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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression
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COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression

机译：对乙酰氨基酚和其他止痛/解热药抑制的环氧合酶1变体COX-3的克隆，结构和表达

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摘要

Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1 a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an ≈5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1 a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1 a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
机译：已知两种环氧合酶同工酶COX-1和-2可催化前列腺素合成的限速步骤，并且是非甾体类抗炎药的目标。在这里，我们描述了第三个不同的COX同工酶COX-3，以及两个较小的COX-1衍生蛋白（部分COX-1或PCOX-1蛋白）。 COX-3和一种PCOX-1蛋白（PCOX-1 a）由COX-1基因制成，但在其mRNA中保留了内含子1。 PCOX-1蛋白还含有COX-1 mRNA外显子5-8的框内缺失。 COX-3和PCOX mRNA在犬的大脑皮层中表达，在其他组织中的表达量较少。在人类中，COX-3 mRNA的表达约为5.2kb，在大脑皮层和心脏中含量最高。内含子1在哺乳动物COX-1基因中的长度和序列均保守。该内含子包含一个ORF，该ORF会将30-34aa的氨基酸（取决于哺乳动物的种类）插入疏水信号肽中，该信号肽将COX-1引入内质网和核膜的内腔。 COX-3和PCOX-1a作为膜结合蛋白在昆虫细胞中有效表达。信号肽未从任何一种蛋白质上切下，并且两种蛋白质都被糖基化。 COX-3，而不是PCOX-1 a，具有糖基化依赖性的环氧合酶活性。犬COX-3活性与鼠COX-1和-2的比较表明，该酶被对乙酰氨基酚，非那西丁，安替比林和双嘧啶等镇痛/解热药选择性抑制，并被某些非甾体类抗炎药有效抑制。因此，抑制COX-3可能代表了这些药物减轻疼痛甚至发烧的主要中心机制。

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