4.4 Article

Tunable Toxicity of Bufadienolides is Regulated through a Configuration Inversion Catalyzed by a Short-Chain Dehydrogenase/Reductase

Journal

CHEMBIOCHEM
Volume 23, Issue 22, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200473

Keywords

3-epi bufadienolides; hydroxysteroid epimerization; short-chain dehydrogenase; reductase; toad liver; toxicity

Funding

  1. National Natural Science Foundation [82173938]
  2. National Natural Science Foundation of Guangdong Province, China [2019A1515011489]
  3. Guangzhou Science and Technology Plan [202002030219]
  4. OSUCCC startup funds

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Bufadienolides are toxic components found in amphibious toads and have a wide range of biological activities. This study identified and characterized several 3-epi-bufadienolides with unique structures from the bile of the Asiatic toad. Toxicology assays showed that 3-hydroxyl epimerization significantly decreased the toxicity of bufadienolides. Furthermore, a hydroxyl epimerase enzyme, HSE-1, was discovered in the toad liver, which regulates the toxicity of natural animal-derived products.
Bufadienolides are toxic components widely found in amphibious toads that exhibit a wide range of biological activities. Guided by UPLC-QTOF-MS analysis, several 3-epi-bufadienolides with unique structures were isolated from the bile of the Asiatic toad, Bufo gargarizans. However, the enzymatic machinery of this epimerization in toads and its significance in chemical ecology remains poorly understood. Herein, we firstly compared the toxicities of two typical bufadienolides, bufalin (featuring a 14 beta-hydroxyl) and resibufogenin (containing a 14, 15-epoxy group), with their corresponding 3-epi isomers in a zebrafish model. The results of the toxicology assays showed that the ratio of maximum non-toxic concentrations of these two pairs of compounds are 256 and 96 times, respectively, thereby indicating that 3-hydroxyl epimerization leads to a significant decrease in toxicity. Aiming to investigate the biotransformation of 3-epi bufadienolides in toads, we applied liver lysate to transform bufalin and found that it could stereoselectively catalyze the conversion of bufalin into its 3 alpha-hydroxyl epimer. Following this, we cloned and characterized a short-chain dehydrogenase/reductase, HSE-1, from the toad liver cDNA library and verified its 3(beta ->alpha)-hydroxysteroid epimerization activity. To the best of our knowledge, this is the first hydroxyl epimerase identified from amphibians that regulates the toxicity of animal-derived natural products.

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