Identification of the putative tumor suppressor Nit2 as omega-amidase, an enzyme metabolically linked to glutamine and asparagine transamination.
Identification of the putative tumor suppressor Nit2 as omega-amidase, an enzyme metabolically linked to glutamine and asparagine transamination.
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DOI：
10.1016/j.biochi.2009.07.003
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发表时间：
2009-09
期刊：
影响因子：
3.9
通讯作者：
Cooper, Arthur J. L.
中科院分区：
文献类型：
--
作者：
Krasnikov, Boris F.;Chien, Chin-Hsiang;Nostramo, Regina;Pinto, John T.;Nieves, Edward;Callaway, Myrasol;Sun, Jin;Huebner, Kay;Cooper, Arthur J. L.
本报告确定了哺乳动物腈水解酶样（Nit）家族成员的酶底物。Nit 2广泛存在于自然界中，被认为是一种肿瘤抑制蛋白。基于与其他酰胺酶的序列同源性和假定的酰胺酶样活性位点的存在，假定该蛋白质是酰胺酶。这一假设最近被小鼠Nit 2晶体结构的出版物所证实。然而，体内底物先前未被鉴定。本文报道大鼠肝脏Nit 2是ω-酰胺二羧酸酰胺水解酶（E.C. 3.5.1.3;缩写为ω-酰胺酶），一种广泛表达的酶，其催化多种酰胺酶、转酰胺酶、酯酶和酯交换反应。体内酰胺酶底物为α-酮戊二酰胺酸和α-酮琥珀酰胺酸，分别由谷氨酰胺和天冬酰胺的转氨作用产生。谷氨酰胺转氨酶用于挽救通过非特异性转氨反应产生的许多α-酮酸（特别是必需氨基酸）。天冬酰胺转氨作用似乎在线粒体代谢和光呼吸中是有用的。谷氨酰胺转氨酶在甲硫氨酸补救途径的关键组分α-酮基-γ-甲硫羟丁酸转氨酶中发挥特别重要的作用。一些证据表明，过量的α-酮戊二酸可能具有神经毒性。此外，α-酮基琥珀酰胺酸酯不稳定，容易转化为许多可能有毒的杂芳族化合物。因此，ω-酰胺酶的一个重要作用是通过将α-酮戊二酰胺酸和α-酮琥珀酰胺酸分别转化为生物学上有用的α-酮戊二酸和草酰乙酸来去除潜在的毒性中间体。尽管它在氮和硫代谢中的重要性，ω-酰胺酶的生物化学意义在很大程度上被忽视。我们的报告可能提供有关Nit 1（Nit家族的另一个成员，这是一种公认的肿瘤抑制蛋白）的生物酰胺酶底物的性质的线索，并强调了a）Nit 2在氮和硫代谢中的关键作用，以及B）Nit 2与癌症生物学的可能联系。
The present report identifies the enzymatic substrates of a member of the mammalian nitrilase-like (Nit) family. Nit2, which is widely distributed in nature, has been suggested to be a tumor suppressor protein. The protein was assumed to be an amidase based on sequence homology to other amidases and on the presence of a putative amidase-like active site. This assumption was recently confirmed by the publication of the crystal structure of mouse Nit2. However, the in vivo substrates were not previously identified. Here we report that rat liver Nit2 is ω-amidodicarboxylate amidohydrolase (E.C. 3.5.1.3; abbreviated ω-amidase), a ubiquitously expressed enzyme that catalyzes a variety of amidase, transamidase, esterase and transesterification reactions. The in vivo amidase substrates are α-ketoglutaramate and α-ketosuccinamate, generated by transamination of glutamine and asparagine, respectively. Glutamine transaminases serve to salvage a number of α-keto acids generated through non-specific transamination reactions (particularly those of the essential amino acids). Asparagine transamination appears to be useful in mitochondrial metabolism and in photorespiration. Glutamine transaminases play a particularly important role in transaminating α-keto-γ-methiolbutyrate, a key component of the methionine salvage pathway. Some evidence suggests that excess α-ketoglutaramate may be neurotoxic. Moreover, α-ketosuccinamate is unstable and is readily converted to a number of hetero aromatic compounds that may be toxic. Thus, an important role of ω-amidase is to remove potentially toxic intermediates by converting α-ketoglutaramate and α-ketosuccinamate to biologically useful α-ketoglutarate and oxaloacetate, respectively. Despite its importance in nitrogen and sulfur metabolism, the biochemical significance of ω-amidase has been largely overlooked. Our report may provide clues regarding the nature of the biological amidase substrate(s) of Nit1 (another member of the Nit family), which is a well-established tumor suppressor protein), and emphasizes a) the crucial role of Nit2 in nitrogen and sulfur metabolism, and b) the possible link of Nit2 to cancer biology.
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5.2
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通讯作者：
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