Thursday, December 28, 2006
In a study recently published online by the journal Developmental Biology, members of Dr. John Herr's laboratory at the University of Virginia Health System report the discovery of a new protein within a sperm's tail that could prove a key target for male contraceptive drugs.
'There's considerable interest in developing new male contraceptives,' said Herr*, who heads UVa's Center for Research in Contraceptive and Reproductive Health. 'To support this effort, our team has been searching for proteins that might serve as target sites for small-molecule drugs.'
The newly discovered protein is called sperm flagellar energy carrier (SFEC). It is the fourth in a family of proteins that perform transfer processes to help cells make and use energy. Inside the cell, these proteins operate much like a shuttle bus, binding and exchanging energy-carrying molecules known as ATP and ADP.
The discovery of SFEC has sparked interest among both basic scientists and contraceptive drug developers because of where it is located in the sperm and the kind of energy-making process that occurs there.
'One approach to male contraception is to disable sperm from swimming, and we think SFEC may be able to play a role in that process,' Herr noted.
Continued at "Male Contraception Discovery"
Based on the paper:
Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece
Young-Hwan Kim, Gerhard Haidl, Martina Schaefer, Ursula Egner and John C. Herr
The longest part of the sperm flagellum, the principal piece, contains the fibrous sheath, a cytoskeletal element unique to spermiogenesis. We performed mass spectrometry proteomics on isolated human fibrous sheaths identifying a unique ADP/ATP carrier protein, SFEC [AAC4], seven glycolytic enzymes previously unreported in the human sperm fibrous sheath, and sorbitol dehydrogenase. SFEC, pyruvate kinase and aldolase were co-localized by immunofluorescence to the principal piece. A homology model constructed for SFEC predicted unique residues at the entrance to the nucleotide binding pocket of SFEC that are absent in other human ADP/ATP carriers, suggesting opportunities for selective drug targeting. This study provides the first evidence of a role for an ADP/ATP carrier family member in glycolysis. The co-localization of SFEC and glycolytic enzymes in the fibrous sheath supports a growing literature that the principal piece of the flagellum is capable of generating and regulating ATP independently from mitochondrial oxidation in the mid-piece. A model is proposed that the fibrous sheath represents a highly ordered complex, analogous to the electron transport chain, in which adjacent enzymes in the glycolytic pathway are assembled to permit efficient flux of energy substrates and products with SFEC serving to mediate energy generating and energy consuming processes in the distal flagellum, possibly as a nucleotide shuttle between flagellar glycolysis, protein phosphorylation and mechanisms of motility.
*Info on John Herr's research interests:
Our laboratory is focused on the structural characterization of sperm proteins and their encoding genes. Two fundamental concepts underlie this work. First, during spermatogenesis, the expression of genes unique to the spermatogenic lineage, results in sperm-specific polypeptides being incorporated into the sperm's cyto architecture. Such testis-specific genes provide good models for understanding the regulation of gene expression during the differentiation of spermatids into mature sperm. Second, the sequestration of sperm from the immune system by the blood-testis barrier allows for many sperm antigens to be recognized immunologically as autoantigens. (More)
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