Amino acids ndiwo akakosha zvikamu zvemapuroteni uye zvakakosha zvikamu zvematishu emunhu, achitamba basa rekuchinjisa chiratidzo chesero, mutemo wekuita enzyme, immune function uye mamwe mabasa emuviri.

Kuwanda kweamino acids mumasero kunowanzo shanduka mune dzakasiyana physiological uye pathological states. Naizvozvo, manzwisisiro anoita muviri shanduko yeamino acid level uye kuita inoshanduka idambudziko rakakosha resainzi rekushushikana kwemetabolism uye sero.

Abnormal amino acid sensing inowirirana zvakanyanya nekenza, chirwere cheshuga, neurodegenerative zvirwere uye kuchembera. Naizvozvo, kuongorora mamorekuru echisina kujairika amino acid induction inogona kupa chinangwa chitsva chekudzivirira kana kurapwa kwezvirwere zvemetabolism nekenza. Valine, seyakakosha branched-chain amino acid, inoita basa rakakosha muprotein synthesis, neurobehavior, uye leukemia kufambira mberi. Zvisinei, maitiro uye basa rekunzwa kweserura yevaline inoramba isina kujeka.

Musi waMbudzi 20, 2024, timu yaWang Ping kubva kuTongji University School of Medicine / 10th Affiliated People's Hospital yakaburitsa bepa rekutsvagisa rine musoro unoti "Human HDAC6 inonzwa valine abundancy kugadzirisa kukuvara kweDNA" mujenari Nature.

Chidzidzo ichi chakaratidza novel valine-specific sensor, human deacetylase HDAC6, uye yakaratidza nzira chaiyo iyo kurambidzwa kwevaline kunotungamira mukufambiswa kwenyukireya kweHDAC6, nekudaro ichiwedzera chiitiko cheTET2 uye kukonzeresa kukuvara kweDNA.

Sezvineiwo, iyi sensing system yakasarudzika kune primates, uye kumwe kuongorora kwemaitiro kwakaratidza kuti primate HDAC6 ine chaiyo serine-rich glutamate-tetranectide (SE14) inodzokorora domain uye inonzwa valine kuwanda kuburikidza neichi dura. Panyaya yekurapa bundu, kudzorwa zvine mwero valine kana kusanganiswa kwePARP inhibitors kunogona kumisa bundu kukura.

Ichi chidzidzo chinoratidza nzira itsva iyo kushushikana kwekudya kunogadzirisa kukuvadzwa kweDNA kuburikidza ne epigenetic modification, uye inopa zano idzva rekurapa bundu nekudya kwevaline-inorambidzwa kusanganiswa nePARP inhibitors.

Amino acid sensors inowanzoda kusanganisa amino acids kuti ione uye ipindure kune shanduko yeamino acid concentration mukati nekunze kwesero, kuitira kuti iite basa ravo rekunzwa.

Kuti vaone zvakarongeka valine-binding proteins, biotinylated valine probes yakashandiswa pakuedza immunocoprecipitate yakasanganiswa ne mass spectrometry, uye kuongorora kusingarereki kwevaline-binding mapuroteni kwakaitwa nemakemikari biology.

Vanyori vakaona kuti kuwedzera kune inozivikanwa valyl tRNA synthetases (VARS), deacetylase HDAC6 yakaratidza simba rakasimba reD-valine rekusunga zvichienzaniswa neVARS. Vanyori vakasimbisa zvakare kuti HDAC6 inogona kusungira zvakananga valine nehukama hweKd ≈ 2μM kuburikidza neisotopu inosunga kuyedza, isothermal titration calorimetry (ITC) kuyedza uye thermal drift miedzo. Kuongororwa kwemaitiro ezvimiro zveamino acids anozivikanwa nekunzwa mapuroteni kunobatsira kuti uwedzere kunzwisisa mamolecular maitiro ekuchinja kweamino acid kuwanda kunokonzerwa nemasero. Nekuongorora zviyedzo zvinosungirwa zvevaline analogues, vanyori vakawana kuti HDAC6 inoziva iyo carboxyl terminal uye parutivi cheni yevaline uye inogona kushivirira iyo amino terminal gadziriso. Mukuwedzera, muHDAC6 masero ekugogodza, mutemo we mTOR yekusaina nzira nekurambidzwa kwevaline kwakanga kusina kunyanya kusiyana neboka rekutonga, zvichiratidza kuti kusungirirwa uku kwakanga kwakasiyana nemaitiro echinyakare amino acid sensing nzira.

Kuti uongorore yakakosha domain uye basa reHDAC6 inonzwa valine. Vanyori vakasimbisazve kuti HDAC6 inosunga valine kuburikidza neyayo SE14 domain kuburikidza neHDAC6 yakatemwa muviri inosunga kuyedza. Sezvineiwo, vanyori vakawana nehomology kuenzanisa kuti iyo SE14 domain inongowanikwa muHDAC6 mumaprimates. Kusiyana neprimate (munhu netsoko) HDAC6, mbeva HDAC6 haisungiri kune valine. Kuwana uku kunoburitsa mutsauko uripo pakati pemhando dzakasiyana muvaline induction, zvichiratidza kuti kushanduka kwezvipenyu kunoita basa rakakosha muamino acid induction.

