Abstract
The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD+. The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD+ and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD+ and REA that we propose to represent two snapshots along the catalytic cycle. Indeed, the isoprenic moiety of REA points either toward the active site cysteine, or moves away adopting the product release conformation. Although ALDH1A3 shares high sequence identity with other members of the ALDH1A family, our structural analysis revealed few peculiar residues in the 1A3 isozyme active site. Our data provide information into the ALDH1As catalytic process and can be used for the structure-based design of selective inhibitors of potential medical interest.
Highlights
Retina development during embryogenesis, neuronal cell differentiation and maintenance of epithelial cell type in adult tissues[10]
Two distinct tumour-derived Glioma stem cell (GSC) subtypes were identified in high-grade glioma: the proneuronal glioma stem cells (PN GSCs) and the mesenchymal glioma stem cells (Mes GSCs) with elevated expression of human ALDH1A3 being observed in Mes GSCs with respect to PN GSCs23
The ALDH1A3 kinetic parameters were determined for NAD+, the natural substrate all-trans retinal and acetaldehyde, a general substrate accepted by many aldehyde dehydrogenase enzymes (ALDHs) isozymes[24]
Summary
Retina development during embryogenesis, neuronal cell differentiation and maintenance of epithelial cell type in adult tissues[10]. Compelling evidence highlight ALDHs as key molecules governing cell proliferation, survival and chemoresistance of CSCs20 and strongly suggests that the development of potent and selective inhibitors may represent a novel CSC-directed therapeutic potential in human cancers[21,22] In this respect, it should be noted that distinct isozymes have a unique relevance in different tumours; for instance, ALDH1A1 is proposed as a sensitive target in human melanoma[18] whereas ALDH1A3 is considered a target in breast cancer[22]. HGGs generated from Mes GSCs display a significantly higher radio-resistance and irradiation has been shown to induce ALDH1A3 up-regulation that is involved in the PN GSCs transformation into Mes GSCs23 Taken together, these data suggest that human ALDH1A3 may represent a valuable target for the development of novel therapeutics against HGGs23. The structure determination of ALDH1A3 in complex with ligands provides novel information to understand catalysis in the ALDH1As subfamily and represents a valuable tool for the structure-based design of potent and selective inhibitors of medical interest as new anticancer agents
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
