Amino acid b? ihe nd? b? isi nke protein na ak?k? d? mkpa nke an? ah? mmad?, na-ar? ?r? nke nt?ghar? mgbaàmà cell, nhazi ?r? enzyme, ?r? mgbochi na ?r? nd? ?z? na-ar? ?r? physiological.

N'?ba nke amino acid d? na sel na-agbanwekar? na steeti physiological na pathological d? iche iche. Ya mere, otu ah? si ach?p?ta mgbanwe nke ?kwa amino acid ma mee nzaghachi mgbanwe b? nsogbu sayens? d? mkpa nke nr?gide metabolic na mkp?r? nd? cell.

Nh?ta amino acid na-ad?gh? mma nwere njik? chiri anya na ?r?a kansa, ?r?a shuga, ?r?a neurodegenerative na usoro ?ka nká. Ya mere, ?gaghar? usoro mkp?r? nd? nke nnabata amino acid na-ad?gh? mma nwere ike inye ebumnuche ?h?r? maka mgbochi ma ? b? ?gw?gw? nke ?r?a metabolic na ?r?a kansa. Valine, d? ka amino acid d? mkpa nwere alaka, na-ar? ?r? d? mkpa na njik? protein, omume neuro, na ?r?a leukemia. Agbanyegh?, usoro na ?r? nke mmet?ta cellular nke valine ka edobegh? anya.

Na N?vemba 20, 2024, nd? otu Wang Ping si Tongji University School of Medicine / 10th Affiliated People's Hospital bip?tara akw?kw? nyocha nke isiokwu ya b? "Human HDAC6 nwere mmet?ta valine ukwuu iji mezie mmebi DNA" na akw?kw? ak?k? Nature.

?m?m? ihe a ch?p?tara ihe mmet?ta valine-specific novel, deacetylase HDAC6 mmad?, wee kpughee usoro a kap?r? ?n? nke mmachi valine na-eduga na nt?ghar? nuklia nke HDAC6, si otú ah? kwalite ?r? TET2 na ?kpata mmebi DNA.

N'?z? na-akpali mmas?, usoro nh?ta a p?r? iche na primates, na nyocha usoro ?z? gosip?tara na primate HDAC6 nwere kp?mkwem serine-rich glutamate-tetranectide (SE14) na-emeghar? ngalaba ma na-ah?ta ?ba nke valine site na ngalaba a. N'ihe gbasara ?gw?gw? etuto ah?, mmachi valine na-agafegh? oke ma ? b? ngwak?ta nke ihe mgbochi PARP nwere ike igbochi uto tumor nke ?ma.

?m?m? ihe a na-ekpughe usoro ?h?r? nke nr?gide oriri na-edozi ah? na-ach?kwa mmebi DNA site na mgbanwe epigenetic, ma t?p?ta at?mat? ?h?r? maka ?gw?gw? akp? na nri nwere valine na-ejik?ta ya na PARP inhibitors.

Ihe mmet?ta Amino acid na-ach?kar? ijik? amino acid iji mata na zaghachi mgbanwe na ntinye amino acid n'ime na n'èzí cell, iji r?? ?r? nh?ta ha.

Iji ch?p?ta n'usoro n'usoro iji ch?p?ta protein nd? na-ejik?ta valine, a na-eji biotinylated valine probes maka nnwale immunocoprecipitate jik?tara ya na spectrometry mass, na nyocha nke na-enwegh? isi nke protein na-ejik?ta valine b? ihe bayoloji kem?kal? mere.

Nd? ode akw?kw? ch?p?tara na na mgbakwunye na valyl tRNA synthetases a ma ama (VARS), deacetylase HDAC6 gosip?tara ikike njide D-valine siri ike ma e jiri ya t?nyere VARS. Nd? ode akw?kw? ah? kwup?takwara na HDAC6 nwere ike jik?ta valine ozugbo na njik?ta nke Kd ≈ 2μM site na nnwale njik? isotoppe, nnwale isothermal titration calorimetry (ITC) na nnwale ?fefe ?k?. Nyocha nke njirimara nhazi nke amino acid gh?tara site n'?ch?p?ta protein na-enyere aka ?gh?takwu usoro molek?la nke mgbanwe nke ?ba amino acid nke mkp?r? nd? na-ebute. Site n'inyocha nnwale njide nke analogues valine, nd? odee ch?p?tara na HDAC6 na-amata ?d? carboxyl na agb? ak?k? nke valine ma nwee ike ?nabata mgbanwe amino ?n?. Na mgbakwunye, na HDAC6 sel knockout, ?kp?r? nke ?z? akara mTOR site na mmachi valine ad?gh? iche na nke otu njikwa, na-at? aro na njik? a d? iche na usoro mgbama amino acid ?d?nala.