Kubva pamhedziso yokuti HDAC6 inosunga zvakananga valine kuburikidza neSE14 domain yayo, vanyori vakafungidzira kuti kuchinja kwesimba rinosunga reHDAC6 uye valine kunogona kukanganisa maitiro ayo uye basa apo kuwanda kwevaline mumasero kunoshanduka. Kuburikidza nehuwandu hwekuedza uye kusanganiswa nemabhuku pamusoro pebasa rinokosha reSE14 domain mu cytoplasmic retention yeHDAC6, vanyori vakaona kuti intracellular valine deficiency inogona kukonzera HDAC6 translocation kune nucleus. Iyo enzyme inoshanda nharaunda (DAC1 uye DAC2) inosungira kune inoshanda dunhu (CD domain) yeDNA hydroxymethylase TET2, ichikurudzira deacetylation yeTET2, uyezve activate yayo enzyme basa. Tichishandisa maitiro emethylomics akadai seWGBS, ACE-Seq uye MAB-Seq, takasimbisa zvakare kuti intracellular valine nzara inogona kukurudzira inoshanda DNA demethylation kuburikidza neHDAC6-TET2 chiratidzo axis. Kare, timu yaAndre Nussenzweig yakawana kuti thymine DNA glycosylase (TDG) -inotsamira inoshanda DNA demethylation yakakonzera DNA imwe-strand kukuvara pane neuronal enhancer. Nekubatanidza TET2 ChIP-Seq neyepamusoro-yekuteedzera tekinoroji END-Seq uye ddC S1 END-Seq, takaona kuti kushomeka kwevaline kunosimudzira kukuvara kweDNA. Kukuvadzwa kweDNA kunokonzerwa nekushaikwa kwevaline kunoenderanawo nekukuvadzwa kwetambo imwechete yakakonzerwa neTDG excision ye oxymethylcytosine (5fC/5caC).

Vakatorwa pamwechete, vanyori vakawana novel valine sensors uye kekutanga kujekesa mamorekuru nzira iyo valine inodzikamisa kuiswa kweDNA kukuvadzwa kuburikidza neiyo HDAC6-TET2-TDG siginecha axis, ichiwedzera chidimbu chitsva pakunzwisisa kwekushanda kweamino acid kushushikana musero.

Kurambidzwa kwekudya kana kunanga kweamino acid metabolism uye kunzwa kwave nzira yekuwedzera yekuwedzera hupenyu uye kurapwa kwezvirwere zvakawanda, kusanganisira cancer. Tichifunga kuti kunyimwa kwevaline kunogona kukonzera kukuvara kweDNA, vanyori vakaenderera mberi nekuongorora kana kurambidzwa kwevaline kunobatsira mukurapa cancer. Mune colorectal cancer xenograft tumor modhi, yakakodzera valine-inorambidzwa kudya (0.41% valine, w/w) yakanyanya kuvharira bundu kukura nekushomeka kwemhedzisiro. Mune ese ari maviri ekudzivirira uye ekurapa mapoka, vanyori vakaratidza zvakare kuti valine-inorambidzwa kudya kwakadzivisa tumorigenesis uye kufambira mberi vachishandisa colorectal cancer PDX modhi. Mune tumor samples, yakadzikira nhanho yevaline yakabatana nekuwedzera HDAC6 nyukireya kutamiswa, 5hmC mazinga, uye DNA kukuvara. Sezvo kukonzeresa kukuvadzwa kweDNA kuri kurapa kwechirwere checancer, zvinokwanisika kuvharisa kugadzirisa kweDNA nekushandisa PARP inhibitors. Vanyori vakaona kuti kusanganiswa kwevaline-inorambidzwa kudya uye PARP inhibitor talazoparib kwakawedzera zvakanyanya antitumor mhedzisiro, ichipa humbowo hwakasimba hwekurapa kurapa cancer nekukonzera kukuvara kweDNA.

Mukupedzisa, chidzidzo chacho chakawana kuti HDAC6 mumaprimates ipuroteni yevaline sensing inozvimiririra, inoburitsa misiyano yevaline sensing pakati pemarudzi akasiyana, zvichiratidza basa rakakosha rekushanduka kwebiological mukunzwa kweamino acid.

Pamusoro pezvo, chidzidzo ichi chinojekesa nzira nyowani yekudyidzana kwekudyara metabolic kushushikana, epigenetic regulation uye DNA kukuvadzwa, inowedzera kukosha kwehutano hwemetabolism kusagadzikana mukushushikana biology, uye inoona kuti kusanganiswa kwevaline-inorambidzwa kudya uye PARP inhibitors inogona kushandiswa senzira nyowani yekurapa cancer.