AI Article Synopsis
- A new fluorogenic substrate for 3alpha-hydroxysteroid dehydrogenases (3alpha-HSD) was created, featuring a ketone that is initially nonfluorescent, but its corresponding alcohol form exhibits strong fluorescence, acting as a redox optical switch.
- Seven compounds were selected based on their optical and stability characteristics and tested against different dehydrogenase enzymes, with probe 5 showing high selectivity for human, rat, and bacterial 3alpha-HSD enzymes.
- Probe 5 demonstrated superior kinetic parameters compared to 5alpha-dihydrotestosterone (a physiological substrate), suggesting it could be a valuable tool for redox imaging applications in physiological research.
Article Abstract
A new fluorogenic substrate was developed for 3alpha-hydroxysteroid dehydrogenases (3alpha-HSD), including the human enzymes implicated in important physiological functions (androgen deactivation, neurosteroid activation). While ketone 5 is nonfluorescent, the corresponding alcohol exhibits high fluorescence with emission maximum at 510 nm, thus constituting a redox optical switch. This study began with a chemical concept of a ketone-alcohol optical switch which guided the synthesis of a focused array of compounds. Subsequently, seven compounds were selected (1-7) on the basis of their optical and chemical (stability) properties and were submitted to a screen against a panel of dehydrogenase enzymes. Probe 5 was found to be highly selective for bacterial, rat, and human 3alpha-HSD enzymes. The kinetic parameters were obtained for human 3alpha-HSD enzyme (type 2 isozyme, AKR 1C3; Km = 2.5 muM, kcat = 8.2 min-1). Remarkably, comparison to 5alpha-dihydrotestosterone (5alpha-DHT, Km = 26 muM, kcat = 0.25 min-1, Figure 4), a likely physiological substrate in prostate, revealed that synthetic probe 5 is in fact a far better substrate for this enzyme. Structure 5 represents an exciting lead for the development of a redox imaging probe.
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