Session: SAT 358-380-Steroid Hormone Biosynthesis & Metabolism
Poster Board SAT-375
To elucidate the function of AKR1B15, we performed tissue distribution and subcellular localization studies as well as activity assays with various physiological substrates. We found that AKR1B15.1 and AKR1B15.2 differ strongly in expression level, subcellular localization and activity. Although sharing high amino acid homology with AKR1B10, we ascertained AKR1B15.1 to co-localize with mitochondria in contrast to other AKR enzymes which are mostly cytosolic. AKR1B15.1 is a predominately reductive enzyme converting 3-keto-acyl CoAs as well as androgens and estrogens with high position selectivity. It exhibits strong cofactor selectivity towards NADPH. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with tested substrates. In accordance to the substrate spectrum, we found the highest expression levels of AKR1B15.1 in steroid-related tissues, namely placenta and testis. Placental expression could be verified on RNA and protein level in BeWo cell line.
As public record links the S8R mutation in AKR1B15.1 to a strong mitochondrial disease phenotype , we aimed to reach a deeper insight into the function of AKR1B15.1 by analyzing the subcellular localization and activity properties of the mutant.
In conclusion, our studies demonstrate the existence of a novel functional and mitochondria-associated AKR enzyme, which is mainly expressed in steroid related tissues. In addition, we analyzed the characteristics of the AKR1B15.1 S8R mutant, claimed to be responsible for a severe mitochondrial defect.
1. Salabei, J.K., Li, X.P, et al. Functional expression of novel human and murine AKR1B genes. Chem Biol Interact. 2011; 191(1-3): 177–184.
2. Calvo, S.E., Compton, A.G., et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012; 4(118):118ra10.
Nothing to Disclose: SW, JKS, GM, AB, OAB, JA
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