Amino acid sune mahimman abubuwan sunadarai da mahimman abubuwan da ke cikin kyallen jikin ?an adam, suna taka rawar siginar siginar tantanin halitta, tsarin aikin enzyme, aikin rigakafi da sauran ayyukan ilimin lissafi.

Yawancin amino acid a cikin sel sau da yawa suna canzawa a cikin yanayi daban-daban na physiological da pathological. Sabili da haka, yadda jiki ke jin canjin matakin amino acid kuma ya ba da amsa mai dacewa da mahimmancin matsalar kimiyya na damuwa na rayuwa da ?addarar tantanin halitta.

Amino acid mara kyau yana da ala?a da kansa sosai, ciwon sukari, cututtukan neurodegenerative da tsarin tsufa. Sabili da haka, bincika tsarin kwayoyin halitta na shigar da amino acid mara kyau na iya samar da sabuwar manufa don rigakafi ko maganin cututtuka na rayuwa da ciwon daji. Valine, a matsayin amino acid mai sar?a??iya mai mahimmanci, yana taka muhimmiyar rawa wajen ha?akar furotin, halayyar neuro, da ci gaban cutar sankarar bargo. Koyaya, tsari da aikin wayar salula na valine ya kasance ba a sani ba.

A ranar 20 ga Nuwamba, 2024, ?ungiyar Wang Ping daga Makarantar Magunguna ta Jami'ar Tongji / Asibitin Jama'a na 10th sun buga takardar bincike mai suna "Human HDAC6 yana jin yawan valine don daidaita lalacewar DNA" a cikin mujallar Nature.

Wannan binciken ya gano wani sabon firikwensin valine-takamaiman firikwensin, ?an adam deacetylase HDAC6, kuma ya bayyana ?ayyadaddun tsarin da ?untatawa na valine ke haifar da canjin nukiliya na HDAC6, ta haka yana ha?aka ayyukan TET2 da haifar da lalacewar DNA.

Abin sha'awa shine, wannan tsarin ji na musamman ga primates, kuma ?arin bincike na injin ya nuna cewa primate HDAC6 ya ?unshi takamaiman yanki mai-arzi?in glutamate-tetranectide (SE14) mai maimaita yanki kuma yana jin yawan valine ta wannan yanki. Dangane da maganin ciwon daji, matsakaicin ?untatawa na valine ko ha?uwa da masu hana PARP na iya hana ci gaban ?ari yadda ya kamata.

Wannan binciken ya bayyana wani sabon tsarin da damuwa mai gina jiki ke sarrafa lalacewar DNA ta hanyar gyaran gyare-gyare na epigenetic, kuma ya ba da shawarar sabon dabarun maganin ciwon daji tare da ?untataccen abinci na valine tare da masu hana PARP.

Amino acid na'urori masu auna firikwensin yawanci suna bu?atar ha?a amino acid don ganewa da amsa canje-canje a cikin tattarawar amino acid a ciki da wajen tantanin halitta, don yin aikin fahimtar su.

Domin a gano sunadaran da ke ?aure valine cikin tsari, an yi amfani da binciken valine na biotinylated don gwaje-gwajen immunocoprecipitate ha?e tare da spectrometry na taro, kuma gwajin rashin son zuciya na sunadaran da ke ?aure valine an yi ta hanyar ilimin kimiyyar sinadarai.

Marubutan sun gano cewa ban da sanannun valyl tRNA synthetases (VARS), deacetylase HDAC6 ya nuna ?arfin ?aurin D-valine mai ?arfi idan aka kwatanta da VARS. Marubutan sun kara tabbatar da cewa HDAC6 na iya ?aure valine kai tsaye tare da kusancin Kd ≈ 2μM ta hanyar gwaje-gwajen ?aurin isotope, gwaje-gwajen calorimetry na isothermal titration (ITC) da gwajin drift na thermal. Binciken sifofin tsarin amino acid da aka gane ta hanyar gano sunadaran suna taimakawa don ?ara fahimtar tsarin kwayoyin halittar canjin yawan amino acid da sel suka jawo. Ta hanyar nazarin gwaje-gwajen dauri na analogues na valine, marubutan sun gano cewa HDAC6 ta gane tashar carboxyl da sarkar valine kuma tana iya jure wa gyare-gyaren tashar amino. Bugu da ?ari, a cikin ?wayoyin ?wan?wasa HDAC6, ?a'idodin hanyar siginar mTOR ta hanyar ?untatawa na valine bai bambanta da na ?ungiyar kulawa ba, yana nuna cewa wannan ?aurin ya bambanta da hanyar siginar amino acid na gargajiya.

