The Angiotensin-converting enzyme (ACE) is an upregulator of blood pressure through its peptidase activity (Hooper, 1994; Turner and Hooper, 2002). A testis-specific isoform of the enzyme exists that is found in both spermatids and spermatozoa. The male testis specific ACE-null mouse (tACE) was found to have reduced fertility (Hagaman et al., 1998). The somatic ACE isoform appears to have no negative effect on sperm function. Sperm from the tACE mutant mice show defective transport through the female tract despite having normal motility, sperm numbers and morphology. Additionally, binding to the zona pellucida was also impaired.
The tACE is a membrane-bound protein and is lost from the membrane during capacitation (Kohn et al., 1995). This is as a result of proteolytic cleavage leaving a specific vestige on the sperm surface (Ehlers et al., 1996; Ramchandran et al., 1994). It has been suggested that this loss of tACE may be important for the release of sperm from the oviductal epithelium. Interestingly, the tACE knockout mouse presents with a similar phenotype to null-mutations of cyritestin (Shamsadin et al., 1999), fertilin p (Cho et al., 1998) and calmegin (Ikawa et al., 2001). These mutant mice may all have a common as yet undiscovered defect in the capacitation process.
ACE has recently been shown to have an additional activity as a glycosyl-phospatidylinositol (GPI)-anchored protein-releasing enzyme (GPIase) (Kondoh et al., 2005). Comparison of immunoblots of sperm from wild type and ACE null mice identified two GPI-anchored proteins (Tesp5 and Ph-20) that are released from sperm. In the mutant mice these proteins are no longer released from the sperm membrane, implying that ACE acts to convert these proteins to their soluble form. Addition of ACE or peptidase-inactivated ACE to sperm from the ACE-null mice restored sperm-zona pellucida binding resulting in the birth of normal Ace +/— pups. These results imply that the release of GPI-anchored proteins is important for sperm-zona binding; this may involve a sperm protein that becomes functional following its release from its GPI-anchor or the unmasking of a zona-binding protein.
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