The metabolism of steroids and retinoids has been studied in detail for a long time, as these compounds are involved in a broad spectrum of physiological processes. Many enzymes participating in the conversion of such compounds are members of the short-chain dehydrogenase/reductase (SDR) superfamily. Despite great effort, there still remain a number of poorly characterized SDR proteins. According to various bioinformatics predictions, many of these proteins may play a role in the metabolism of steroids and retinoids. Dehydrogenase/reductase (SDR family) member 7 (DHRS7) is one such protein. In a previous study, we determined DHRS7 to be an integral membrane protein of the endoplasmic reticulum facing the lumen which has shown at least in vitro NADPH-dependent reducing activity toward several eobiotics and xenobiotics bearing a carbonyl moiety. In the present paper pure DHRS7 was used for a more detailed study of both substrate screening and an analysis of kinetics parameters of the physiologically important substrates androstene-3,17-dione, cortisone and all-trans-retinal. Expression patterns of DHRS7 at the mRNA as well as protein level were determined in a panel of various human tissue samples, a procedure that has enabled the first estimation of the possible biological function of this enzyme. DHRS7 is expressed in tissues such as prostate, adrenal glands, liver or intestine, where its activity could be well exploited. Preliminary indications show that DHRS7 exhibits dual substrate specificity recognizing not only steroids but also retinoids as potential substrates and could be important in the metabolism of these signalling molecules.

• Klíčová slova
• Carbonyl reduction, DHRS7, Metabolism, Retinoids, SDR, Steroids,
• MeSH
• androstendion metabolismus   MeSH
• cirkulární dichroismus MeSH
• fylogeneze MeSH
• kinetika MeSH
• kortison metabolismus   MeSH
• lidé MeSH
• oxidoreduktasy chemie   genetika   metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• retinaldehyd metabolismus   MeSH
• steroidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androstendion MeSH
• DHRS7 protein, human MeSH Prohlížeč
• DHRS7c protein, human MeSH Prohlížeč
• kortison MeSH
• oxidoreduktasy MeSH
• retinaldehyd MeSH
• steroidy MeSH

Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly known. Here, the purified recombinant enzyme has been subjected to substrate specificity characterization, kinetic analysis and inhibitor screening, combined with structural modeling. AKR1B15 is active towards a variety of carbonyl substrates, including retinoids, with lower kcat and Km values than AKR1B10. In contrast to AKR1B10, which strongly prefers all-trans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cis-retinaldehyde, the best substrate found for this enzyme. With ketone and dicarbonyl substrates, AKR1B15 also shows higher catalytic activity than AKR1B10. Several typical AKR inhibitors do not significantly affect AKR1B15 activity. Amino acid substitutions clustered in loops A and C result in a smaller, more hydrophobic and more rigid active site in AKR1B15 compared with the AKR1B10 pocket, consistent with distinct substrate specificity and narrower inhibitor selectivity for AKR1B15.

• MeSH
• aldehydreduktasa antagonisté a inhibitory   genetika   metabolismus   MeSH
• aldo-keto reduktasy MeSH
• diterpeny MeSH
• inhibitory enzymů farmakologie   MeSH
• katalytická doména genetika   MeSH
• kinetika MeSH
• konformace proteinů MeSH
• lidé MeSH
• molekulární modely MeSH
• oxidoreduktasy působící na aldehydy nebo donory oxo-skupin antagonisté a inhibitory   genetika   metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• retinaldehyd metabolismus   MeSH
• sekvence aminokyselin MeSH
• strukturní homologie proteinů MeSH
• substituce aminokyselin MeSH
• substrátová specifita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-cis-retinal MeSH Prohlížeč
• AKR1B10 protein, human MeSH Prohlížeč
• AKR1B15 protein, human MeSH Prohlížeč
• aldehydreduktasa MeSH
• aldo-keto reduktasy MeSH
• diterpeny MeSH
• inhibitory enzymů MeSH
• oxidoreduktasy působící na aldehydy nebo donory oxo-skupin MeSH
• rekombinantní proteiny MeSH
• retinaldehyd MeSH