?O nā amino acids nā ?āpana kumu o nā protein a me nā ?āpana ko?iko?i o nā ?i?o kanaka, e pā?ani ana i ka hana o ka transduction hō?ailona cell, ka ho?oponopono hana enzyme, ka hana immune a me nā hana physiological ?ē a?e.

Ho?ololi pinepine ka nui o nā amino acids i nā ?āpana i nā kūlana physiological a me nā pathological. No laila, pehea ke kino e ?ike ai i ka ho?ololi ?ana o ka pae amino acid a hana i kahi pane adaptive he pilikia ?epekema ko?iko?i o ke ko?iko?i metabolic a me ka hopena cell.

Pili loa ka ?ike ?ana i ka amino acid i ka ma?i kanesa, ka ma?i diabetes, nā ma?i neurodegenerative a me ke ka?ina hana ?elemakule. No laila, ?o ka ?imi ?ana i ke ?ano molekala o ka induction amino acid abnormal hiki ke hā?awi i kahi pahuhopu hou no ka pale ?ana a i ?ole ka mālama ?ana i nā ma?i metabolic a me ke kanesa. ?O Valine, ma ke ?ano he ?akika amino branched-chain ko?iko?i, he kuleana ko?iko?i i ka synthesis protein, neurobehavior, a me ka holomua leukemia. Eia nō na?e, ?a?ole maopopo ka mīkini a me ka hana o ka ?ike kelepona o valine.

Ma Nowemapa 20, 2024, ua pa?i ka hui o Wang Ping mai ke kula ?o Tongji University of Medicine / 10th Affiliated People's Hospital i kahi pepa noi?i i kapa ?ia "Human HDAC6 senses valine abundancy to regulate DNA damage" ma ka puke pai Nature.

Ua ?ike kēia ha?awina i kahi sensor valine-specific novel, deacetylase HDAC6 kanaka, a hō?ike i ke ?ano kiko?ī e alaka?i ai ka palena o valine i ka translocation nuklea o HDAC6, a laila e ho?onui ai i ka hana TET2 a me ka ho?oulu ?ana i ka pō?ino DNA.

?O ka mea e mahalo ai, ?oko?a kēia ?ano hana ?ike i nā primates, a ua hō?ike hou ?ia ka loiloi ?ana i ka primate HDAC6 i kahi kikowaena serine-rich glutamate-tetranectide (SE14) hou a ?ike i ka nui o valine ma o kēia kikowaena. Ma ke ?ano o ka mālama ?ana i ka ma?i tumora, hiki i ka palena ha?aha?a valine a i ?ole ka hui pū ?ana o ka PARP inhibitors hiki ke pale pono i ka ulu ?ana o ka tumor.

Hō?ike kēia ha?awina i kahi hana hou e ho?oponopono ai ke ko?iko?i mea?ai i ka pō?ino DNA ma o ka ho?ololi ?ana epigenetic, a ke hāpai nei i kahi ho?olālā hou no ka mālama ?ana i ka ma?i tumora me ka mea?ai i ho?opa?a ?ia i ka valine i hui pū ?ia me nā mea ho?opane?e PARP.

Pono nā mea ?ike amino acid e hui pū i nā ?akika amino i mea e ?ike ai a pane aku i nā loli i ka ho?onui ?ana i ka ?akika amino i loko a i waho o ke keena, i mea e hana ai i kā lākou hana ?ike.

I mea e ?ike pono ai i nā protein pa?a valine, ua ho?ohana ?ia nā ?imi noi?i biotinylated valine no nā ho?okolohua immunocoprecipitate i hui pū ?ia me ka spectrometry lehulehu, a ua hana ?ia ka nānā ?ole ?ana o nā protein pa?a valine e ka biology kemika.

