Wikipedia

User:Zachcharry/Acrosin

Acrosin
Identifiers
EC no.3.4.21.10
CAS no.9068-57-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Acrosin is a digestive enzyme that acts as a protease. In humans, acrosin is encoded by the ACR gene.[1][2] Acrosin is released from the acrosome of spermatozoa as a consequence of the acrosome reaction. It aids in the penetration of the Zona Pellucida.

Enzyme Mechanism

edit

Acrosin is a typical serine proteinase with trypsin-like specificity.

 
Acrosin catalytic mechanism

The 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.

Biological Function

edit

Acrosin is the major proteinase present in the acrosome of mature spermatozoa. It is stored in the acrosome in its precursor form, proacrosin. Upon stimulus, the acrosome releases its contents onto the zona pellucida. After this reaction occurs, the zymogen form of the protease is then processes into its active form, β-acrosin. The active enzyme then functions in the lysis of the zona pellucida, thus facilitating penetration of the sperm through the innermost glycoprotein layers of the ovum.[3] Importantly, it has been found through knockout experiments that mouse spermatozoa lacking β-acrosin (the active protease) still have the ability to penetrate the zona pellucida.[4] 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.[5][6][7] Acrosin thus could serve a role in binding to molecules on the zona pellucida, tethering the spermatozoa and the egg: penetration is thus able to ensure due to an applied thrust.[8]

Research has shown that Protein C inhibitor (PCI) has been found to inactivate acrosin. PCI is present in the male reproductive tract at 40x higher concentrations than in blood plasma.[9] PCI has been demonstrated to inhibit the proteolytic activity of acrosin.[9] 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.[10]

Structure

edit

β-acrosin demonstrates a high degree of sequence identity (70-80%) between boar, bull, rat, guinea pig, mouse, and human isoforms.[3] There exists a somewhat similar (27-35%) sequence identity between β-acrosin and other serine proteases such as trypsin or chymotrypsin.[3] While most serine proteases are activated through one cleavage event, proacrosin requires processing at both the N and C-terminal domains. Proacrosin is first cleaved between Arg-22 and adjacent Valine to create a 22 residue light chain, and an active protease termed α-acrosin.[3] This light chain remains associated with the heavy chain, cross-linked through two disulfide bonds to form a heterodimer. Following these N-terminal cleavage events, three cleavages at the C-terminal domain removes 70 residues, yielding β-acrosin.[3] Two sites have been identified as possible N-glycosylation sites: Asn-2 and Asn-169.[3]

The catalytic triad consists of residues His-57, Asp-102, and Ser-195.[3] 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.[11] The S1 pocket regulates Acrosin's specifity for Arg and Lys substrates, with a conserved Trp-215 serving as a "gatekeeper" residue for the binding site entrance.[3]

 
Acrosin active site residues, shown with competitive inhibitor benzamidine.
 
Acrosin active site surface contour, shown with competitive inhibitor benzamidine. Trp-215 "gatekeeper" residue is shown partially occluding the "top" (as pictured here) entrance to the binding cavity.

An important structural element of β-acrosin is its highly charged patch on its surface region, that has been termed the "anion binding exosite."[3] 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.[12][13][14]

Disease and Pharmaceutical Relevance

edit

Although it has been reported that in mice, acrosin is not a necessary component of zona pellucida penetration, studies in humans have shown an association between acrosomal proteinase activity and infertility.[15] In rabbit models, an intravaginal contraceptive device that secreted tetradecyl sodium sulfate, a known inhibitor of acrosin and hyaluronidases, had a complete contraceptive effect.[16] Acrosin could thus serve as a novel target for contraceptive agents. In particular, acrosin may serve as a uniquely viable target due to its location and high cellular specificity.[17] Thus, developing inhibitors of acrosin could provide the basis for safe, reversible male contraceptives, or female contraceptives through the use of intravaginal contraceptive devices.[17]

