Document Detail


Inhibiting wild-type and C299S mutant AKR1B10; a homologue of aldose reductase upregulated in cancers.
MedLine Citation:
PMID:  18325492     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Malkhey Verma; Hans-Joerg Martin; Wahajul Haq; Timothy R O'Connor; Edmund Maser; Ganesaratnam K Balendiran
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-02-05
Journal Detail:
Title:  European journal of pharmacology     Volume:  584     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-08     Completed Date:  2008-07-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  213-21     Citation Subset:  IM    
Affiliation:
Division of Immunology, Beckman Research Institute, City of Hope National Medical Center, 1450 E. Duarte Road, Duarte, CA 91010, USA.
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Reductase / antagonists & inhibitors*,  genetics,  metabolism
Antibiotics, Antineoplastic / metabolism
Antineoplastic Agents / pharmacology*
Benzothiazoles / pharmacology
Clofibric Acid / pharmacology
Cysteine
Daunorubicin / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Glyceraldehyde / metabolism
Humans
Imidazolidines / pharmacology
Kinetics
Mutation
Neoplasms / enzymology*
Oxidation-Reduction
Phthalazines / pharmacology
Pyrimidines / pharmacology
Recombinant Proteins / antagonists & inhibitors
Serine
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antineoplastic Agents; 0/Benzothiazoles; 0/Enzyme Inhibitors; 0/Imidazolidines; 0/Phthalazines; 0/Pyrimidines; 0/Recombinant Proteins; 110703-94-1/zopolrestat; 20830-81-3/Daunorubicin; 367-47-5/Glyceraldehyde; 50892-23-4/pirinixic acid; 52-90-4/Cysteine; 56-45-1/Serine; 68367-52-2/sorbinil; 882-09-7/Clofibric Acid; EC 1.1.1.-/AKR1B10 protein, human; EC 1.1.1.21/Aldehyde Reductase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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