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**COPIED FROM HIV-1 protease*

HIV-1 Protease (Retropepsin)
HIV-1 protease dimer in white and grey, with peptide substrate in black and active site aspartate side chains in red. (PDB: 1KJF​)
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EC no.3.4.23.16
CAS no.144114-21-6
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HIV-1 protease is a retroviral aspartyl protease (retropepsin) that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.[1][2] HIV protease cleaves newly synthesized polyproteins (namely, Gag and Gag-Pol[3]) at nine cleavage sites to create the mature protein components of an infectious HIV virion.[4] Without effective HIV protease, HIV virions remain uninfectious.[5][6] Thus, mutation of HIV protease's active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells,[7] making HIV protease inhibition the subject of considerable pharmaceutical research. [8]

Structure edit

 
HIV-1 Protease has the classic AspThrGly of Aspartyl Proteases. These amino acids are located at position 25, 26, and 27, and are responsible for the catalytic activity.

HIV-1 Protease Precursor edit

The Gag-Pol polyprotein, which contains premature coding proteins, includes the precursor domain of HIV-1 protease (PR).[9] PR is located between the reverse transcriptase (which is at the C-terminus of PR) and the p6pol (which is at the N-terminus of PR) of the transframe region (TFR).[10]

In order for this precursor to become a functional protein, each monomer must associate with another HIV-1 PR monomer to form a functional catalytic active site by each contributing the Asp25 of their respective catalytic triads.[9]

Mature HIV-1 Protease edit

HIV protease exists as a 22kDa homodimer, with each subunit made up of 99 amino acids.[11] A single active site lies between the identical subunits and has the characteristic Asp-Thr-Gly (Asp25, Thr26 and Gly27) catalytic triad sequence common to aspartic proteases.[12] As HIV-1 PR can only function as a dimer, the mature protease contains two Asp25 amino acids, one from each monomer, that act in conjunction with each other as the catalytic residues.[9] Additionally, HIV protease has two molecular "flaps" which move a distance of up to 7 Å when the enzyme becomes associated with a substrate.[13]

Function edit

When viral HIV-RNA enters the cell, it is accompanied by a reverse transcriptase, an integrase, and a mature protease. The reverse transcriptase essentially converts viral RNA into DNA, facilitating incorporation of viral genetic information with the host cell DNA, via integrase. The proviral DNA can either remain dormant in the nucleus or be transcribed into mRNA and translated into the Gag-Pol polyprotein by the host cell. Not only is precursor HIV-1 PR is responsible for catalyzing its own production into mature PR enzymes, mature protease hydrolyzes peptide bonds on the Gag-Pol polyproteins at nine specific sites, processing the resulting subunits into mature, fully-functional proteins. These cleaved proteins, including reverse transcriptase, integrase, and RNaseH, form the coding (from Gag-Pol) components necessary for viral replication.[4]

Synthesis edit

The HIV-1 PR precursor catalyzes its own production by facilitating its cleavage from the Gag-Pol polyprotein in a mechanism known as auto-processing. The mature PR enzyme then cleaves other fully-functional, essential viral proteins, such as reverse transcriptase, RNase H, and integrase, from the Gag-Pol polyprotein. Autoprocessing of HIV-1 PR is characterized by two sequential steps: (1) the intramolecular cleavage of the N-terminus at the p6pol-protease cleavage site, which serves to finalize PR processing, and (2) the intermolecular cleavage of the C-terminus at the protease-reverse transcriptase cleavage site, which assembles the PR subunits into mature dimers. Dimerization of the two subunits allows for the functional active site to form.[12]

Mechanism edit

According to the mechanism for HIV-1 protease cleavage proposed by Mariusz Jaskolski and colleagues, water acts as a nucleophile, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond.[14]

As an aspartic protease, the dimerized HIV-1 PR can activate a water molecule via the aspartyl group complex, in order to perform hydrolysis. Of the two Asp25 residues on the combined catalytic active site of HIV-1 PR, one is deprotonated while the other is protonated due to pH differences in the microenvironment.

In a general aspartic protease mechanism, the deprotonated aspartate undergoes base catalysis, rendering the incoming water molecule a better nucleophile by deprotonating it and protonating itself, while the resulting hydroxyl group attacks the carbonyl carbon on the aromatic amino acid, forming an intermediate with a transient oxyanion. The oxyanion re-forms the carbonyl, breaking the peptide bond between the two amino acids, while the initially deprotonated Asp25 undergoes acid catalysis to donate its proton to the amino group, making the amino group a better leaving group.

