Discovery of specific activity of 2-HPA acting on the membrane progestin receptor alpha (paqr7) by purification of natural products from the marine algae Padina

Abstract

Abstract Membrane progestin receptors (mPRs) are members of the progestin and adipoQ (PAQR) receptor family that are stimulated by endogenous steroids to initiate rapid intracellular signalling through a nongenomic pathway. Previously, water-soluble compounds with mPRα-binding activity from the marine algae Padina arborescens were fractionated by HPLC steps. In this study, the structure of one of the major compounds in the fraction was identified as 2-hydroxypentanoic acid (2-HPA) using Nuclear Magnetic Resonance spectroscopy. 2-HPA showed a substantial competitive binding affinity for hmPRα in the GQD-hmPRα binding assay. In contrast, synthetic structural analogues of 2-HPA showed no competitive binding activity. The physiological activity of 2-HPA and its analogues was then investigated using in vitro goldfish and in vivo zebrafish oocyte maturation and ovulation assays. As with the hmPRα binding assay, only 2-HPA showed inhibitory activity on oocyte maturation and ovulation of fish oocytes. Furthermore, the inhibitory activity of 2-HPA was compared between S- and R-type 2-HPA. The results showed that both types had the same level of activity. These results indicate that 2-HPA, found as a secreted compound from Padina arborescens, is a novel mPRα antagonist and its chemical structure is highly restricted to show its activity.