Amino acids waa qaybaha aasaasiga ah ee borotiinnada iyo qaybaha muhiimka ah ee unugyada bini'aadamka, iyagoo ciyaaraya doorka gudbinta calaamadaha unugyada, habaynta hawlaha enzyme, shaqada difaaca iyo hawlaha kale ee jireed.

Badanaa asiidhyada amino-yada ee unugyadu waxay inta badan isku beddelaan xaalado nafsiyeed iyo cudurro kala duwan. Sidaa darteed, sida jidhku u dareemo isbeddelka heerka amino acid oo u sameeyo jawaab-celin la-qabsi ah waa dhibaato cilmiyeed oo muhiim ah oo ku saabsan walbahaarka dheef-shiid kiimikaadka iyo qaddarka unugyada.

Dareenka amino acid-ka aan caadiga ahayn wuxuu si dhow ula xiriiraa kansarka, sonkorowga, cudurrada neerfaha iyo habka gabowga. Sidaa darteed, sahaminta habka molecular ee soo-saarka amino acid-ka aan caadiga ahayn waxay bixin kartaa bartilmaameed cusub oo ka hortagga ama daaweynta cudurrada dheef-shiid kiimikaadka iyo kansarka. Valine, oo ah amino acid silsilad laamood ah oo lagama maarmaan ah, ayaa door muhiim ah ka ciyaarta isku-dhafka borotiinka, dabeecadda neerfaha, iyo horumarka leukemia. Si kastaba ha ahaatee, habka iyo shaqada dareenka gacanta ee valine weli ma cadda.

Noofambar 20, 2024, kooxda Wang Ping ee ka socota Dugsiga Caafimaadka ee Jaamacadda Tongji / 10aad ee Xiriirinta Dadka ee Cisbitaalka ayaa daabacay warqad cilmi baaris ah oo cinwaankeedu yahay "Human HDAC6 waxay dareemeysaa faa'iido badan oo valine si loo xakameeyo dhaawaca DNA" joornaalka Nature.

Daraasadani waxay aqoonsatay dareeme cusub oo valine-gaar ah, deacetylase HDAC6, waxayna daaha ka qaaday habka gaarka ah ee xaddidaadda valine ay u horseedayso beddelka nukliyeerka ee HDAC6, taas oo kor u qaadeysa waxqabadka TET2 oo ay keento dhaawaca DNA.

Waxa xiisaha lihi leh, habkan dareenka ahi waa mid gaar u ah primates, iyo falanqayn farsamo oo dheeri ah ayaa shaaca ka qaaday in primate HDAC6 ay ka kooban tahay glutamate-tetranectide (SE14) oo qani ah oo gaar ah ku celi domain waxayna dareemeysaa badinnimada valine iyada oo loo marayo qaybtan. Marka la eego daawaynta burada, xaddidaadda valine dhexdhexaadka ah ama isku darka dawooyinka PARP waxay si wax ku ool ah u joojin karaan koritaanka burada.

Daraasadani waxay daaha ka qaadaysaa hab cusub oo cadaadiska nafaqadu uu ku maamulo waxyeelada DNA iyada oo loo marayo isbeddelka epigenetic, waxayna soo jeedinaysaa istaraatiijiyad cusub oo loogu talagalay daaweynta burooyinka oo leh cunto xaddidan oo valine ah oo ay weheliso PARP inhibitors.

Dareemayaasha amino acids sida caadiga ah waxay u baahan yihiin inay isku daraan asiidhyada amino si ay u aqoonsadaan ugana jawaabaan isbeddelada ku yimaada uruurinta amino acid gudaha iyo dibadda unugga, si ay u gutaan shaqadooda dareen.

Si si nidaamsan loo aqoonsado borotiinada ku xidhan valine-ka, baadhitaanada valine-ka ee biotinylated valine-ka ayaa loo isticmaalay tijaabooyinka difaaca jirka oo ay weheliso spectrometry mass, iyo baadhista aan eex lahayn ee borotiinada xidhidha valine-ka ayaa lagu sameeyay bayoloji kiimikaad.