References

edit
  1. ^ Adham IM, Klemm U, Maier WM, Engel W (Jan 1990). "Molecular cloning of human preproacrosin cDNA". Human Genetics. 84 (2): 125–8. doi:10.1007/bf00208925. PMID 2298447.
  2. ^ Honda A, Siruntawineti J, Baba T (2002). "Role of acrosomal matrix proteases in sperm-zona pellucida interactions". Human Reproduction Update. 8 (5): 405–12. doi:10.1093/humupd/8.5.405. PMID 12398221.
  3. ^ a b c d e f g h i Tranter, Rebecca; Read, Jon A.; Jones, Roy; Brady, R. Leo (2000-11-15). "Effector Sites in the Three-Dimensional Structure of Mammalian Sperm β-Acrosin". Structure. 8 (11): 1179–1188. doi:10.1016/S0969-2126(00)00523-2. ISSN 0969-2126. PMID 11080640.
  4. ^ 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., 269 (1994), pp. 31845–31849
  5. ^ K. Yamagata, T. Baba, et al. Acrosin accelerates the dispersal of sperm acrosomal proteins during acrosome reaction. J. Biol. Chem., 273 (1998), pp. 10470–10474
  6. ^ R. Jones, C.R. Brown. Identification of a zona-binding protein from boar spermatozoa as proacrosin. Expl. Cell Res., 171 (1987), pp. 505–508
  7. ^ R. Jones. Interaction of zona pellucida glycoproteins, sulphated carbohydrates and synthetic polymers with proacrosin, the putative egg-binding protein from mammalian spermatozoa. Development, 111 (1991), pp. 1155–1163
  8. ^ 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. Fert., 83 (1988), pp. 377–387
  9. ^ a b Laurell, M; Christensson, A; Abrahamsson, PA; Stenflo, J; Lilja, H (1992). "Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system". J Clin Invest. 89 (4): 1094–1101. doi:10.1172/JCI115689. PMC 442965. PMID 1372913.
  10. ^ Zheng, X; Geiger, M; Ecke, S (1994). "Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa". Am. J. Physiol. 267 (2 Pt 1): C466-72. doi:10.1152/ajpcell.1994.267.2.C466. PMID 7521127.
  11. ^ I. Schechter, A. Berger. On the size of the active site in proteases. I. Papain. Biochim. Biophys. Res. Commun, 27 (1967), pp. 157–162.
  12. ^ R. Jones, R. Parry, L. Lo Leggio, P. Nickel. Inhibition of sperm-zona binding by suramin, a potential “lead” compound for design of new anti-fertility agents. Mol. Hum. Rep., 2 (1996), pp. 597–605
  13. ^ 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., 258 (1983), pp. 5858–5863
  14. ^ M. Nakano, T. Tobets, et al. Further fractionation of the glycoprotein families of porcine zona pellucida by anion exchange HPLC and some characterization of the separated fractions. J. Biochem., 107 (1990), pp. 144–150
  15. ^ Welker B., Bernstein G.S., Diedrich K., Nakamura R.M., Krebs D. Acrosomal proteinase activity of human spermatozoa and relation of results to semen quality. Hum Reprod. 1988 Oct;3 Suppl 2:75-80.
  16. ^ Burck P.J., Zimmerman R.E. An intravaginal contraceptive device for the delivery of an acrosin and hyaluronidase inhibitor. Fertil Steril. 1984 Feb;41(2):314-8.
  17. ^ a b Ning, Weiwei; Zhu, Ju; Zheng, Canhui; Liu, Xuefei; Song, Yunlong; Zhou, Youjun; Zhang, Xiaomeng; Zhang, Ling; Sheng, Chunquan (2013-04-01). "Fragment-Based Design of Novel Quinazolinon Derivatives as Human Acrosin Inhibitors". Chemical Biology & Drug Design. 81 (4): 437–441. doi:10.1111/cbdd.12106. ISSN 1747-0285. PMID 23331539.

Further reading

edit
edit

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


 

This hydrolase article is a stub. You can help Wikipedia by expanding it.

Category:EC 3.4.21

Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Zachcharry/Acrosin&oldid=1023409985"