Cancer biomarker AKR1B10 and carbonyl metabolism.
A member of the aldo-keto reductase (AKR) protein superfamily, AKR1B10, is overexpressed in human liver cancers as well as in many adenocarcinoma cases due to smoking. AKR1B10 is also detected in instances of cervical and endometrial cancer in uterine cancer patients. In addition, AKR1B10 has been identified as a biomarker for non-small-cell lung cancer by a combined bioinformatics and clinical analysis. Furthermore, in breast cancer cells, fatty acid biosynthesis is regulated by AKR1B10. AKR1B10 contains 316 residues, shares 70% sequence identity with aldose reductase (AKR1B1) and has the conserved Cys residue at position 299. Carbonyl groups in some anticancer drugs and dl-glyceraldehyde are converted by AKR1B10 to their corresponding alcohols. The anticancer drug daunorubicin, which is currently used in the clinical treatment of various forms of cancer, is converted by AKR1B10 to daunorubicinol with a K(m) and k(cat) of 1.1+/-0.18 mM and 1.4+/-0.16 min(-1), respectively. This carbonyl reducing activity of AKR1B10 decreases the anticancer effectiveness of daunorubicin. Similarly, kinetic parameters K(m) and k(cat) (NADPH, DL-glyceraldehyde) for the reduction of dl-glyceraldehyde by wild-type AKR1B10 are 2.2+/-0.2 mM and 0.71+/-0.05 sec(-1), respectively. Mutation of residue 299 from Cys to Ser in AKR1B10 reduces the protein affinity for dl-glyceraldehyde and enhances AKR1B10's catalytic activity but overall catalytic efficiency is reduced. For dl-glyceraldehyde reduction that is catalyzed by the Cys299Ser mutant AKR1B10, K(m) is 15.8+/-1.0mM and k(cat) (NADPH, DL-glyceraldehyde) is 2.8+/-0.2 sec(-1). This implies that the substrate specificity of AKR1B10 is drastically affected by mutation of residue 299 from Cys to Ser. In the present paper, we use this mutation in AKR1B10 to characterize a library of compounds regarding their different inhibitory potency on the carbonyl reducing activity of wild-type and the Cys299Ser mutant AKR1B10.
Balendiran
Ganesaratnam K
GK
Department of Chemistry, Ward Beecher Science Hall, Youngstown State University, One University Plaza, Youngstown State University, OH 44555, USA. pl_note@yahoo.com
Martin
Hans-Joerg
HJ
El-Hawari
Yasser
Y
Maser
Edmund
E
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D011110:Polymorphism, Genetic
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D011345:Fenofibrate