Amino acide nibintu by'ibanze bigize poroteyine n'ibice by'ingenzi bigize ingirangingo z'umuntu, bigira uruhare mu kwanduza ibimenyetso by'utugingo ngengabuzima, kugenzura ibikorwa bya enzyme, imikorere y’umubiri n’ibindi bikorwa bya physiologiya.

Ubwinshi bwa aside amine muri selile akenshi ihinduka muburyo butandukanye bwa physiologique na patologi. Kubwibyo, uburyo umubiri wumva ihinduka ryurwego rwa aside amine kandi ugatanga igisubizo kijyanye n'imihindagurikire y'ikirere ni ikibazo gikomeye cya siyansi yo guhangayikishwa no guhindagurika kwa selile.

Kumva aminide idasanzwe bifitanye isano na kanseri, diyabete, indwara zifata ubwonko ndetse no gusaza. Kubwibyo, gushakisha uburyo bwa molekuline yo kwinjiza aside amine idasanzwe birashobora gutanga intego nshya yo gukumira cyangwa kuvura indwara ziterwa na kanseri na kanseri. Valine, nka acide ya amine acide yingenzi, igira uruhare runini muguhindura poroteyine, neurobehavior, no gutera leukemia. Nyamara, uburyo n'imikorere ya selile sensing ya valine ntibisobanutse neza.

Ku ya 20 Ugushyingo 2024, itsinda rya Wang Ping ryo mu Ishuri Rikuru ry’Ubuvuzi rya Tongji / Ibitaro bya 10 by’Abaturage by’Abaturage byasohoye inyandiko y’ubushakashatsi yise "Umuntu HDAC6 yumva ubwinshi bwa valine kugira ngo agenzure ibyangiritse kuri ADN" mu kinyamakuru Nature.

Ubu bushakashatsi bwerekanye icyerekezo gishya cya valine, sensor deacetylase ya HDAC6, kandi bugaragaza uburyo bwihariye bwo kubuza valine kuganisha ku guhinduranya ingufu za kirimbuzi HDAC6, bityo bikazamura ibikorwa bya TET2 no kwangiza ADN.

Igishimishije, ubu buryo bwo kumva bwihariye kuri primates, kandi ubundi isesengura ryakozwe ryerekanye ko primaire HDAC6 ikubiyemo serine ikungahaye kuri glutamate-tetranectide (SE14) isubiramo indangarugero kandi ikumva ubwinshi bwa valine binyuze muri iyi domeni. Kubijyanye no kuvura ibibyimba, kugabanya valine igereranije cyangwa guhuza PARP inhibitor irashobora kubuza neza gukura kwikibyimba.

Ubu bushakashatsi bugaragaza uburyo bushya bwerekana imirire igabanya ibyangiritse kuri ADN binyuze mu guhindura epigenetike, ikanatanga ingamba nshya zo kuvura ibibyimba hamwe nimirire yabujijwe na valine hamwe na PARP inhibitor.

Ibyuma bya aside amine mubisanzwe bikenera guhuza aside amine kugirango tumenye kandi dusubize impinduka ziterwa na aside amine imbere na selile, kugirango ikore umurimo wo kumva.

Kugirango tumenye neza poroteyine zihuza vitamine, ubushakashatsi bwa biotinylated valine bwakoreshejwe mubushakashatsi bwikingira bwa immunocoprecipitate buvanze na sprometrike ya misa, kandi kwipimisha kutabogamye kwa poroteyine zihuza intungamubiri byakozwe na biologiya chimique.

Abanditsi basanze ko usibye synthetase ya valyl tRNA izwi (VARS), deacetylase HDAC6 yerekanye ubushobozi bukomeye bwa D-valine ugereranije na VARS. Abanditsi bakomeje kwemeza ko HDAC6 ishobora guhuza valine mu buryo butaziguye na Kd ≈ 2μM binyuze mu bushakashatsi bwa isotope, ubushakashatsi bwa isothermal titration calorimetry (ITC) hamwe nubushakashatsi bwa drift. Isesengura ryimiterere iranga aside amine yamenyekanye no kumva poroteyine bifasha kurushaho gusobanukirwa nuburyo bwa molekile yo guhindura aside aside amine iterwa na selile. Mu gusesengura ubushakashatsi buhuza ibigereranyo bya valine, abanditsi basanze HDAC6 imenya itumanaho rya carboxyl hamwe numurongo wuruhande rwa valine kandi ishobora kwihanganira ihinduka rya amino. Byongeye kandi, muri selile ya HDAC6 ya knockout, amabwiriza ya mTOR yerekana inzira yerekana inzira yo kubuza valine ntaho yari atandukaniye cyane nay'itsinda rishinzwe kugenzura, byerekana ko uku guhuza kwari gutandukanye n'inzira gakondo ya aminide acide yerekana inzira.