Ua ?ike nā mea kākau ma kahi o nā valyl tRNA synthetases (VARS) i ?ike ?ia, ua hō?ike ka deacetylase HDAC6 i kahi mana pa?a D-valine ikaika i ho?ohālikelike ?ia me VARS. Ua hō?oia hou nā mea kākau e hiki i ka HDAC6 ke ho?opa?a pololei i ka valine me kahi pili o Kd ≈ 2μM ma o nā ho?okolohua ho?opa?a isotope, nā ho?okolohua isothermal titration calorimetry (ITC) a me nā ho?okolohua thermal drift. ?O ka nānā ?ana i nā hi?ohi?ona o nā ?akika amino i ?ike ?ia e ka ?ike ?ana i nā protein he mea kōkua ia e ho?omaopopo hou i ke ?ano molekala o ka ho?ololi ?ana o ka nui o ka waikawa amino i ho?oulu ?ia e nā cell. Ma ke kālailai ?ana i nā ho?okolohua pa?a o nā analogues valine, ua ?ike nā mea kākau ua ?ike ?o HDAC6 i ka pahu carboxyl a me ke kaulahao ?ao?ao o valine a hiki ke ?ae i ka ho?ololi ?ana o ka terminal amino. Eia hou, i loko o HDAC6 knockout cell, ?a?ole i ?oko?a loa ka ho?oponopono ?ana o ke ala hō?ailona mTOR e ka palena o valine mai ka pū?ulu ho?omalu, e hō?ike ana he ?oko?a kēia pa?a ?ana mai ke ala hō?ailona amino acid ku?una.

I mea e ?imi ai i ka domain ko?iko?i a me ka hana o HDAC6 sensing valine. Ua ho?oholo hou nā mea kākau e ho?opa?a ?o HDAC6 i ka valine ma kāna kikowaena SE14 ma o ka ho?okolohua ho?opa?a pa?a kino HDAC6. ?O ka mea kupanaha, loa?a nā mea kākau e ka homology ho?ohālikelike ?o ka SE14 domain aia wale nō ma HDAC6 i nā primates. ?A?ole like me ka primate (kanaka a me ka monkey) HDAC6, ?a?ole pili ka ?iole HDAC6 i valine. Hō?ike kēia ?ike i nā ?oko?a ma waena o nā ?ano ?ano like ?ole i loko o ka induction valine, e hō?ike ana he mea ko?iko?i ka ulu ?ana o nā ?ano i loko o ka induction acid amino.

Ma muli o ka hopena i ho?opa?a pono ?ia ?o HDAC6 i ka valine ma o kāna kikowaena SE14, ua mana?o nā mea kākau e ho?ololi i ka ikaika pa?a o HDAC6 a me valine i kona ?ano a me kāna hana i ka wā e loli ai ka nui o ka valine i loko o nā cell. Ma o ke?ano o nā ho?okolohua a hui pū?ia me nā puke e pili ana i ka hana nui o ka SE14 domain i ka cytoplasmic pa?a o HDAC6, ua?ike nā mea kākau i ka hiki?ole o ka valine intracellular ke ho?oulu i ka translocation HDAC6 i ka nucleus. Ho?opili ka ?āpana hana enzyme (DAC1 a me DAC2) i ka ?āpana hana (CD domain) o ka DNA hydroxymethylase TET2, e ho?oikaika ana i ka deacetylation o TET2, a laila ho?āla i kāna hana enzyme. Ke ho?ohana nei i nā ?enehana methylomics e like me WGBS, ACE-Seq a me MAB-Seq, ua hō?oia hou mākou e hiki i ka pōloli valine intracellular ke ho?oikaika i ka demethylation DNA ikaika ma o ka axis hō?ailona HDAC6-TET2. Ma mua, ua ?ike ka hui o Andre Nussenzweig i ka thymine DNA glycosylase (TDG) -dependent active DNA demethylation i hopena i ka DNA single-strand pō?ino ma ka neuronal enhancer. Ma ka ho?ohui ?ana i ka TET2 ChIP-Seq me ka ?enehana sequencing ki?eki?e END-Seq a me ddC S1 END-Seq, ua ho?oholo mākou i ka hemahema o ka valine e hāpai i ka pō?ino DNA. ?O ka pō?ino DNA i ho?oulu ?ia e ka hemahema valine e hilina?i pū ?ia i ka pō?ino o ke kaula ho?okahi i hana ?ia e ka TDG excision o ka oxymethylcytosine (5fC/5caC).