While HIV-1 PR shares many of the same characteristics as non-viral aspartic protease, evidence by Ashraf Brik and Chi-Huey Wong has shown that HIV-1 PR catalyzes hydrolysis in a concerted manner; in other words, the nucleophilic water molecule and the protonated Asp25 simultaneously attack the peptide bond under HIV-1 PR catalysis.[15]

HIV-1 Protease as a Drug Target edit

With its integral role in HIV replication, HIV protease has been a prime target for drug therapy. HIV protease inhibitors work by specifically binding to the active site by mimicking the tetrahedral intermediate of its substrate and essentially becoming “stuck,” disabling the enzyme. After assembly and budding, viral particles lacking active protease cannot mature into infectious virions. Several protease inhibitors have been licensed for HIV therapy.[16]

There are ten HIV-1 PR inhibitors that are currently approved by the Food and Drug Administration. These include indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, amprenavir, fosamprenevir, atazanavir, tipranavir, and darunavir. Many of the inhibitors have different molecular components and thus different mechanistic actions, such as blocking the active site or Thus, their functional roles also extend to influencing circulation concentrations of other inhibitor drugs (ritonavir) and being used only for special circumstances in which the virus exhibits tolerance.[4]

Resistance and Evolution edit

Due to the high mutation rates of retroviruses, and considering that changes to a few amino acids within HIV protease can render it much less visible to an inhibitor, the active site of this enzyme can change rapidly when under the selective pressure of replication-inhibiting drugs.[17]

Two types of mutations are generally associated with increasing drug resistance: "major" mutations and "secondary" mutations. Major mutations involve a mutation on the active site of HIV-1 PR, preventing the selective inhibitors from binding it, while secondary mutations refer to molecular changes on the periphery of the enzyme, by which the virus may exhibit tolerance of an inhibitor due to prolonged exposure of similar chemicals.[3]

One approach to minimizing the development of drug-resistance in HIV is to administer a combination of drugs which inhibit several key aspects of the HIV replication cycle simultaneously, rather than one drug at a time. Other drug therapy targets include reverse transcriptase, virus attachment, membrane fusion, cDNA integration and virion assembly.[18][19]

Rough Outline edit

I would like to restructure this page {and add additional sections} and the following information:

  • Structure
    • Precursor: part of gag-pol polyprotein, flanked between p6pol (of transframe region on the N-terminus) and reverse transcriptase (on C-terminus)
      • must associate with another HIV-1 Protease precursor to form functional catalytic active site.
    • Mature Protein: 22kDa homodimer with 99 residues on each subunit[12]
  • Function
    • HIV-1 protease not only mediates its own release, but its fully functional form cleaves out other proteins essential for viral synthesis.[12]
      • I would like to add brief information of some of the important proteins that it cleaves out
    • will use the following articles as sources: 18, 19, 20
  • {Synthesis}
    • HIV-1 Protease is originally a part of the Gag-Pol polyprotein precursor but undergoes autoprocessing, an enzymatic activity for production of the same enzyme, via its precursor domain that ultimately cleaves mature HIV-1 protease proteins for cleaving other mature viral proteins from the polyprotein.
      • ## I just thought that this part of the current version of the article ("HIV protease is encoded within the pol gene, and is cleaved out by HIV protease") was a bit ambiguous.
    • Draft: The precursor domain of HIV-1 protease, encoded within the pol gene and a component of the Gag-Pol polyprotein, catalyzes its own production by facilitating the cleavage of functional HIV-1 proteases, a mechanism known as autoprocessing. [20]
      • Mechanism for synthesis:
        • Intramolecular cleavage of N-terminus, followed by intermolecular cleavage of C-terminus[12]
  • {Mechanism}
    • A protease is a catalytic protein (specifically, a hydrolase) that cleaves polypeptides with the addition of water.
    • ##I would like to add information about the specific roles of the residues in this protease's catalytic triad (Asp-Thr-Gly)
      • Aspartate of triad involved in catalysis[21]
      • Dimerization of the two protease subunits allows for the active site containing these catalytic triads to form[21]
    • will use the following articles as sources: 20, 21
  • HIV-1 Protease as a Drug Target
    • ##I would like to add a more detailed description of the chemical mechanism regarding how the inhibitors bind to the active site of HIV-1 protease
    • ##I would like to add more information about the functionally critical regions of the HIV-1 protease that render this area a target for enzyme inhibition
    • will use the following articles as sources: 21, 23, 24
    • {Resistance and Evolution}
      • ##I would like to include more information about increasing HIV-1 protease resistance to inhibitors due to recombinants with different structural configurations from the wild type
      • will use the following articles as sources: 22, 25

Bibliography edit

I have decided HIV-1 Protease as my article to edit. Attached are my sources.[22][15][23][24][25][26]

