title: The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex.
abstract: The basal fungus Allomyces macrogynus (A. macrogynus) produces motile male gametes displaying well-studied chemotaxis toward their female counterparts. This chemotaxis is driven by sirenin, a sexual pheromone released by the female gametes. The pheromone evokes a large calcium influx in the motile gametes, which could proceed through the cation channel of sperm (CatSper) complex. Herein, we report the total synthesis of sirenin in 10 steps and 8% overall yield and show that the synthetic pheromone activates the CatSper channel complex, indicated by a concentration-dependent increase in intracellular calcium in human sperm. Sirenin activation of the CatSper channel was confirmed using whole-cell patch clamp electrophysiology with human sperm. Based on this proficient synthetic route and confirmed activation of CatSper, analogues of sirenin can be designed as blockers of the CatSper channel that could provide male contraceptive agents.
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Shameem Sultana
authors.initials: SS
authors.lastname: Syeda
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Erick J
authors.initials: EJ
authors.lastname: Carlson
authors.affiliation: Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.|Department of Physiology, University of California , San Francisco, California 94158, United States.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Rawle
authors.initials: R
authors.lastname: Francis
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Department of Neurobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.affiliation: Department of Molecular and Cell Biology, University of California , Berkeley, California 94720, United States.
authors.forename: Polina V
authors.initials: PV
authors.lastname: Lishko
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Hawkinson
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Hook
authors.affiliation: Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55414, United States.
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D055134:Allomyces / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D006801:Humans; D008297:Male; D010675:Pheromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism
chemical_list: C438823:CATSPER1 protein, human; D015220:Calcium Channels; D010675:Pheromones; D002118:Calcium