I ka hui pū ?ana, ua ?ike nā mea kākau i nā sensor valine hou a no ka manawa mua i wehewehe i ke ?ano molecular kahi e kaupalena ai ?o valine i ka ho?okomo ?ana o ka pō?ino DNA ma o ka HDAC6-TET2-TDG hō?ailona axis, e ho?ohui ana i kahi ?ano hou i ka ho?omaopopo ?ana i ka hana o ke ko?iko?i amino acid i ka ho?oholo ?ana i ka hopena cell.

?O ka ho?opa?a ?ana i ka mea?ai a i ?ole ka huli ?ana i ka metabolism amino acid a me ka ?ike ?ana ua lilo i ho?olālā ho?ohui no ka ho?onui ?ana i ke ola a me ka mālama ?ana i nā ma?i he nui, me ka ma?i kanesa. Ma muli o ka hiki ?ole o ka valine ke ho?oulu i ka pō?ino DNA, ua noi?i hou nā mea kākau inā he kuleana ka palena o valine i ka mālama ?ana i ka ma?i kanesa. I loko o kahi kumu ho?ohālike xenograft ma?i kanesa colorectal, ?o ka mea?ai i ho?opa?a ?ia i ka valine kūpono (0.41% valine, w/w) i kāohi nui i ka ulu ?ana o ka ma?i me ka li?ili?i o nā hopena ?ao?ao. Ma nā pū?ulu pale a me ka mālama ?ana, ua hō?ike hou nā mea kākau i ka mea?ai i ho?opa?a ?ia i ka valine i kāohi i ka tumorigenesis a me ka holomua me ka ho?ohana ?ana i kahi kumu ho?ohālike PDX ma?i ma?i colorectal. I loko o nā hō?ailona tumo, ua ho?opili maika?i ?ia nā pae valine i ho?emi ?ia me ka ho?onui ?ia ?ana o ka ho?ololi nuklea HDAC6, nā pae 5hmC, a me ka pō?ino DNA. No ka mea ?o ka ho?oulu ?ana i ka pō?ino DNA he lā?au anticancer, hiki i ke kauka ke pale i ka ho?oponopono DNA ma o ka ho?ohana ?ana i nā mea pa?i PARP. Ua ?ike nā mea kākau i ka hui pū ?ana o ka mea?ai i kaupalena ?ia ?o valine a me ka PARP inhibitor talazoparib i ho?onui nui i ka hopena antitumor, e hā?awi ana i nā hō?ike ikaika no ka lā?au lapa?au e mālama i ka ma?i kanesa ma o ka ho?oulu ?ana i ka pō?ino DNA.

I ka hopena, ua ?ike ?ia ka ha?awina ?o HDAC6 i loko o nā primates he novel valine sensing protein kū?oko?a i nā mea ?ike ku?una, e hō?ike ana i nā ?oko?a o ka ?ike valine ma waena o nā ?ano ?ano like ?ole, e hō?ike ana i ke kuleana ko?iko?i o ka evolution biological i ka ?ike amino acid.

Eia kekahi, ua wehewehe kēia ha?awina i kahi hana hou o ka ho?oponopono pāna?i o ke ko?iko?i metabolic mea?ai, ka ho?oponopono epigenetic a me ka pō?ino DNA, ho?onui i ke ko?iko?i o ke ko?iko?i metabolic i loko o ke ko?iko?i ko?iko?i, a ?ike i ka hui pū ?ana o ka mea?ai i kaupalena ?ia a me ka PARP inhibitors hiki ke ho?ohana ?ia ma ke ?ano he ho?olālā hou no ka mālama ?ana i ka ma?i kanesa.