Qorayaashu waxay ogaadeen in marka lagu daro valyl tRNA synthetases-ka loo yaqaan (VARS), deacetylase HDAC6 ay muujisay awood adag oo D-valine ah marka la barbar dhigo VARS. Qorayaashu waxay sii xaqiijiyeen in HDAC6 ay si toos ah ugu xidhi karto valine xidhiidhka Kd ≈ 2μM iyada oo loo marayo tijaabooyinka isotope ee isku xidhka, tijaabooyinka calorimetry isothermal titration (ITC) iyo tijaabooyin kuleyl ah. Falanqaynta sifooyinka qaabdhismeedka amino acids ee lagu aqoonsaday borotiinnada ayaa waxtar leh si loo sii fahmo habka molecular ee isbeddelka tirada badan ee amino acids ee ay keeneen unugyadu. Marka la falanqeeyo tijaabooyinka isku xidhka ee analooga valine, qorayaashu waxay ogaadeen in HDAC6 ay aqoonsan tahay terminaalka karboksylka iyo silsiladda dhinaca ee valine waxayna u dulqaadan kartaa wax ka beddelka terminalka amino. Intaa waxaa dheer, gudaha HDAC6 unugyada garaaca, nidaaminta dariiqa calaamadaynta mTOR ee xaddidaadda valine aad ugama duwana kooxda kantaroolka, taas oo soo jeedinaysa in xidhitaankani uu ka duwan yahay dariiqa dareenka dareenka amino acid dhaqameed.

Si loo sahamiyo domainka muhiimka ah iyo shaqada HDAC6 dareenka valine. Qorayaashu waxay si dheeraad ah u go'aamiyeen in HDAC6 ay ku xidho valine iyada oo loo marayo domainka SE14 iyada oo loo marayo HDAC6 tijaabada xiritaanka jirka. Waxaa la yaab leh, qorayaashu waxay ogaadeen isbarbardhigga homology-ga in domain SE14 uu ku jiro HDAC6 oo keliya ee primates. Si ka duwan daanyeer (dad iyo daayeer) HDAC6, mouse HDAC6 kuma xidhna valine. Natiijooyinkani waxay daaha ka qaadayaan farqiga u dhexeeya noocyada kala duwan ee valine induction, taasoo soo jeedinaysa in kobcinta noocyada ay door muhiim ah ka ciyaaraan soo saarista amino acid.

Iyada oo ku saleysan gabagabada in HDAC6 ay si toos ah ugu xirto valine iyada oo loo marayo domainka SE14, qorayaashu waxay ku qiyaaseen in isbeddelada xoogga ku xiran ee HDAC6 iyo valine ay saameyn karaan qaab-dhismeedkeeda iyo shaqadeeda marka tirada badan ee valine ee unugyada isbeddelaan. Iyada oo loo marayo tijaabooyin taxane ah oo lagu daray suugaanta doorka muhiimka ah ee domain SE14 ee xajinta cytoplasmic ee HDAC6, qorayaashu waxay ogaadeen in yaraanta valine ee intracellular ay keeni karto HDAC6 u wareejinta nukleus. Gobolka firfircoon ee enzyme (DAC1 iyo DAC2) waxay ku xidhan tahay gobolka firfircoon (CD domain) ee DNA hydroxymethylase TET2, kor u qaadida deacetylation ee TET2, ka dibna dhaqaajiso hawsheeda enzyme. Isticmaalka farsamooyinka methylomics sida WGBS, ACE-Seq iyo MAB-Seq, waxaan sii xaqiijinay in gaajada valine intracellular ay kor u qaadi karto demethylation DNA firfircoon iyada oo loo marayo dhidibka signal HDAC6-TET2. Markii hore, kooxda Andre Nussenzweig waxay ogaatay in thymine DNA glycosylase (TDG) -ku-tiirsanaanta firfircoonida DNA-da ee demethylation ay keentay dhaawaca hal-xadhig DNA ah oo ku saabsan kor u qaadka neuronal. Marka la isku daro TET2 ChIP-Seq iyo tignoolajiyada iskuxigta sare ee END-Seq iyo ddC S1 END-Seq, waxaan go'aansanay in yaraanta valine ay kor u qaaddo dhaawaca DNA. Dhaawaca DNA-da ee ay keentay yaraanta valine waxay sidoo kale ku xiran tahay dhaawaca hal xarig oo ay sababtay goynta TDG ee oxymethylcytosine (5fC/5caC).

