Sperm enzyme is essential for male fertility, study shows

A study led by scientists at the University of North Carolina at Chapel Hill has determined that a novel enzyme in sperm
is essential for sperm motility and male fertility.


The new study may offer a potential target for an effective, non-hormonal male contraceptive, the researchers said. The
findings will be published today (Nov. 15) in the online early edition of the journal Proceedings of the National Academy of
Sciences. A report also will appear Nov. 23 in the journal's print edition.


Collaborating with UNC were scientists from the U.S. National Institute of Environmental Health Sciences (NIEHS); Fudan
University in Shanghai, China; and the U.S. Environmental Protection Agency.


Sperm motility, produced by the coordinated movement of the extremely long sperm tail, requires substantial energy in the
form of adenosine triphosphate, or ATP, the major energy currency of the cell.


Specialized cellular structures known as mitochondria were thought to provide a substantial portion of the ATP needed for
sperm motility. In contrast, Dr. Deborah A. O'Brien, associate professor of cell and developmental biology at UNC's School of
Medicine, and her colleagues found that sperm motility and ATP production depend primarily on a metabolic pathway known as
glycolysis. This pathway uses sugar to produce energy, a common process in animal and plant cells.


The researchers focused on the enzyme glyceraldehyde 3-phosphate dehydrogenase-S, or GAPDS, a novel enzyme in the glycolytic
pathway that is expressed only in germ cells very late in the process of sperm production.


GAPDS is tightly bound to a structural element that extends along most of the length of the sperm tail. The study team used
gene targeting, or gene knockout technology, to produce mice that could not make this unique enzyme.


Without GAPDS, glycolysis is selectively blocked in sperm and this pathway produces no ATP. As expected, the females were
normal and the males had normal testes and sperm counts, but they were infertile, O'Brien said.


And when the researchers analyzed sperm movement under a microscope, they found a surprise.


"We expected that a type of motility known as 'hyperactivated motility' would be inhibited, but found that all progressive
movement was absent in sperm without GAPDS," O'Brien said.


"Glycolysis may not be as efficient as mitochondria for producing energy, but the enzymes are abundant and in the right place
for quick, localized energy production along the sperm tail. This paper provides proof of principle that GAPDS may be an
effective target for a contraceptive agent."


Co-authors with O'Brien are Dr. Kiyoshi Miki, research assistant professor in cell and developmental biology; Dr. Weidong Qu,
postdoctoral researcher at UNC and associate professor at Fudan University; Eugenia Goulding and William Willis, research
technicians at the NIEHS; Dr. Donna Bunch, assistant professor of medicine at UNC; Lillian Strader, research technician at
the EPA; Dr. Sally Perreault, chief, gamete and early embryo biology branch at the EPA; and Dr. Edward M. Eddy, who heads the
gamete biology section at the NIEHS.


By JAN MCCOLM

UNC School of Medicine


This research was supported by the Specialized Cooperative Centers Program in Reproductive Research at the National Institute
of Child Health and Human Development, the NIEHS, the National Institutes of Health's Fogarty International Center and the
EPA.


Note: Contact O'Brien at 919-962-8105 or daomed.unc.

School of Medicine contact: Les Lang, 919-843-9687 or llangmed.unc


Contact: Leslie H. Lang

llangmed.unc

919-843-9687

University of North Carolina School of Medicine