Chemopreventive mechanisms of α-keto acid metabolites of naturally occurring organoselenium compounds.
Chemopreventive mechanisms of α-keto acid metabolites of naturally occurring organoselenium compounds.
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DOI：
10.1007/s00726-010-0578-3
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发表时间：
2011-06
期刊：
影响因子：
3.5
通讯作者：
Cooper, Arthur J. L.
中科院分区：
文献类型：
--
作者：
Pinto, John T.;Lee, Jeong-In;Sinha, Raghu;MacEwan, Melanie E.;Cooper, Arthur J. L.
关键词：
以往关于膳食硒的化学预防机制的研究主要集中在其与抗氧化硒蛋白的结合上，如谷胱甘肽过氧化物酶和硫氧还蛋白还原酶。然而，一些研究表明，膳食中以l -硒代蛋氨酸和第21氨基酸硒半胱氨酸形式存在的硒也具有内在的抗癌特性。先前研究的有助于其抗癌作用的生化机制涉及β-和γ-裂解酶反应。一些含吡哆醛5′-磷酸（PLP）的酶能与se -甲基-l -硒代半胱氨酸（MSC）催化β-裂解酶反应，生成丙酮酸和氨。其他plp酶可催化γ-裂解酶与l -硒代蛋氨酸（SM）反应生成α-酮丁酸盐和氨。在这两种情况下，声称的第三种产物是甲基硒醇（CH3SeH）。虽然不能直接量化，但由于其极端疏水性和高蒸气压，已间接观察到CH3SeH通过改变氧化还原反应信号和转录因子上的蛋白质巯基部分起作用，从而维持非增殖的细胞内环境。我们已经考虑了通过转氨化和/或l -氨基酸氧化酶反应产生的MSC（即甲基硒丙酮酸酯；MSP）和SM（即α-酮-γ-甲基硒丁酸酯；KMSB）的α-酮酸类似物也可能具有化学保护作用。事实上，这些化合物被证明可以增加人类前列腺和结肠癌细胞中组蛋白h3乙酰化的水平。MSP和KMSB在结构上类似于几种组蛋白去乙酰化酶的抑制剂丁酸盐。因此，MSC和SM的硒α-酮酸代谢物，以及β-和γ-裂解酶反应产生的CH3SeH，可能是有机硒的潜在直接作用代谢物，导致沉默的肿瘤抑制蛋白的去抑制和/或基因和信号分子的调节。
Previous studies on the chemopreventive mechanisms of dietary selenium have focused on its incorporation into antioxidative selenoproteins, such as glutathione peroxidase and thioredoxin reductase. Several studies, however, have revealed that dietary selenium in the form of L-selenomethionine and the 21st amino acid, selenocysteine, also have intrinsic anti-cancer properties. Biochemical mechanisms previously investigated to contribute to their anticancer effects involve β- and γ-lyase reactions. Some pyridoxal 5′-phosphate (PLP)-containing enzymes can catalyze a β-lyase reaction with Se-methyl-L-selenocysteine (MSC) generating pyruvate and ammonia. Other PLP-enzymes can catalyze a γ-lyase reaction with L-selenomethionine (SM) generating α-ketobutyrate and ammonia. In both cases, a purported third product is methylselenol (CH3SeH). Although not directly quantifiable, as a result of its extreme hydrophobicity and high vapor pressure, CH3SeH has been indirectly observed to act through the alteration of protein-sulfhydryl moieties on redox-responsive signal and transcription factors, thereby maintaining a non-proliferative intracellular environment. We have considered the possibility that α-keto acid analogues of MSC (i.e., methylselenopyruvate; MSP) and SM (i.e., α-keto-γ-methylselenobutyrate; KMSB), generated via a transamination and/or L-amino acid oxidase reaction may also be chemoprotective. Indeed, these compounds were shown to increase the level of histone-H3 acetylation in human prostate and colon cancer cells. MSP and KMSB structurally resemble butyrate, an inhibitor of several histone deacetylases. Thus, the seleno α-keto acid metabolites of MSC and SM, along with CH3SeH derived from β- and γ-lyase reactions, may be potential direct-acting metabolites of organoselenium that lead to de-repression of silenced tumor suppressor proteins and/or regulation of genes and signaling molecules.
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