Isku soo wada duuboo, qorayaashu waxay ogaadeen dareemayaasha cusub ee valine waxayna markii ugu horeysay si cad u qeexeen habka molecular kaas oo valine uu xaddidayo soo saarista dhaawaca DNA iyada oo loo marayo dhidibka calaamadaynta HDAC6-TET2-TDG, isagoo ku daray cabbir cusub oo fahamka shaqada walaaca amino acid ee go'aaminta qaddarka unugyada.

Xannibaadda cuntada ama bartilmaameedka dheef-shiid kiimikaadka iyo dareenka amino acid waxay noqotay istaraatijiyad isku dhafan oo loogu talagalay fidinta nolosha iyo daaweynta cudurro badan, oo uu ku jiro kansar. Marka la eego in valine-ka oo yaraada ay keeni karto dhaawac DNA, qorayaashu waxay sii baareen in xaddidaadda valine ay door ku leedahay daaweynta kansarka. Qaabka burada kansarka mindhicirka xenograft, cunno xaddidan valine-ku habboon (0.41% valine, w/w) waxay si weyn u joojisay korriinka burada oo leh waxyeellooyin yar. Kooxaha ka-hortagga iyo daaweynta labadaba, qorayaashu waxay si dheeraad ah u muujiyeen in cuntada xaddidan ee valine ay joojiso burada iyo horumarka iyadoo la adeegsanayo qaabka kansarka mindhicirka ee PDX. Shaybaarada burooyinka, heerarka valine-ka ee hoos u dhacay ayaa si togan loola xiriiriyay kororka beddelka nukliyeerka HDAC6, heerarka 5hmC, iyo dhaawaca DNA. Mar haddii keenista dhaawaca DNA-da ay tahay daawaynta kansarka ka-hortagga, bukaan-socod ahaan waa suurtogal in la joojiyo dayactirka DNA-da iyada oo la adeegsanayo PARP-ka-horyaalka. Qorayaashu waxay ogaadeen in isku-darka cuntada xaddidan ee valine-ka iyo PARP inhibitor talazoparib ay si weyn u xoojiyeen saameynta antitumor, iyagoo siinaya caddayn xooggan oo daaweyn ah oo lagu daweeyo kansarka iyada oo ay soo jiidanayso dhaawaca DNA.

Gebagebadii, daraasaddu waxay ogaatay in HDAC6 ee primates ay tahay borotiinka dareemayaasha valine cusub oo ka madax bannaan dareemayaasha dhaqameed, oo muujinaya kala duwanaanshaha dareenka valine ee noocyada kala duwan, taas oo muujinaysa doorka muhiimka ah ee horumarka noolaha ee dareenka amino acid.

Intaa waxaa dheer, daraasaddan ayaa sharraxaysa habka cusub ee isdhexgalka isdhexgalka ee cadaadiska dheef-shiid kiimikaadka nafaqada, xakamaynta epigenetic iyo dhaawaca DNA, waxay ballaarisaa muhiimada diiqada dheef-shiid kiimikaadka ee bayoolajiga walaaca, waxayna ogaatay in isku-darka cuntada xaddidan ee valine-ka iyo PARP inhibitors loo isticmaali karo istaraatiijiyad cusub oo loogu talagalay daaweynta kansarka.