Inhibiting wild-type and C299S mutant AKR1B10; a homologue of aldose reductase upregulated in cancers.
AKR1B10 is an aldose reductase (AR) homologue overexpressed in liver cancer and various forms of that enzyme in carcinomas catalyze the reduction of anticancer drugs, potential cytostatic drug, and dl-glyceraldehyde but do not catalyze the reduction of glucose. Kinetic parameters for wild-type and C299S mutant AKR1B10 indicate that substitution of serine for cysteine at position 299 reduces the affinity of this protein for dl-glyceraldehyde and enhances its catalytic activity. Fibrates suppress peroxisome proliferation and the development of liver cancer in human. Here we report the potency of fibrate-mediated inhibition of the carbonyl reduction catalyzed by wild-type and C299S mutant AKR1B10 and compare it with known AR inhibitors. Wild-type AKR1B10-catalyzed carbonyl reduction follows pure non-competitive inhibition kinetics using zopolrestat, EBPC or sorbinil, whereas fenofibrate, Wy 14,643, ciprofibrate and fenofibric acid follow mixed non-competitive inhibition kinetics. In contrast, catalysis of reaction by the C299S AKR1B10 mutant is not inhibited by sorbinil and EBPC. Despite these differences, the C299S AKR1B10 mutant still manifests kinetics similar to the wild-type protein with other fibrates including zopolrestat, fenofibrate, Wy 14,346, gemfibrozil and ciprofibrate that show mixed non-competitive inhibition kinetics. The reaction of the mutant AKR1B10 is inhibited by fenofibric acid, but manifests pure non-competitive inhibition kinetics that are different from those demonstrated for the wild-type enzyme.
Verma
Malkhey
M
Division of Immunology, Beckman Research Institute, City of Hope National Medical Center, 1450 E. Duarte Road, Duarte, CA 91010, USA.
Martin
Hans-Joerg
HJ
Haq
Wahajul
W
O'Connor
Timothy R
TR
Maser
Edmund
E
Balendiran
Ganesaratnam K
GK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology; D002995:Clofibric Acid / Q000494:pharmacology; D003545:Cysteine; D003630:Daunorubicin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005985:Glyceraldehyde / Q000378:metabolism; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology; D007700:Kinetics; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D010084:Oxidation-Reduction; D010793:Phthalazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012694:Serine
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D010793:Phthalazines; D011743:Pyrimidines; D011994:Recombinant Proteins; C067172:zopolrestat; D005985:Glyceraldehyde; D012694:Serine; D002995:Clofibric Acid; C006253:pirinixic acid; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C026411:sorbinil; D003545:Cysteine; D003630:Daunorubicin