Ma amino acid ndi zigawo zikuluzikulu za mapuloteni ndi zigawo zofunika kwambiri za minofu ya munthu, zomwe zimagwira ntchito yosinthira ma cell, kuwongolera zochita za ma enzyme, chitetezo chamthupi ndi ntchito zina zathupi.

Kuchuluka kwa ma amino acid m'maselo nthawi zambiri kumasintha m'malo osiyanasiyana amthupi komanso ma pathological. Chifukwa chake, momwe thupi limawonera kusintha kwa mulingo wa amino acid ndikupanga kuyankha kosinthika ndivuto lofunikira lasayansi la kupsinjika kwa metabolic ndi tsogolo la cell.

Kuzindikira kwa amino acid kumagwirizana kwambiri ndi khansa, shuga, matenda a neurodegenerative komanso kukalamba. Chifukwa chake, kuyang'ana momwe ma cell amapangidwira amino acid atha kupereka chandamale chatsopano popewa kapena kuchiza matenda a metabolic ndi khansa. Valine, monga gawo lofunikira la amino acid, amatenga gawo lofunikira pakuphatikizika kwa mapuloteni, neurobehavior, ndi leukemia. Komabe, makina ndi ntchito ya ma cell sensors ya valine sizikudziwika.

Pa Novembara 20, 2024, gulu la a Wang Ping ochokera ku Tongji University School of Medicine / 10th Affiliated People's Hospital adasindikiza pepala lofufuza lotchedwa "Human HDAC6 imamva kuchuluka kwamphamvu kuti ilamulire kuwonongeka kwa DNA" m'magazini ya Nature.

Kafukufukuyu adawonetsa sensa yatsopano ya valine-specific sensor, human deacetylase HDAC6, ndipo idawulula njira yomwe kuletsa kwa valine kumabweretsa kusamutsa kwa nyukiliya ya HDAC6, potero kumakulitsa zochitika za TET2 ndikupangitsa kuwonongeka kwa DNA.

Chochititsa chidwi n'chakuti, kachipangizo kameneka kamakhala kosiyana ndi anyani, ndipo kusanthula kwina kwina kunawonetsa kuti primate HDAC6 ili ndi serine-rich glutamate-tetranectide (SE14) yobwereza domain ndipo imamva kuchuluka kwa valine kupyolera mu derali. Pankhani ya chithandizo cha chotupa, kuletsa kwapang'onopang'ono kwa valine kapena kuphatikiza kwa PARP inhibitors kumatha kulepheretsa kukula kwa chotupa.

Kafukufukuyu akuwonetsa njira yatsopano yomwe kupsinjika kwazakudya kumawongolera kuwonongeka kwa DNA kudzera mukusintha kwa epigenetic, ndipo akupereka njira yatsopano yochizira chotupa ndi zakudya zoletsedwa ndi valine kuphatikiza ndi PARP inhibitors.

Masensa a amino acid nthawi zambiri amafunika kuphatikiza ma amino acid kuti azindikire ndikuyankha kusintha kwa ma amino acid mkati ndi kunja kwa selo, kuti agwire ntchito yawo yozindikira.

Pofuna kudziwa mwadongosolo mapuloteni omangira valine, ma probes a biotinylated valine anagwiritsidwa ntchito poyesera immunocoprecipitate pamodzi ndi mass spectrometry, ndipo kufufuza mopanda tsankho kwa mapuloteni omangirira valine kunachitika ndi biology ya mankhwala.

Olembawo adapeza kuti kuwonjezera pa zodziwika bwino za valyl tRNA synthetases (VARS), deacetylase HDAC6 inasonyeza mphamvu yomangirira ya D-valine poyerekeza ndi VARS. Olembawo adatsimikiziranso kuti HDAC6 ikhoza kumangirira mwachindunji valine ndi mgwirizano wa Kd ≈ 2μM kupyolera mu kuyesa kwa isotopu, kuyesa kwa isothermal titration calorimetry (ITC) ndi kuyesa kwa kutentha kwa kutentha. Kusanthula kwa mapangidwe a ma amino acid omwe amadziwika pozindikira mapuloteni ndikothandiza kumvetsetsa momwe mamolekyulu amasinthira kuchuluka kwa amino acid komwe kumapangidwa ndi maselo. Powunika zoyeserera zomangirira za ma analogues a valine, olemba adapeza kuti HDAC6 imazindikira terminal ya carboxyl ndi unyolo wam'mbali wa valine ndipo imatha kulekerera kusintha kwa amino terminal. Kuphatikiza apo, m'maselo ogogoda a HDAC6, kuwongolera kwa njira yozindikiritsa ya mTOR mwa kuletsa kwa valine sikunali kosiyana kwambiri ndi gulu lowongolera, kutanthauza kuti kumangiriraku kunali kosiyana ndi njira yachikhalidwe yozindikira amino acid.

Kuti mufufuze madera ofunikira ndi ntchito ya valine yomvera ya HDAC6. Olembawo adatsimikizanso kuti HDAC6 imamanga valine kudzera mu domain yake ya SE14 kudzera mu kuyesa kwa HDAC6 kocheperako. Chodabwitsa n'chakuti, olemba adapeza poyerekezera ndi homology kuti SE14 domain imapezeka mu HDAC6 mu anyani. Mosiyana ndi anyani (anthu ndi nyani) HDAC6, mbewa HDAC6 sichimangirira ku valine. Izi zikuwonetsa kusiyana pakati pa mitundu yosiyanasiyana ya valine induction, kutanthauza kuti kusinthika kwa mitundu kumachita gawo lofunikira pakulowetsa kwa amino acid.