Domin bincika mahimman yanki da aikin HDAC6 na gano valine. Marubutan sun ?ara ?addara cewa HDAC6 tana ?aure valine ta hanyar yanki na SE14 ta hanyar gwajin ?aurin jiki na HDAC6. Abin mamaki, marubutan sun samo ta hanyar kwatanta homology cewa yankin SE14 yana cikin HDAC6 kawai a cikin primates. Ba kamar primate (mutum da biri) HDAC6 ba, linzamin kwamfuta HDAC6 baya ?aure da valine. Wannan binciken ya bayyana bambance-bambance tsakanin nau'ikan nau'ikan nau'ikan induction na valine, yana nuna cewa juyin halittar nau'in yana taka muhimmiyar rawa wajen shigar da amino acid.

Dangane da ?addamar da cewa HDAC6 ta ?aure valine kai tsaye ta hanyar yankin SE14, marubutan sun yi hasashen cewa canje-canje a cikin ?arfin ?aure na HDAC6 da valine na iya shafar tsarinta da aikinsa lokacin da yawan valine a cikin sel ya canza. Ta hanyar gwaje-gwajen gwaje-gwaje da kuma ha?e tare da wallafe-wallafe game da muhimmiyar rawa na yankin SE14 a cikin cytoplasmic ri?ewar HDAC6, mawallafa sun gano cewa rashi na valine na ciki zai iya haifar da HDAC6 canzawa zuwa tsakiya. Yankin enzyme mai aiki (DAC1 da DAC2) yana ?aure zuwa yanki mai aiki (yankin CD) na DNA hydroxymethylase TET2, yana ha?aka deacetylation na TET2, sannan yana kunna ayyukan enzyme. Yin amfani da dabarun methylomics irin su WGBS, ACE-Seq da MAB-Seq, mun ?ara tabbatar da cewa yunwar valine na ciki na iya inganta demethylation na DNA mai aiki ta hanyar siginar HDAC6-TET2. A baya can, ?ungiyar Andre Nussenzweig ta gano cewa thymine DNA glycosylase (TDG) - dogara da DNA demethylation mai aiki ya haifar da lalacewar DNA guda ?aya akan ha?akar neuronal. Ta hanyar ha?a TET2 ChIP-Seq tare da fasaha mai mahimmanci na END-Seq da ddC S1 END-Seq, mun ?addara cewa ?arancin valine yana inganta lalacewar DNA. Lalacewar DNA da rashi na valine ya haifar kuma ya dogara ne akan lalacewar madauri ?aya da TDG ke haifarwa na oxymethylcytosine (5fC/5caC).

A hade tare, marubutan sun gano na'urori masu auna firikwensin valine kuma a karon farko sun bayyana tsarin kwayoyin halitta wanda valine ke iyakance shigar da lalacewar DNA ta hanyar siginar siginar HDAC6-TET2-TDG, yana ?ara sabon girma zuwa fahimtar aikin damuwa na amino acid a cikin ?addarar ?addarar ?wayoyin cuta.

?untatawa na abinci ko niyya na metabolism na amino acid da ganewa ya zama dabarar ha?in gwiwa don tsawaita rayuwa da maganin cututtuka da yawa, gami da ciwon daji. Ganin cewa rashi valine na iya haifar da lalacewar DNA, marubutan sun ?ara bincika ko ?untatawa na valine yana taka rawa wajen maganin ciwon daji. A cikin nau'in ciwon daji na xenograft na ciwon daji, abincin da ya dace na valine mai ?untataccen abinci (0.41% valine, w / w) yana hana ci gaban ?wayar cuta tare da ?ananan sakamako masu illa. A cikin duka ?ungiyoyin rigakafi da ?ungiyoyin jiyya, marubutan sun ?ara nuna cewa rage cin abinci na valine ya hana ?wayar cuta da ci gaba ta amfani da samfurin PDX na ciwon daji mai launi. A cikin samfuran ?ari, raguwar matakan valine yana da ala?a da ala?a da ha?aka ha?akar nukiliya na HDAC6, matakan 5hmC, da lalata DNA. Tunda haifar da lalacewar DNA shine maganin ciwon daji, yana yiwuwa a asibiti don toshe gyaran DNA ta amfani da masu hanawa PARP. Marubutan sun gano cewa ha?uwa da rage cin abinci na valine da mai hana PARP talazoparib ya inganta tasirin antitumor sosai, yana ba da shaida mai karfi don maganin ciwon daji ta hanyar haifar da lalacewar DNA.

A ?arshe, binciken ya gano cewa HDAC6 a cikin Protascs ne mai sanyin ilimin na gargajiya, wanda ke nuna mahimmancin rawar da juyin halittu, a cikin amino acid din.

Bugu da ?ari, wannan binciken ya ?addamar da wani sabon tsarin tsarin tsarin hul?ar abinci mai gina jiki na damuwa mai gina jiki, tsarin epigenetic da lalacewar DNA, yana fa?a?a mahimmancin damuwa na abinci mai gina jiki a cikin ilimin halitta na danniya, kuma ya gano cewa ha?uwa da rage cin abinci na valine da masu hana PARP za a iya amfani da su azaman sabon dabarun maganin ciwon daji.