White G A, Elliott W B
Can J Biochem. 1980 Jan;58(1):9-22. doi: 10.1139/o80-003.
Gladiolic acid (GA, 4-methoxy-5-methyl-0-phthalaldehyde-3-carboxylic acid), an antifungal aromatic ortho dialdehyde produced by Penicillium gladioli was found to be a potent inhibitor of electron transport and oxidative phosphorylation reactions in sweet potato and mung bean mitochondria. Similar results were also found with the naturally occurring ortho dialdehydes, cyclopaldic acid, quadrilineatin, and flavipin as well as the synthetic dialdehydes, 3-formyl opianic acid and 0-phthalaldehyde. Because of their highly reactive ortho-diformyl grouping, GA and structurally related dialdehydes apparently act as multisite inhibitors affecting electron transport and oxidative phosphorylation (at each coupling site). Gladiolic acid has no uncoupling effect like 2,4-dinitrophenol and does not have the same point of interaction in the energy transfer process as oligomycin. Several "partial" reactions of phosphorylation (Mg+2-DNP-stimulated ATPase; ATP-Pi exchange) were strongly inhibited by the various dialdehydes. Flavipin and quadrilineatin are potent inhibitors (80% at a concentration of 25 microM) of site III phosphorylation. Gladiolic acid and related ortho dialdehydes inactivate the catalytic activity of native cytochrome c in vitro. Lysyl epsilon-NH2 rich cytochrome c may be a major site of GA action in the intact mitochondrion. In view of the high chemical reactivity of the orthodiformyl group, it is suggested that mitochondrial function may be affected by aromatic ortho dialdehydes through a combination of reactions involving cross-linking of amino groups on membrane polypeptides and monofunctional reaction with free amino groups important for enzyme function, including epsilon-NH2 groups on cytochrome c. Cross-linking in mitochondrial membrane systems might affect function by interfering with molecular motion in the operation of the terminal portion of the electron-transport chain. The primary toxicological mode of action of GA and related dialdehydes appears to be due to inhibition of mitochondrial function.
剑兰酸（GA，4-甲氧基-5-甲基-邻苯二甲醛-3-羧酸）是由剑兰青霉产生的一种抗真菌芳香邻二醛，被发现是甘薯和绿豆线粒体中电子传递和氧化磷酸化反应的有效抑制剂。在天然存在的邻二醛、环戊醛酸、四线菌素和黄曲霉素以及合成二醛、3-甲酰基阿片酸和邻苯二甲醛中也发现了类似结果。由于它们具有高反应性的邻二羰基基团，GA和结构相关的二醛显然作为多位点抑制剂影响电子传递和氧化磷酸化（在每个偶联位点）。剑兰酸没有像2,4-二硝基苯酚那样的解偶联作用，并且在能量转移过程中没有与寡霉素相同的相互作用点。各种二醛强烈抑制磷酸化的几个“部分”反应（Mg+2-DNP刺激的ATP酶；ATP-Pi交换）。黄曲霉素和四线菌素是位点III磷酸化的有效抑制剂（浓度为25 microM时抑制率达80%）。剑兰酸和相关的邻二醛在体外使天然细胞色素c的催化活性失活。富含赖氨酰ε-NH2的细胞色素c可能是完整线粒体中GA作用的主要位点。鉴于邻二羰基基团的高化学反应性，有人提出线粒体功能可能受到芳香邻二醛的影响，其方式是一系列反应的组合，包括膜多肽上氨基的交联以及与对酶功能重要的游离氨基（包括细胞色素c上的ε-NH2基团）的单功能反应。线粒体膜系统中的交联可能通过干扰电子传递链末端部分运作中的分子运动来影响功能。GA和相关二醛的主要毒理学作用模式似乎是由于线粒体功能受到抑制。