Malingana ndi mfundo yakuti HDAC6 imamangiriza mwachindunji valine kupyolera mu gawo lake la SE14, olembawo ankaganiza kuti kusintha kwa mphamvu yomangirira ya HDAC6 ndi valine kungakhudze kapangidwe kake ndi ntchito yake pamene kuchuluka kwa valine m'maselo kumasintha. Kupyolera m'mayesero angapo komanso kuphatikizapo zolemba pa ntchito yofunikira ya SE14 domain mu cytoplasmic retention ya HDAC6, olemba adapeza kuti kusowa kwa intracellular valine kungapangitse HDAC6 kusuntha ku nucleus. Chigawo chogwira ntchito cha enzyme (DAC1 ndi DAC2) chimamangiriza ku dera logwira ntchito (CD domain) ya DNA hydroxymethylase TET2, kulimbikitsa deacetylation ya TET2, ndiyeno kuyambitsa ntchito yake ya enzyme. Pogwiritsa ntchito njira za methylomics monga WGBS, ACE-Seq ndi MAB-Seq, tinatsimikiziranso kuti intracellular valine njala ikhoza kulimbikitsa DNA demethylation kudzera mu HDAC6-TET2 chizindikiro axis. Poyamba, gulu Andre Nussenzweig anapeza kuti thymine DNA glycosylase (TDG) - amadalira yogwira DNA demethylation zinachititsa DNA single-strand kuwonongeka pa neuronal enhancer. Pophatikiza TET2 ChIP-Seq ndiukadaulo wotsogola kwambiri END-Seq ndi ddC S1 END-Seq, tidatsimikiza kuti kusowa kwa valine kumalimbikitsa kuwonongeka kwa DNA. Kuwonongeka kwa DNA komwe kumabwera chifukwa cha kusowa kwa valine kumadaliranso kuwonongeka kwa chingwe chimodzi chomwe chinayambitsidwa ndi TDG kuchotsa oxymethylcytosine (5fC/5caC).

Kutengera pamodzi, olembawo adapeza masensa atsopano a valine ndipo kwa nthawi yoyamba adafotokozera momwe ma molekyulu a valine amalepheretsa kuwonongeka kwa DNA kudzera pa HDAC6-TET2-TDG siginecha axis, ndikuwonjezera gawo latsopano pakumvetsetsa kwa magwiridwe antchito a amino acid kupsinjika pakutsimikiza tsogolo la cell.

Kuletsa zakudya kapena kutsata kagayidwe ka amino acid ndi kumva kwakhala njira yowonjezera moyo komanso kuchiza matenda ambiri, kuphatikiza khansa. Popeza kuti kusowa kwa valine kungayambitse kuwonongeka kwa DNA, olembawo adafufuzanso ngati kuletsa kwa valine kumathandiza pa chithandizo cha khansa. Mu mtundu wa chotupa cha colorectal xenograft chotupa, zakudya zoyenera zoletsa valine (0.41% valine, w/w) zimalepheretsa kukula kwa chotupa ndi zotsatirapo zochepa. M'magulu onse oletsa komanso ochizira, olembawo adawonetsanso kuti zakudya zoletsedwa ndi valine zimalepheretsa tumorigenesis ndi kupita patsogolo pogwiritsa ntchito mtundu wa PDX wa khansa ya colorectal. Mu zitsanzo zotupa, kuchepa kwa valine kunali kogwirizana ndi kuwonjezeka kwa HDAC6 nyukiliya, milingo ya 5hmC, ndi kuwonongeka kwa DNA. Popeza kuyambitsa kuwonongeka kwa DNA ndi mankhwala oletsa khansa, ndizotheka kuletsa kukonza kwa DNA pogwiritsa ntchito zoletsa za PARP. Olembawo adapeza kuti kuphatikiza kwa zakudya zoletsedwa ndi valine ndi PARP inhibitor talazoparib kumawonjezera mphamvu ya antitumor, ndikupereka umboni wamphamvu wamankhwala ochizira khansa poyambitsa kuwonongeka kwa DNA.

Pomaliza, kafukufukuyu adapeza kuti HDAC6 mu anyani ndi puloteni yodziwikiratu ya valine yosagwirizana ndi masensa achikhalidwe, ikuwonetsa kusiyana kwa kumva kwa valine pakati pa mitundu yosiyanasiyana, kuwonetsa gawo lofunikira la kusinthika kwachilengedwe pakuzindikira kwa amino acid.

Kuphatikiza apo, kafukufukuyu akuwonetsa njira yatsopano yolumikizirana ndi kupsinjika kwa kagayidwe kazakudya, malamulo a epigenetic ndi kuwonongeka kwa DNA, kumakulitsa kufunikira kwa kupsinjika kwa kagayidwe kazakudya mu biology yopsinjika, ndikupeza kuti kuphatikiza kwa zakudya zoletsedwa ndi valine ndi PARP inhibitors zitha kugwiritsidwa ntchito ngati njira yatsopano yothandizira khansa.