Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.
Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.
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DOI：
10.1021/cr200085w
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发表时间：
2011-10-12
期刊：
影响因子：
62.1
通讯作者：
Kokotos, George
中科院分区：
文献类型：
--
作者：
Dennis, Edward A.;Cao, Jian;Hsu, Yuan-Hao;Magrioti, Victoria;Kokotos, George
1.1. 磷脂酶是最早被鉴定和研究的酶活性之一，磷脂酶A2 （PLA2）超家族（见图1中定义特异性1）的起源可以追溯到19世纪末对蛇毒裂解作用的鉴定。该酶最初是从眼镜蛇毒液和响尾蛇毒液中纯化和鉴定的。随着20世纪70年代蛋白质测序方法的进步，这些酶的半胱氨酸含量异常高（约占氨基酸的10%），而且作为分泌酶，它们都以二硫键的形式存在。进一步认识到，在PLA2的情况下，眼镜蛇和响尾蛇有六个共同的二硫化物，但一个二硫化物键位于明显不同的位置。这导致眼镜蛇（旧世界的蛇）和响尾蛇（新世界的蛇）分别被指定为1型和2型。在同一时期，对猪胰腺消化酶水解磷脂的研究导致确定这种哺乳动物酶（也是人类胰腺酶）具有与眼镜蛇相同的二硫键模式，因此将眼镜蛇酶命名为IB，而将眼镜蛇酶命名为IA。1988年7月，在第一次FASEB夏季磷脂酶会议上，来自加利福尼亚生物技术公司的Jeffery J. Seilhamer和Lorin K. Johnson以及来自Biogen研究公司的Ruth M. Kramer独立地、大张旗鼓地、兴奋地报道了第一个人类非胰腺分泌PLA2的纯化、测序和克隆，引起了更广泛科学界的注意。他们都是从患关节炎的膝关节的滑膜液中分离出来的。由于序列显示二硫键模式更像响尾蛇而不是人类胰腺酶，因此这种新形式的PLA2被命名为IIA。所有这些酶都被称为分泌酶或sPLA2s。直到20世纪80年代末，pla2样活性才在哺乳动物细胞中被报道，与来自毒液和胰腺的细胞外分泌活性形成对比。1992年7月，在第二届FASEB夏季磷脂酶会议上，遗传学研究所的James D. Clark和Ruth M. Kramer（已转到礼来研究实验室）独立报告了从U937巨噬细胞系中纯化、测序和克隆第一个人细胞质PLA2 （cPLA2）。该序列与分泌酶的序列无关。为了追踪这种新的酶和潜在的其他PLA2s，利用先前存在的毒液名称I和II建立了一个群体编号系统7，并将其扩展到包括IA， IB和IIA亚群（GIA， GIB， GIIA）；对从蜂毒中纯化的明显不同的PLA2加入III组（GIII）；建立新的细胞质PLA2 （cPLA2）的IV组（GIV）名称。这是偶然的，因为不久之后发现了一种新的分泌PLA2。它是由巨噬细胞产生的，它与第一组和第二组有相同的六个二硫键，
1.1. Discovery of the Phospholipase A2 Superfamily Phospholipases represent one of the earliest enzyme activities to be identified and studied, and the phospholipase A2 (PLA2) superfamily (see defining specificity1 in Figure 1) traces its roots to the identification of lytic actions of snake venom at the end of the 19th century. The enzyme was first purified and characterized from cobra venom and later from rattlesnake venom. As protein sequencing methodologies advanced in the 1970s, it became apparent that these enzymes had an unusually large number of cysteines (> 10% of the amino acids) and, as secreted enzymes, that they were all in the form of disulfide bonds. It was further recognized that, in the case of PLA2, cobras and rattlesnakes had six disulfides in common, but one disulfide bond is located in distinctly different locations. This led to the designation of Type 1 and Type 2 for cobras (old world snakes) and rattlesnakes (new world snakes), respectively. 2 During that same period, studies on the porcine pancreatic digestive enzyme that hydrolyzes phospholipids led to the determination that this mammalian enzyme (and also the human pancreatic enzyme) had the same disulfide bonding pattern as cobras and hence the designation as IB with the cobra enzyme as IA. A dramatic change in the phospholipase A2 field that attracted the attention of the broader scientific community occurred in July, 1988, when at the first FASEB Summer Conference on Phospholipases, Jeffery J. Seilhamer and Lorin K. Johnson from California Biotechnology Inc. 3 and Ruth M. Kramer from Biogen Research Corporation4 independently and with much fanfare and excitement reported the purification, sequencing, and cloning of the first human nonpancreatic secreted PLA2, which they each had isolated from the human synovial fluid of arthritic knee joints. Because the sequence revealed that the disulfide bond pattern was more like the rattlesnake than the human pancreatic enzyme, this new form of PLA2 was designated IIA. All of these enzymes then became known as secreted or sPLA2s. It was not until the late 1980s that PLA2-like activities were reported in mammalian cells in contrast to extracellular secreted activities from venom and pancreas. In July, 1992, at the second FASEB Summer Conference on Phospholipases, James D. Clark from the Genetics Institute5 and Ruth M. Kramer (who had moved to Lilly Research Laboratories) 6 independently reported the purification, sequencing, and cloning of the first human cytosolic PLA2 (cPLA2) from the U937 macrophage cell line. The sequence was unrelated to those of the secreted enzymes. To track this new enzyme and potentially additional PLA2s, a group numbering system7 was established utilizing the preexisting venom designation of I and II and expanding them to include subgroups IA, IB, and IIA (GIA, GIB, GIIA); adding group III (GIII) for the clearly different PLA2, which had been purified from bee venom; and establishing the group IV (GIV) designation for the new cytosolic PLA2 (cPLA2). This was fortuitous because soon thereafter a new form of secreted PLA2 was discovered. It was produced by macrophages and it had the same six disulfide bonds as group I and group II,
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