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Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors

機(jī)譯：芳香族氨基酸羥化酶作為組蛋白脫乙酰酶抑制劑的脫靶點(diǎn)

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The aromatic amino acid hydroxylases (AAAHs) phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylases 1 and 2 are structurally related enzymes that contain an active site iron atom and depend on tetrahydrobiopterin (BH4) as cosubstrate. Due to their important roles in synthesis of serotonin, dopamine, noradrenaline, and adrenaline and their involvement in cardiovascular, neurological, and endocrine disorders, AAAHs have been targeted by substrate analogs, iron chelators, and allosteric ligands. Phenylalanine hydroxylase is also off-target of the histone deacetylase (HDAC) inhibitor panobinostat. To systematically explore the binding of HDAC inhibitors to AAAHs, we screened a library of 307 HDAC inhibitors and structural analogs against tryptophan hydroxylase 1 using a fluorescence-based thermal stability assay, followed by activity assays. Selected hits were enzymatically tested against all four purified human AAAHs. Cellular thermal shift assay was performed for phenylalanine hydroxylase. We show that panobinostat and structurally related compounds such as TB57, which similarly to panobinostat also contains a cinnamoyl hydroxamate, bind to human AAAHs and inhibit these enzymes with high selectivity within the class (panobinostat inhibition (IC50): phenylalanine hydroxylase (18 nM) > tyrosine hydroxylase (450 nM) > tryptophan hydroxylase 1 (1960 nM). This study shows that panobinostat and related hydroxamic acid type HDAC inhibitors inhibit all AAAHs at therapeutically relevant concentrations. Our results warrant further investigations of the off-target relevance of HDAC inhibitors intended for clinical use and provide directions for new dual HDAC/AAAH and selective AAAH inhibitors. These findings may also provide a new mechanistic link between regulation of histone modification, AAAH function, and monoaminergic neurotransmission.
機(jī)譯：芳香族氨基酸羥化酶 （AAAH）、苯丙氨酸羥化酶、酪氨酸羥化酶和色氨酸羥化酶 1 和 2 是結(jié)構(gòu)相關(guān)的酶，含有活性位點(diǎn)鐵原子，并依賴于四氫生物蝶呤 （BH4） 作為共底物。由于 AAAH 在血清素、多巴胺、去甲腎上腺素和腎上腺素的合成中發(fā)揮重要作用，并且參與心血管、神經(jīng)和內(nèi)分泌疾病，因此 AAAH 已成為底物類似物、鐵螯合劑和變構(gòu)配體的靶標(biāo)。苯丙氨酸羥化酶也是組蛋白脫乙酰酶 （HDAC） 抑制劑 panobinostat 的脫靶目標(biāo)。為了系統(tǒng)地探索 HDAC 抑制劑與 AAAH 的結(jié)合，我們使用基于熒光的熱穩(wěn)定性測(cè)定篩選了 307 種 HDAC 抑制劑和針對(duì)色氨酸羥化酶 1 的結(jié)構(gòu)類似物，然后進(jìn)行活性測(cè)定。針對(duì)所有四種純化的人 AAAH 對(duì)選定的命中進(jìn)行酶促測(cè)試。對(duì)苯丙氨酸羥化酶進(jìn)行細(xì)胞熱轉(zhuǎn)移測(cè)定。我們表明，panobinostat 和結(jié)構(gòu)相關(guān)化合物如 TB57，與 panobinostat 類似，也含有肉桂酰異羥肟酸鹽，與人 AAAH 結(jié)合并以高選擇性抑制這些酶（panobinostat 抑制 （IC50）：苯丙氨酸羥化酶 （18 nM） >酪氨酸羥化酶 （450 nM） >色氨酸羥化酶 1 （1960 nM）。這項(xiàng)研究表明，panobinostat 和相關(guān)的異羥肟酸型 HDAC 抑制劑在治療相關(guān)濃度下抑制所有 AAAH。我們的結(jié)果值得進(jìn)一步研究用于臨床的 HDAC 抑制劑的脫靶相關(guān)性，并為新的雙重 HDAC/AAAH 和選擇性 AAAAH 抑制劑提供方向。這些發(fā)現(xiàn)還可能提供組蛋白修飾調(diào)節(jié)、AAAH 功能和單胺能神經(jīng)傳遞之間的新機(jī)制聯(lián)系。

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