  1. ^ Davies DR (1990). "The structure and function of the aspartic proteinases". Annual Review of Biophysics and Biophysical Chemistry. 19 (1): 189–215. doi:10.1146/annurev.bb.19.060190.001201. PMID 2194475.
  2. ^ Brik A, Wong CH (January 2003). "HIV-1 protease: mechanism and drug discovery". Organic & Biomolecular Chemistry. 1 (1): 5–14. doi:10.1039/b208248a. PMID 12929379.
  3. ^ a b Huang X, Britto MD, Kear-Scott JL, Boone CD, Rocca JR, Simmerling C, Mckenna R, Bieri M, Gooley PR, Dunn BM, Fanucci GE (June 2014). "The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics". The Journal of Biological Chemistry. 289 (24): 17203–14. doi:10.1074/jbc.M114.571836. PMC 4059161. PMID 24742668.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ a b c Lv Z, Chu Y, Wang Y (April 2015). "HIV protease inhibitors: a review of molecular selectivity and toxicity". Hiv/Aids. 7: 95–104. doi:10.2147/hiv.s79956. PMC 4396582. PMID 25897264.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Kräusslich HG, Ingraham RH, Skoog MT, Wimmer E, Pallai PV, Carter CA (February 1989). "Activity of purified biosynthetic proteinase of human immunodeficiency virus on natural substrates and synthetic peptides". Proceedings of the National Academy of Sciences of the United States of America. 86 (3): 807–11. doi:10.1073/pnas.86.3.807. PMC 286566. PMID 2644644.
  6. ^ Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS (July 1988). "Active human immunodeficiency virus protease is required for viral infectivity". Proceedings of the National Academy of Sciences of the United States of America. 85 (13): 4686–90. doi:10.1073/pnas.85.13.4686. PMC 280500. PMID 3290901.
  7. ^ Seelmeier S, Schmidt H, Turk V, von der Helm K (September 1988). "Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A". Proceedings of the National Academy of Sciences of the United States of America. 85 (18): 6612–6. doi:10.1073/pnas.85.18.6612. PMC 282027. PMID 3045820.
  8. ^ McPhee F, Good AC, Kuntz ID, Craik CS (October 1996). "Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation". Proceedings of the National Academy of Sciences of the United States of America. 93 (21): 11477–81. doi:10.1073/pnas.93.21.11477. PMC 56635. PMID 8876160.
  9. ^ a b c Pettit, Steven C.; Everitt, Lorraine E.; Choudhury, Sumana; Dunn, Ben M.; Kaplan, Andrew H. (2004-8). "Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism". Journal of Virology. 78 (16): 8477–8485. doi:10.1128/JVI.78.16.8477-8485.2004. ISSN 0022-538X. PMID 15280456. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Gronenborn, Angela M.; Louis, John M.; Clore, G. Marius (1999-09-01). "Autoprocessing of HIV-1 protease is tightly coupled to protein folding". Nature Structural Biology. 6 (9): 868–875. doi:10.1038/12327. ISSN 1072-8368.
  11. ^ Davies DR (1990). "The structure and function of the aspartic proteinases". Annual Review of Biophysics and Biophysical Chemistry. 19 (1): 189–215. doi:10.1146/annurev.bb.19.060190.001201. PMID 2194475.
  12. ^ a b c d e Chatterjee, Amarnath; Mridula, P.; Mishra, Ram Kumar; Mittal, Rohit; Hosur, Ramakrishna V. (2005-03-25). "Folding Regulates Autoprocessing of HIV-1 Protease Precursor". Journal of Biological Chemistry. 280 (12): 11369–11378. doi:10.1074/jbc.M412603200. ISSN 0021-9258. PMID 15632156.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Miller M, Schneider J, Sathyanarayana BK, Toth MV, Marshall GR, Clawson L, Selk L, Kent SB, Wlodawer A (December 1989). "Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution". Science. 246 (4934): 1149–52. doi:10.1126/science.2686029. PMID 2686029.
  14. ^ Jaskólski M, Tomasselli AG, Sawyer TK, Staples DG, Heinrikson RL, Schneider J, Kent SB, Wlodawer A (February 1991). "Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor". Biochemistry. 30 (6): 1600–9. doi:10.1021/bi00220a023. PMID 1993177.
  15. ^ a b Brik, Ashraf; Wong, Chi-Huey (2002-11-26). "HIV-1 protease: mechanism and drug discovery". Organic & Biomolecular Chemistry. 1 (1): 5–14. doi:10.1039/b208248a. ISSN 1477-0520.
  16. ^ H.P. Rang (2007). Rang and Dale's pharmacology (6th ed.). Philadelphia, Pa., U.S.A.: Churchill Livingstone/Elsevier. ISBN 9780808923541.
  17. ^ Watkins T, Resch W, Irlbeck D, Swanstrom R (February 2003). "Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors". Antimicrobial Agents and Chemotherapy. 47 (2): 759–69. doi:10.1128/AAC.47.2.759-769.2003. PMC 151730. PMID 12543689.
  18. ^ Moore JP, Stevenson M (October 2000). "New targets for inhibitors of HIV-1 replication". Nature Reviews. Molecular Cell Biology. 1 (1): 40–9. doi:10.1038/35036060. PMID 11413488.
  19. ^ De Clercq E (December 2007). "The design of drugs for HIV and HCV". Nature Reviews. Drug Discovery. 6 (12): 1001–18. doi:10.1038/nrd2424. PMID 18049474.
  20. ^ Huang, Liangqun; Chen, Chaoping (2013-07). "Understanding HIV-1 protease autoprocessing for novel therapeutic development". Future Medicinal Chemistry. 5 (11): 1215–1229. doi:10.4155/fmc.13.89. ISSN 1756-8919. PMC 3826259. PMID 23859204. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  21. ^ a b Zhang, Shuxing; Kaplan, Andrew H.; Tropsha, Alexander (2008-11-15). "HIV-1 Protease Function and Structure Studies with the Simplicial Neighborhood Analysis of Protein Packing (SNAPP) Method". Proteins. 73 (3): 742–753. doi:10.1002/prot.22094. ISSN 0887-3585. PMC 2765824. PMID 18498108.{{cite journal}}: CS1 maint: PMC format (link)
  22. ^ "HIV-1 Protease". Protein Data Bank. Retrieved 1 May 2018.
  23. ^ Huang, Xi; Britto, Manuel D.; Kear-Scott, Jamie L.; Boone, Christopher D.; Rocca, James R.; Simmerling, Carlos; Mckenna, Robert; Bieri, Michael; Gooley, Paul R. (2014-06-13). "The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics". Journal of Biological Chemistry. 289 (24): 17203–17214. doi:10.1074/jbc.M114.571836. ISSN 0021-9258. PMC 4059161. PMID 24742668.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  24. ^ Wang, Yong; Lv, Zhengtong; Chu, Yuan (2015-04). "HIV protease inhibitors: a review of molecular selectivity and toxicity". HIV/AIDS - Research and Palliative Care. 7: 95. doi:10.2147/hiv.s79956. ISSN 1179-1373. PMC 4396582. PMID 25897264. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  25. ^ Loeb, Daniel D.; Swanstrom, Ronald; Everitt, Lorraine; Manchester, Marianne; Stamper, Susan E.; Hutchison, Clyde A. (August 1989). "Complete mutagenesis of the HIV-1 protease". Nature. 340 (6232): 397–400. doi:10.1038/340397a0. ISSN 0028-0836.
  26. ^ Yilmaz, Nese Kurt; Schiffer, Celia A. (2017). Antimicrobial Drug Resistance. Springer, Cham. pp. 535–544. doi:10.1007/978-3-319-46718-4_35. ISBN 9783319467160.