Iji nyochaa ngalaba na ?r? d? mkpa nke HDAC6 sensing valine. Nd? ode akw?kw? ah? kpebisiri ike na HDAC6 na-ejik?ta valine site na ngalaba SE14 ya site na nnwale njide ah? agbat? HDAC6. N'?z? d? ?t?nanya, nd? odee h?r? site na nt?nyere homology na ngalaba SE14 d? naan? na HDAC6 na primates. N'ad?gh? ka primate (mmad? na enwe) HDAC6, òké HDAC6 anagh? ejik?ta na valine. Nch?p?ta a na-ekpughe ?d?iche d? n'etiti ?d? d? iche iche na ntinye valine, na-at? aro na ?d? evolush?n na-ekere òkè d? mkpa na ntinye amino acid.

Dabere na nkwubi okwu na HDAC6 na-ejik?ta valine ozugbo site na ngalaba SE14 ya, nd? na-ede akw?kw? kwuru na mgbanwe na ike njide nke HDAC6 na valine nwere ike imet?ta nhazi ya na ?r? ya mgbe ?bara valine na sel gbanwere. Site na usoro nyocha na jik?tara ya na akw?kw? ak?k? na ?r? d? mkpa nke ngalaba SE14 na njigide cytoplasmic nke HDAC6, nd? na-ede akw?kw? ch?p?tara na ?k? valine intracellular nwere ike ime ka HDAC6 gbanwee na nucleus. Mpaghara enzyme na-ar? ?r? (DAC1 na DAC2) na-ejik?ta na mpaghara n? n'?r? (ngalaba CD) nke DNA hydroxymethylase TET2, na-akwalite deacetylation nke TET2, wee mee ka ?r? enzyme ya r?? ?r?. N'iji usoro methylomics d? ka WGBS, ACE-Seq na MAB-Seq, any? kwadoro na ag?? valine intracellular nwere ike ?kwalite DNA demethylation na-ar? ?r? site na axis HDAC6-TET2. Na mb?, nd? otu Andre Nussenzweig ch?p?tara na thymine DNA glycosylase (TDG) -dependent activation DNA demethylation butere DNA single strand mebiri na neuronal enhancer. Site na ijik? TET2 ChIP-Seq na tekn?z? usoro nr?p?ta d? elu END-Seq na ddC S1 END-Seq, any? kpebiri na ?k? valine na-akwalite mmebi DNA. Nbibi DNA nke ?k? valine kpatara na-adaberekwa na mmebi otu eriri nke TDG mp? nke oxymethylcytosine (5fC/5caC) kpatara.

N'?ch?k?ta ?n?, nd? ode akw?kw? ch?p?tara sens? valine novel na nke mb? k?wap?tara usoro mkp?r? nd? nke valine na-amachi ntinye nke mmebi DNA site na HDAC6-TET2-TDG axis akara, na-agbakwunye ak?k? ?h?r? na ngh?ta nke ?r? nke nr?gide amino acid na mkpebi mkp?r? nd?.

Mgbochi nri ma ? b? ?ch?so amino acid metabolism na ngh?ta ab?r?la at?mat? mgbakwunye maka ?gbat? nd? yana ?gw?gw? nke ?t?t? ?r?a, g?nyere kansa. Nyere na ?k? valine nwere ike ?kpata mmebi DNA, nd? dere nyocha gara n'ihu ma mgbochi valine na-ekere òkè na ?gw?gw? ?r?a kansa. N'ime ?d? ?r?a cancer colorectal xenograft tumor, nri nwere oke valine kwes?r? ekwes? (0.41% valine, w/w) gbochiri uto etuto na obere mmet?ta. Na ma mgbochi na ?gw?gw? d? iche iche, nd? edemede gosip?tara n'ihu na nri na-egbochi valine na-egbochi tumorigenesis na ?ganihu site na iji ?d? ?r?a cancer colorectal PDX. N'omume etuto ah?, ?kwa valine mbelata na-ejik?ta nke ?ma yana mm?ba HDAC6 ntughar? nuklia, ?kwa 5hmC, na mmebi DNA. Ebe ? b? na ?kpata mmebi DNA b? ?gw?gw? anticancer, ? ga-ekwe omume igbochi nr?zi DNA site na iji ihe mgbochi PARP. Nd? ode akw?kw? ch?p?tara na nchikota nke nri na-egbochi valine na PARP inhibitor talazoparib mere ka mmet?ta antitumor d?kwuo mma, na-enye ihe akaebe siri ike maka ?gw?gw? ah? iji gw?? ?r?a kansa site na imebi DNA.

N'ikpeaz?, ?m?m? ah? ch?p?tara na HDAC6 na primates b? protein na-ah? maka valine nke na-adabere na ihe mmet?ta ?d?nala, na-ekpughe ?d?iche d? na valine sensing n'etiti ?d? d? iche iche, na-egosi ?r? d? mkpa nke evolush?n ndu na amino acid sensing.

T?kwas? na nke a, ?m?m? ihe a na-ak?wap?ta usoro ?h?r? nke usoro mmek?r?ta mmek?r?ta nke nr?gide metabolic na-edozi ah?, ?kp?r? epigenetic na mmebi DNA, na-eme ka mkpa nke nr?gide metabolic na-edozi ah? d? na usoro ihe omimi nke nr?gide, ma ch?p?ta na nchikota nke nri na-egbochi valine na nd? na-emechi PARP nwere ike iji d? ka at?mat? ?h?r? maka ?gw?gw? ?r?a cancer.