HIV-1 protease

HIV-1 PR'''''' ko PR   retroviral aspartyl protease ne (retropepsin), enzyme da ke da likitoci da peptide bond hydrolysis a cikin retrovirus, wanda ke da amadi ga rayuwar HIV, retrovirus wanda ke da cutar da kanjamau.   HIV-1 PR ya raba sabon Pol" id="mwFw" rel="mw:WikiLink" title="Polyprotein">polyprotein (watau, Gag da Gag-Pol ) a tara don wasu dalilai furotin masu girma na virion HIV, nau'in cutar da cutar a waje da tantanin haifar.  .

 Tsarinsa 
Balagagge protease na HIV yana kasancewa a matsayin homodimer 22 kDa, tare da kowane ɓangaren da ya ƙunshi amino acid 99.  Rukunin da ke aiki ɗaya ya ta'allaka ne tsakanin ƙananan sassan guda ɗaya kuma yana da sifa ta Asp-Thr-Gly (Asp25, Thr26 da Gly27) jerin abubuwan triad na catalytic na gama gari ga ƙwayoyin cuta na aspartic.  Kamar yadda kwayar cutar HIV-1 PR ke aiki kawai azaman dimer, balagagge protease ya ƙunshi amino acid Asp25 guda biyu, ɗaya daga kowane monomer, waɗanda ke aiki tare da juna a matsayin ragowar kuzari.[3].  Bugu da ƙari, kwayar cutar HIV tana da "flaps" guda biyu na kwayoyin halitta waɗanda ke motsawa tazarar har zuwa 7 Å lokacin da enzyme ya zama hade da wani abu.  Ana iya ganin wannan tare da raye-rayen buɗewa da rufewa.

 Biosynthesis 

 Mai gabatarwa 
Gag-pol polyprotein, wanda ya ƙunshi sunadarai masu ƙididdiga, gami da HIV-1 PR. PR yana tsakanin juyawa transcriptase (wanda yake a ƙarshen C na PR) da p6pol (wanda yake A ƙarshen N na PR) na yankin transframe (TFR). 

Don wannan precursor ya zama furotin mai aiki, kowane monomer dole ne ya haɗu da wani HIV-1 PR monomer don samar da wani aiki catalytic mai aiki ta kowane mai ba da gudummawa Asp25 na triads.

Lokacin da kwayar cutar HIV-RNA ta shiga cikin tantanin halitta, tana tare da transcriptase, integrase, da kuma HIV-1 PR mai girma. Transcriptase mai juyawa yana canza RNA na kwayar cuta zuwa DNA, yana sauƙaƙa rawar da integrase ke takawa wajen haɗa bayanan kwayar cutaa tare da DNA na kwayar halitta. DNA na kwayar cuta na iya kasancewa a cikin tsakiya ko kuma a fassara shi cikin mRNA kuma a fassarar ta hanyar kwayar halitta a cikin Gag-Pol polyprotein, wanda za a raba shi cikin sunadarai masu aiki (gami da sabon HIV-1 PR) ta hanyar HIV-1 PR mai girma.

Maganin HIV-1 PR yana haɓaka samar da kansa ta hanyar sauƙaƙe rarraba shi daga Gag-pol polyprotein a cikin hanyar da aka sani da sarrafa kansa. Auto-processing na HIV-1 PR yana da matakai biyu na tsari: (1) tsagewar intramolecular na N-ƙarewa a shafin tsagewar p6pol-protease, wanda ke aiki don kammala aikin PR da haɓaka aikin enzymatic tare da sabon PR-reverse transcriptase na tsakiya, da kuma (2) tsagewar intermolecular na C-ƙarewa na protease-reverse, wanda ke haifar da haɗuwa da subunits biyu na PR a cikin dimers. Dimerization na sassan biyu yana ba da damar cikakken aiki, haɗin yanar gizo mai aiki, wanda ke da alamun Asp25 catalytic guda biyu (ɗaya daga kowane monomer), don samarwa.


 Ayyuka 
HIV-1 PR yana da manufa biyu. Precursor HIV-1 PR yana da alhakin haɓaka nasa samarwa cikin ƙwayoyin PR masu girma ta hanyar sarrafa kansa na PR. Mature protease yana iya hydrolyze peptide bonds a kan Gag-Pol polyproteins a takamaiman shafuka tara, sarrafa sakamakon subunits zuwa manya, cikakkun sunadarai masu aiki. Wadannan sunadarai masu rarraba, gami da reverse transcriptase, integrase, da RNaseH, an tsara su ne ta hanyar abubuwan da ke cikin yankin da ake buƙata don kwayar cutar.

 Hanyar aiki 
A matsayin aspartic protease, dimerized HIV-1 PR yana aiki ta hanyar aspartyl group complex, don yin hydrolysis. Daga cikin ragowar Asp25 guda biyu a kan shafin da aka haɗu da shi na HIV-1 PR, ɗayan ya lalace yayin da ɗayan ya lalafe, saboda bambancin pKa daga micro-muhalli.

