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ACR

Official Full Name
acrosin
Background
Acrosin is the major proteinase present in the acrosome of mature spermatozoa. It is a typical serine proteinase with trypsin-like specificity. It is stored in the acrosome in its precursor form, proacrosin. The active enzyme functions in the lysis of the zona pellucida, thus facilitating penetration of the sperm through the innermost glycoprotein layers of the ovum. The mRNA for proacrosin is synthesized only in the postmeiotic stages of spermatogenesis. In humans proacrosin first appears in the haploid spermatids.
Synonyms
ACR; acrosin; preproacrosin; Acrosin precursor; ACRS; Proacrosin

The ACR gene encodes a sperm acrosome enzyme. Acrosin is a serine protein lyase(SP), located on the inner lining of the sperm head, is a membrane-bound enzyme. The acrosomal enzyme is mainly distributed on the inner membrane of the sperm acrosome and the equatorial membrane and is connected with the sperm acrosome membrane, which is essentially a trypsin-like serine protease. Mammalian fertilization is the process of combining sperm and egg. The sperm head has to pass through the zona pellucida. In addition to the morphological changes in the sperm head, it is more important that the acrosome reaction occurs. That is, the inactive acrosome zymogen is activated into an active acrosin and released, hydrolyzing the egg zona pellucida. Sperm vigorous movement and wedge-like action, smoothly through the cumulus and then through the zona pellucida to complete the fertilization process. In addition, acrosin also has the effect of increasing genital kinin release, enhancing sperm motility and promoting sperm motility. It can be seen that the acrosomal enzyme is a neutral protein hydrolase which is indispensable in the process of fertilization. The activity of the acrosome is largely determined by whether the fertilization process can proceed smoothly.

Mao et al. showed that the acrosome protein signal disappeared within 3 seconds after the acrosome reaction, while the signals of other acrosome components (eg, MN7 and MC41) remained for at least 15 minutes. The rapid disappearance of acrosome protein signals suggests that acrosomal enzymes may not participate in ZP (zona pellucida) penetration as previously thought. It is possible that early activation of acrosomal enzymes indicates a role prior to ZP infiltration.

ACRFigure 1. Sperm–egg interaction. (Mao, et al. 2013)

Kim et al. showed that Acrosin Binding Protein (ACRBP) can be used to monitor normal spermatogenesis or in vitro germ cell development in testis tissue. Because ACRBP is present in the germ cells of a stalled stallion, it can be used as an indicator of stroma sexual maturity. Zhang et al. showed that semen superoxide dismutase (SOD) activity was significantly reduced in male infertile patients with positive antisperm antibodies (AsAb) compared to the normal fertility group. Similarly, sperm acrosome enzyme activity in AsAb-positive patients was also significantly reduced. This suggests that infertility caused by positive AsAb may be related to changes in semen SOD and sperm acrosome enzyme activity.

Factors Affecting Sperm Acrosin Activity

The clinical observation showed that the acrosome activity of the sperm at 1 to 5 days of abstinence was stable, but with the prolonged abstinence time, the acrosome activity decreased significantly after reaching 10 days. In addition, sperm acrosin activity has a certain correlation with sperm acrosome integrity rate and a significant positive correlation with the percentage of normal spermatozoa. This indicates that sperm turnover time in the body directly affects the fertilization process and is closely related to sperm acrosome enzyme activity.

The environment has a significant impact on conventional indicators such as sperm morphology and sperm count. With the deepening of the research, it was found that men who have been exposed to aromatic organic solvents or organochlorine insecticides for a long time have significantly reduced sperm motility and acrosin activity, and the extent of the decrease is closely related to the concentration and frequency of exposure. This suggests that these organic solvents may affect male fertility and accessory gonadal function.

Non-bacterial prostatitis (CAP IIIA) and chronic prostatitis (type IV prostatitis) can significantly reduce sperm acrosome enzyme activity, total sperm motility, sperm motility, normal morphological rate and sperm hypotonic swelling, but there was no significant effect on density and semen volume. Because these patients contain a large number of activated inflammatory cells in the prostatic fluid, they promote inflammation and on the other hand damage sperm by direct contact with sperm. On the other hand, the production of soluble substances by granulocytes increases the level of reactive oxygen species (ROS) in the seminal plasma and impairs sperm function.

Acrosin Inhibitor

The main functions of acrosin inhibitors are: First, to prevent premature release of sperm acrosin, damage to sperm to take action to protect the epithelial cells of the female reproductive tract during sperm and sperm transport. The second is to ensure the transparent band binding site and participate in sperm egg recognition. It may act through receptor molecules that bind to the surface of the sperm and become an important factor in stabilizing sperm-egg binding. That is, during the genital tract of the sperm in the mother, the binding site of the zona pellucida is exposed after the release of the inhibitor.

Human acrosome protease is an attractive target for the discovery of novel male contraceptives. Juntao et al. demonstrated that the isoxazole derivative ISO-1, a small molecule weak human acrosome enzyme inhibitor, was used as an optimized entry point. After two rounds of structure-based design inhibitors, a highly potent inhibitor of B6 (IC50 = 1.44 μM) was successfully confirmed. It shows better selectivity than trypsin and represents one of the most active human acrosome enzyme inhibitors to date.

Chen et al. showed that the four inhibitors designed showed effective acrosome inhibition activity. The scaffold of the compound was found to be important for the inhibitory activity. Several compounds are more active than the positive control TLCK, a previously reported acrosin small molecule inhibitor, suggesting that they can serve as a good starting point for the discovery of novel male contraceptives.

References:

  1. Mao, H. T., & Yang, W. X. (2013). Modes of acrosin functioning during fertilization. Gene, 526(2), 75-79.
  2. Kim, J. T., Jung, H. J., Song, H., & Yoon, M. J. (2015). Acrosin-binding protein (acrbp) in the testes of stallions. Animal Reproduction Science,163, 179-186.
  3. Zhang, H., Zhao, E., Zhang, C., & Li, X. (2015). The change of semen superoxide dismutase and acrosin activity in the sterility of male patients with positive antisperm antibody. Cell Biochemistry & Biophysics, 73(2), 1-3.
  4. Juntao, Z., Wei, T., Jingjing, Q., Diya, L., Yang, L., & Yan, J., et al. (2014). Design and synthesis of phenylisoxazole derivatives as novel human acrosin inhibitors. Bioorganic & Medicinal Chemistry Letters, 24(13), 2802-2806.
  5. Chen, Q., Tian, W., Han, G., Qi, J., Zheng, C., & Zhou, Y., et al. (2013). Design and synthesis of novel benzoheterocyclic derivatives as human acrosin inhibitors by scaffold hopping. European Journal of Medicinal Chemistry, 59, 176-182.

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