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  • AKR1B10, the origin of lung cancer

    images76AKR1B10 is a aldocetoreductasa (AKR) especially interesting for two reasons: it is overexpressed in lung cancer and precancerous lesions of smokers and becomes very efficient, the retinal to retinol, retinal reductase being the most active among AKR. Researchers from the Universitat Autònoma de Barcelona, IBMB, IRB Barcelona, and Universidade de Vigo CRQT propose that both features could be related through the alteration of the signaling pathway of retinoic acid. This compound, synthesized by successive oxidation of retinol (vitamin A) to retinal, and thence to acid molecule is a potent regulator of cell differentiation.

    A high AKR1B10 expression, potentially induced by snuff, would result in a significant decrease in retinal cell levels and, consequently, retinoic acid, which could lead to lack of differentiation, and induce cell proliferation and cancer.

    This work demonstrates the specificity of AKR1B10 by trans-retinal, and their high activity both in vitro and in cell cultures. It has solved the crystal structure of AKR1B10 and compared with other AKR related structure, aldose reductase, a hundred times less active than AKR1B10. Using molecular dynamics simulations of both models were built with retinal enzymes in the active site. The comparison of the complex revealed that the retinal molecule induces a different conformation in a region of the active site of the two proteins. The residues involved have been replaced by site-directed mutagenesis, confirming that these residues, located in an outer loop of the protein, are responsible for the differential interaction of retinoids with AKR1B10 and aldose reductase, as their catalytic properties.

    This information opens the possibility of designing specific inhibitors for AKR1B10, with potential application as antitumor drugs. Furthermore, data structure / function provided provided new approaches to the identification of new inhibitors against aldose reductase, an enzyme widely studied for their glucose reductase activity in hyperglycemia and is heavily involved in the development of secondary complications of diabetes.

    Published on November 30, 2012 · Filed under: Bioscience; Tagged as: , ,
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