Kugirango tumenye ibyingenzi nibikorwa bya HDAC6 sensing valine. Abanditsi bongeye kwemeza ko HDAC6 ihuza valine ikoresheje indangarugero ya SE14 ibinyujije mu bushakashatsi bwa HDAC6 bwaciwe. Igitangaje, abanditsi basanze kugereranya homology ko domaine SE14 iboneka gusa muri HDAC6 muri primates. Bitandukanye na primate (muntu ninguge) HDAC6, imbeba HDAC6 ntabwo ihuza na valine. Ubu bushakashatsi bugaragaza itandukaniro riri hagati yubwoko butandukanye mu kwinjiza valine, byerekana ko ubwihindurize bw’ibinyabuzima bugira uruhare runini mu kwinjiza aside amine.

Hashingiwe ku mwanzuro w'uko HDAC6 ihuza valine mu buryo butaziguye na SE14, abanditsi batekereje ko impinduka mu mbaraga zihuza za HDAC6 na valine zishobora kugira ingaruka ku miterere n'imikorere iyo ubwinshi bwa valine mu ngirabuzimafatizo buhindutse. Binyuze mu bushakashatsi bwakozwe kandi bufatanije n’ubuvanganzo ku ruhare rukomeye rw’umudugudu wa SE14 mu kugumana cytoplasmeque ya HDAC6, abanditsi basanze ibura rya valine internacellularulaire rishobora gutuma HDAC6 ihinduka muri nucleus. Enzyme ikora mukarere (DAC1 na DAC2) ihuza akarere gakora (CD domaine) ya ADN hydroxymethylase TET2, igateza imbere deacetylation ya TET2, hanyuma igakora ibikorwa bya enzyme. Twifashishije tekinike ya methylomics nka WGBS, ACE-Seq na MAB-Seq, twashimangiye kandi ko inzara yo mu mitsi yo mu nda ishobora gutera ADN ikora binyuze mu kimenyetso cya HDAC6-TET2. Mbere, itsinda rya Andre Nussenzweig ryasanze thymine ADN glycosylase (TDG) -bishingiye ku mikorere ya ADN ya demethylation yatumye ADN yangirika rimwe gusa ku byongera imbaraga za neuronal. Muguhuza TET2 ChIP-Seq hamwe nikoranabuhanga rikoresha ibicuruzwa byinshi END-Seq na ddC S1 END-Seq, twahisemo ko kubura valine bitera kwangiza ADN. Iyangirika rya ADN riterwa no kubura valine naryo riterwa no kwangirika k'umugozi umwe uterwa no gucukurwa kwa TDG kwa oxymethylcytosine (5fC / 5caC).

Hamwe na hamwe, abanditsi bavumbuye ibyuma bifata ibyuma bifata ibyuma bya vine kandi ku nshuro yabo ya mbere basobanuye uburyo bwa molekile ikoreshwa na valine igabanya kwinjiza kwangirika kwa ADN binyuze mu kimenyetso cyerekana ibimenyetso bya HDAC6-TET2-TDG, bikongeraho urwego rushya mu gusobanukirwa imikorere y’imihindagurikire ya aside amine mu kugena ibizazane.

Kubuza imirire cyangwa kwibasirwa na metabolisme ya aside amine no kumva byabaye ingamba zifatika zo kongera ubuzima no kuvura indwara nyinshi, harimo na kanseri. Urebye ko kubura valine bishobora gutera ADN kwangirika, abanditsi bakomeje gukora iperereza niba kubuza valine bigira uruhare mu kuvura kanseri. Muri kanseri yibara ya kanseri yibibyimba, indyo ikwiye yagabanijwe na valine (0.41% valine, w / w) yabujije cyane gukura kwikibyimba hamwe ningaruka nke. Mu matsinda yombi yo gukumira no kuvura, abanditsi berekanye kandi ko indyo yagabanijwe na valine yabujije tumorigenez no gutera imbere ikoresheje kanseri yibara PDX. Mu byitegererezo by'ibibyimba, igabanuka rya valine ryahujwe neza no kongera ingufu za kirimbuzi za HDAC6, urugero rwa 5hmC, no kwangiza ADN. Kubera ko kwangiza ADN ari imiti igabanya ubukana, birashoboka ko mubuvuzi bushobora guhagarika gusana ADN ukoresheje PARP inhibitor. Abanditsi basanze guhuza indyo yagabanijwe na valine hamwe na PARP inhibitor talazoparib byongereye cyane ingaruka za antitumor, bitanga ibimenyetso bifatika byerekana imiti ivura kanseri yangiza ADN.

Mu gusoza, ubushakashatsi bwerekanye ko HDAC6 muri primates ari poroteyine nshya yerekana ibyiyumvo bya poroteyine idashingiye ku byuma gakondo, bigaragaza itandukaniro riri hagati y’imiterere y’imiterere y’ibinyabuzima bitandukanye, byerekana uruhare rukomeye rw’ihindagurika ry’ibinyabuzima mu kumva aside amine.

Byongeye kandi, ubu bushakashatsi burasobanura uburyo bushya bwo kugenzura imikoreshereze y’imirire mibi y’imirire, kugenga epigenetike no kwangirika kwa ADN, byagura akamaro ko guhangayikishwa n’imirire mibi mu binyabuzima bihangayikishije, kandi isanga guhuza indyo yuzuye iterwa na valine hamwe n’ibikoresho bya PARP bishobora gukoreshwa nk’ingamba nshya zo kuvura kanseri.