A cikin tsarin aspartic protease na gabaɗaya, da zarar an ɗaure substrate ɗin da kyau zuwa wurin aiki na enzyme, asp25 catalytic amino acid da aka lalatar yana fuskantar catalysis na tushe, yana mai da kwayar ruwa mai shigowa mafi kyawun nucleophile ta hanyar lalata shi.  Sakamakon hydroxyl ion yana kai hari ga carbonyl carbon na peptide bond, yana samar da tsaka-tsaki tare da oxyanion na wucin gadi, wanda aka daidaita shi ta hanyar protonated Asp25.  Oxyanion ya sake samar da haɗin gwiwa biyu, wanda ke haifar da ɓarkewar haɗin peptide tsakanin amino acid guda biyu, yayin da Asp25 da aka rushe da farko ya fara shan catalysis na acid don ba da gudummawar proton ɗinsa ga rukunin amino, yana mai da rukunin amino mafi kyawun barin rukunin don cikakkiyar ƙulla haɗin peptide kuma komawa zuwa asalin da aka lalatar.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.

Duk da yake HIV-1 PR yana da halaye iri ɗaya kamar yadda ba kwayar cuta ba, wasu shaidu sun nuna cewa HIV-1 PR tana haɓaka hydrolysis a cikin hanyar da aka tsara; a wasu kalmomi, kwayar ruwa ta nucleophilic da Asp25 mai protonated a lokaci guda suna kai farmaki ga haɗin scissile peptide yayin catalysis.Liu H, Müller-Plathe F, van Gunsteren WF (August 1996). "A combined quantum/classical molecular dynamics study of the catalytic mechanism of HIV protease". Journal of Molecular Biology. 261 (3): 454–69. doi:10.1006/jmbi.1996.0476. PMID 8780786.
Tare da rawar da take takawa a cikin kwafin cutar kanjamau, protease na cutar kanjamaun HIV ya kasance babban burin maganin magani. Masu hana cutar kanjamau suna aiki ta hanyar ɗaurewa musamman ga shafin mai aiki ta hanyar kwaikwayon matsakaicin tetrahedral na substratum kuma ya zama "mai kamawa," yana kashe enzyme. Bayan taro da budding, ƙwayoyin ƙwayoyin cuta da ba su da protease mai aiki ba za su iya girma cikin virions masu kamuwa da cuta ba. An ba da lasisi ga masu hana protease da yawa don maganin cutar kanjamau.

Akwai masu hana cutar HIV-1 PR guda goma waɗanda Hukumar Abinci da Magunguna ta amince da su a halin yanzu: indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, amprenavir, fosamprenevir, atazanavir, tipranavir, da darunavir.  Yawancin masu hanawa suna da sassa daban-daban na ƙwayoyin cuta don haka ayyuka daban-daban na injina, kamar toshe wurin aiki.  Ayyukan aikin su kuma sun bazu zuwa tasirin tasirin sauran magunguna masu hanawa (ritonavir) kuma ana amfani da su kawai don wasu yanayi waɗanda kwayar cutar ke nuna juriya ga sauran masu hanawa (tipranavir).Lv Z, Chu Y, Wang Y (April 2015). "HIV protease inhibitors: a review of molecular selectivity and toxicity". HIV/AIDS: Research and Palliative Care. 7: 95–104. doi:10.2147/hiv.s79956. PMC 4396582. PMID 25897264.

 Juyin Halitta da juriya 
Saboda yawan maye gurbi na retroviruses, musamman saboda yankuna masu saukin kamuwa da maye gurbi (musamman yankin da ke dauke da jerin triad), da kuma la'akari da cewa canje-canje zuwa 'yan amino acid a cikin HIV protease na iya sa ba su da ganuwa ga mai hanawa, shafin mai aiki na wannan enzyme na iya canzawa cikin sauri lokacin da yake ƙarƙashin matsin lamba na magungunan da ke hanawa. Duk da mafi yawan sanannun maye gurbin da aka sani na iya shafar kwanciyar hankali na HIV-1 PR,  wannan furotin har yanzu yana iya yin aikinsa na haɓaka, wani lokacin ana sauƙaƙe shi ta hanyar maye gurbin biyan kuɗi. 

Nau'ikan maye gurbi guda biyu suna da alaƙa da karuwar juriya ta miyagun ƙwayoyi: maye gurbi "mafi girma" da maye gurbi na "na biyu". Manyan maye gurbi sun haɗa da maye gurbi a shafin aiki na HIV-1 PR, yana hana masu hana zaɓaɓɓu daga ɗaure shi. Canje-canje na biyu suna nufin canje-canje na kwayoyin a gefen enzyme saboda dogon bayyanar irin waɗannan sunadarai, wanda zai iya shafar ƙayyadaddun mai hanawa ga HIV-1 PR.

Ɗaya daga cikin hanyoyin da za a rage ci gaban juriya a cikin kwayar cutar kanjamau shine gudanar da haɗuwa da magunguna waɗanda ke hana mahimman fannoni da yawa na sake zagayowar kwayar cutar HIV a lokaci guda, maimakon magani ɗaya a lokaci guda. Sauran manufofi na maganin magunguna sun haɗa da transcriptase, haɗewar kwayar cuta, haɗin membrane, haɗin cDNA da taron virion.

 Dubi kuma 

 Gudanar da cutar kanjamau / AIDS
 Bincike da ci gaban masu hana cutar kanjamau
Rukuni:Shafuka masu fassarorin da ba'a duba ba