Conversion of canavanine to alpha-keto-gamma-guanidinooxybutyrate and to vinylglyoxylate and 2-hydroxyguanidine.
Conversion of canavanine to alpha-keto-gamma-guanidinooxybutyrate and to vinylglyoxylate and 2-hydroxyguanidine.
复制标题
将刀豆氨酸转化为α-酮-γ-胍基羟基丁酸酯以及乙烯基乙醛酸酯和2-羟基胍。
DOI：
10.1016/0003-9861(89)90553-5
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发表时间：
1989
影响因子：
3.9
通讯作者：
Cooper,AJ
中科院分区：
文献类型：
--
作者：
Hollander,MM;Reiter,AJ;Horner,WH;Cooper,AJ
先前观察到，2-氨基-4-胍氧基丁酸刀豆碱(2-氨基-4-胍氧基丁酸酯)与氨基酸氧化酶反应生成羟基胍。本工作表明羟基胍是由β，-γ-C上的酶氧化后的非酶α消除反应生成的，而β-H的提取是一般碱催化的。消除反应需要在α位置上存在一个阴离子稳定基团-质子化的亚氨基(亚胺基团)或羰基。亚胺离子基团比羰基更活泼。鸟嘌呤氧基的质子化进一步促进了消除。在消除反应中形成的另一种产物被鉴定为乙二酸乙烯酯(2-氧代-3-丁烯酸)，一种非常亲电的物质。氧化后的水解产物被鉴定为α-酮-γ-胍氧基丁酸酯(酮钒)。羟基胍与酮钒的比例取决于碱性催化剂的浓度和碱性程度以及pH。在氨基脲存在下，由于缩氨基上的亚氨基没有被明显质子化，消除反应被阻止。刀豆素与5‘-脱氧吡哆醛孵育也产生了羟基胍。由于消除反应是在温和的条件下进行的，它们可以在体内发生在l-刀豆氨酸的α-C处(内源性摄入或形成)或其他在γ-位有良好离开基团的氨基酸(如S-腺苷蛋氨酸、蛋氨酸亚硫胺、同型半胱氨酸或半胱氨酸-同型半胱氨酸混合二硫化物)被ANL-氨基酸氧化酶、转氨酶或脱氢酶氧化后发生。因此，乙二酸乙烯酯在哺乳动物体内可能是一种正常的代谢物，在较高的浓度下可能会导致刀豆碱和上述一些其他氨基酸的体内毒性。
It was observed previously that hydroxyguanidine is formed in the reaction of canavanine(2-amino-4-guanidinooxybutanoate) with amino acid oxidases. The present work shows that hydroxyguanidine is formed by a nonenzymatic β,-γ-elimination reaction following enzymatic oxidation at the α-C and that the abstraction of the β-H is general-base catalyzed. The elimination reaction requires the presence in the α-position of an anion-stabilizing group—the protonated imino group (iminium ion group) or the carbonyl group. The iminium ion group is more activating than the carbonyl group. Elimination is further facilitated by protonation of the guanidinooxy group. The other product formed in the elimination reaction was identified as vinylglyoxylate (2-oxo-3-butenoate), a very highly electrophilic substance. The product resulting from hydrolysis following oxidation was identified as α-keto-γ-guanidinooxybutyrate (ketocanavanine). The ratio of hydroxyguanidine to ketocanavanine depended upon the concentration and degree of basicity of the basic catalyst and on pH. In the presence of semicarbazide, the elimination reaction was prevented because the imino group in the semicarbazone derivative of ketocanavanine is not significantly protonated. Incubation of canavanine with 5′-deoxypyridoxal also yielded hydroxyguanidine. Since the elimination reactions take place under mild conditions, they may occurin vivofollowing oxidation at the α-C ofl-canavanine (ingested or formed endogenously) or of other amino acids with a good leaving group in the γ-position (e.g.,S-adenosylmethionine, methionine sulfoximine, homocyst(e)ine, or cysteine-homocysteine mixed disulfide) by anl-amino acid oxidase, a transaminase, or a dehydrogenase. Therefore, vinylglyoxylate may be a normal metabolite in mammals which at elevated concentrations may contribute to thein vivotoxicity of canavanine and of some of the other above-mentioned amino acids.