of an adaptive protective mechanism.
2.6.4 Quinone Reductase (NQO)
These enzymes catalyze the reduction of quinones to hydroquinones (bothpara
andortho)
H+ + NAD(P)H + + NAD(P)
+OHOHOO28 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS