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The aldo-keto reductases (AKRs): Overview
#MMPMID25304492
Penning TM
Chem Biol Interact
2015[Jun]; 234
(?): 236-46
PMID25304492
show ga
The aldo-keto reductase (AKR) protein superfamily contains >190 members that fall
into 16 families and are found in all phyla. These enzymes reduce carbonyl
substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins,
retinals, quinones, and lipid peroxidation by-products. Exceptions include the
reduction of steroid double bonds catalyzed by AKR1D enzymes (5?-reductases); and
the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic
hydrocarbons; while the ?-subunits of potassium gated ion channels (AKR6 family)
control Kv channel opening. AKRs are usually 37kDa monomers, have an
(?/?)8-barrel motif, display large loops at the back of the barrel which govern
substrate specificity, and have a conserved cofactor binding domain. AKRs
catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first
and leaves last. In enzymes that favor NADPH, the rate of release of NADP(+) is
governed by a slow isomerization step which places an upper limit on kcat. AKRs
retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117
(AKR1C9 numbering). There is conservation of the catalytic mechanism with
short-chain dehydrogenases/reductases (SDRs) even though they show different
protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and
AKR1B10 have been implicated in diabetic complications, steroid hormone dependent
malignancies, bile acid deficiency and defects in retinoic acid signaling,
respectively. Inhibitor programs exist world-wide to target each of these enzymes
to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1
enzymes are implicated in defects in the development of male genitalia and bile
acid deficiency, respectively, and occur in evolutionarily conserved amino acids.
The human AKRs have a large number of nsSNPs and splice variants, but in many
instances functional genomics is lacking. AKRs and their variants are now poised
to be interrogated using modern genomic and informatics approaches to determine
their association with human health and disease.
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