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Acrosin is a digestive enzyme that acts as a protease. In humans, acrosin is encoded by the ACR gene. Acrosin is released from the acrosome of spermatozoa as a consequence of the acrosome reaction. It aids in the penetration of the Zona Pellucida.
reaction proceeds according to the usual serine protease mechanism. First, His-57 deprotonates Ser-195, allowing it to serve as a nucleophile. Deprotonated Ser-195 then reacts with the carbonyl carbon of a peptide, forming a tetrahedral intermediate. The tetrahedral intermediate then collapses, resulting in an H2N-R1 leaving group, which is protonated through His-57. Finally, His-57 deprotonates a water molecule, which can then serve as a nucleophile by similarly reacting with the carbonyl carbon. Collapse of the tetrahedral intermediate then results in a Ser-195 leaving group, which is protonated through His-57, resulting in all residues returned to their pre-catalytic state, and a carboxylic acid where there was previously a peptide bond.
The importance of acrosin in the acrosome reaction has been contested. It has been found through genetic knockout experiments that mouse spermatozoa lacking β-acrosin (the active protease) still have the ability to penetrate the zona pellucida.T. Baba, S. Azuma, S. Kashiwabara, Y. Toyoda. Sperm from mice carrying a targeted mutation of the acrosin gene can penetrate the oocyte zona pellucida and effect fertilization" J. Biol. Chem. 1994; 269, pp. 31845–31849 Thus, some argue for its role in assisting in the dispersal of acrosomal contents following the acrosome reaction, while others demonstrate evidence for its role as a secondary binding protein between the spermatozoa and zona pellucida.K. Yamagata, T. Baba, et al. Acrosin accelerates the dispersal of sperm acrosomal proteins during acrosome reaction" J. Biol. Chem. 1998; 273, pp. 10470–10474R. Jones, C.R. Brown. Identification of a zona-binding protein from boar spermatozoa as proacrosin. Expl" Cell Res 1987; 171, pp. 505–508R. Jones. Interaction of zona pellucida glycoproteins, sulphated carbohydrates and synthetic polymers with proacrosin, the putative egg-binding protein from mammalian spermatozoa" Development 1991; 111, pp. 1155–1163 Under the secondary binding protein hypothesis, acrosin could serve a role in binding to molecules on the zona pellucida, tethering the spermatozoa to the egg. This "tethering" would ensure penetration due to the applied motile force of the spermatozoa.D.P. Green. The head shapes of some mammalian spermatozoa and their possible relationship to the shape of the penetration slit through the zona pellucida. J. Reprod. Fertil., 83 (1988), pp. 377–387
Acrosin regulation has been found to occur through protein C inhibitor (PCI). PCI is present in the male reproductive tract at 40x higher concentrations than in blood plasma. PCI has been demonstrated to inhibit the proteolytic activity of acrosin. Thus, PCI has been hypothesized to have a protective role: if acrosomal enzymes were released prematurely, or if the spermatozoa was degenerated within the male reproductive tract, the high concentrations of PCI would inhibit acrosin from inflicting proteolytic damage on nearby tissues.
The catalytic triad consists of residues His-57, Asp-102, and Ser-195. These residues are found in a binding pocket that has been termed the "S1" pocket, consistent with the naming scheme that has been adopted for other proteases.I. Schechter, A. Berger. On the size of the active site in proteases. I. Papain. Biochim. Biophys. Res. Commun, 27 (1967), pp. 157–162. The S1 pocket regulates acrosin's specificity for Arg and Lys substrates, with a conserved Trp-215 serving as a "gatekeeper" residue for the binding site entrance.
important structural element of β-acrosin is a highly charged patch (formed through both amino acids and post-translational modifications) on its surface region, that has been termed the "anion binding exosite." This site consists of an area of excess positive charge, which has been hypothesized to be important in binding to the matrix of the zona pellucida, a heavily glycosylated and sulfated region with excess negative charge. This structural feature is consistent with the secondary binding protein hypothesis, as charge-charge interactions would stabilize a protein-zona pellucida "tethering" complex.S. Shimizu, M. Tsuji, J. Dean. In vitro biosynthesis of three sulphated glycoproteins of murine zonae pellucidae by oocytes grown in follicle culture" J. Biol. Chem. 1983; 258, pp. 5858–5863 Further consistent with this structural hypothesis is the knowledge that suramin - a polysulfated drug (with substantial corresponding negative charge) has been found to inhibit sperm-zona pellucida binding.
Moreover, as serine proteases are important in the potentiation of HIV, research has found that an acrosin inhibitor, 4'-acetamidophenyl 4-guanidinobenzoate, possess the ability to inhibit HIV infection in virus-inoculated . This suggests the further role of acrosin inhibitors as potentially viable agents in the prevention of HIV transmission.
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