The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Abstract

The Aldo-Keto Reductase (AKR) superfamily comprises of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. Substrates of the family include glucose, steroids, glycosylation end products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β/α) 8 barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the Phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.

Acute exposure to organic and inorganic sources of copper: Differential response in intestinal cell lines

“…In HT29, SQSTM1, AKR1B15, PICALM, SRXN1, and MT1E and MT1G were only significantly altered following treatment with the organic copper compounds. SRXN1 is a redox‐activated thiol switch important in the reversal of glutathionylation reactions (Findlay et al., 2006), while AKR1B1 is involved in lipid peroxidation detoxification (Barski, Tipparaju, & Bhatnagar, 2008). SQSTM1 and PICALM have both been implicated in autophagy (Moreau et al., 2014; Pankiv et al., 2007).…”

Substrate profiling and aldehyde dismutase activity of the Kvβ2 subunit of the mammalian Kv1 potassium channel

“…A continuous spectrophotometric assay has also been described for the aldehyde reducing activity of Kvβ2 (Tipparaju et al, 2008). Such a multiple turnover assay is possible since the oxidized cofactor resulting from aldehyde reduction will exchange with externally added NADPH to recommence the catalytic cycle.…”

“…The use of a single turnover reaction allows for the screening of a range of substrates. More detailed studies of kinetic constants were not pursued due to the low activity of Kvβ2 with the carbonyls tested as previously noted (Tipparaju et al, 2008).…”

“…Initially, two Kvβ substrates were identified (4-cyanobenzaldehyde and 4-carboxybenzaldehyde) as being able to reversibly oxidize Kvβ2-bound NADPH (Weng et al, 2006). Tipparaju et al (2008) carried out a more detailed study of the Kvβ2 substrate specificity using a multiple turnover reaction and showed that Kvβ2 could catalyse the reduction of aldehydes and ketones with equal affinity.…”

“…It has been suggested that it may respond to changes in the concentration of intracellular carbonyl substrates. Thus, an oxygen or metabolism-dependent change in carbonyl substrate concentration could rapidly alter the catalytic rate of Kvβ2, leading to cofactor oxidation and to changes in Kv function (Tipparaju et al, 2008). The physiological substrates responsible for the reduction/oxidation of the enzyme-bound cofactor are not known.…”