20. HIV-1 Protease: This website elucidates the structure of this protein, such as the length of its sequence (99), number of subunits (2 unique, 3 total), and classification as a hydrolase/hydrolase inhibitor.

21.HIV-1 Protease - mechanism and drug discovery: The mechanism of the HIV-1 Protease was elucidated, especially its general category as an aspartic protease and similar catalytic mechanism, with the exception of the one-step process of the hydrolysis reaction.

22. Subtype Polymorphisms on HIV-1 Protease: Mutations on the HIV-1 Protease active site and on the surface of the protein can potentially lead to increased resistance of inhibiting drugs. Using a pulsed double-electron-electron-resonance (DEER) system, this paper works to elucidate these molecular mechanisms by which these polymorphisms can potentially increase drug resistance.

23. HIV Protease Inhibitors: This article provides a review of HIV-1 protease, namely (1) its main function (cleaving Gag and Gal-Pol polypeptide precursors at nine sites for processing mature, virally active proteins), (2) its inhibition mechanism via inhibitors binding to its active site, as well as (3) specific examples of inhibitors, (4) possible ancillary effects of inhibiting drugs on essential proteins, and (5) improvements of inhibiting drugs based on their water solubility and bioavailability.

24. Complete mutagenesis: This article described a mutagenesis and phenotypic-screening approach to determine the most functionally critical regions of HIV-1 protease.

25. Antimicrobial Drug Resistance -- I am also planning to reference this source...

References edit


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