Control of Prostaglandin Stereochemistry at the 15-Carbon by Cyclooxygenases-1 and -2
Control of Prostaglandin Stereochemistry at the 15-Carbon by Cyclooxygenases-1 and -2
复制标题
环加氧酶-1和-2对前列腺素15位碳立体化学的控制
DOI：
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发表时间：
2002
影响因子：
4.8
通讯作者：
A. Brash
中科院分区：
文献类型：
--
作者：
C. Schneider;W. Boeglin;J. Prusakiewicz;S. Rowlinson;L. Marnett;N. Samel;A. Brash
Prostaglandin synthesis by cyclooxygenases-1 and -2 (COX-1 and COX-2) involves an initial oxygenation of arachidonic acid at C-11, followed by endoperoxide and cyclopentane ring formation, and then a second reaction with molecular oxygen in the Sconfiguration at C-15. The resulting 15S-hydroxyl group of prostaglandins is crucial for their bioactivity. Using human COX-1 and human and murine COX-2, we have identified two amino acids located in the oxygenase active site that control the stereochemistry at C-15. The most crucial determinant is Ser-530, the residue that is acetylated by aspirin. In COX-2, site-directed mutagenesis of Ser-530 to methionine, threonine, or valine produced highly active enzymes that formed 82–95% 15R-configuration prostaglandins; these have the opposite stereochemistry at C-15 to the natural products. In COX-1, the corresponding Ser-530 mutations inactivated the enzyme. The second residue, Val-349, exerts a more subtle influence. When Val-349 was replaced by isoleucine, the mutant COX-1 and COX-2 enzymes formed 41 and 65% 15R-prostaglandins, respectively. This change was highly specific for isoleucine, as mutations of Val-349 to alanine, leucine, asparagine, or threonine did not alter or only slightly altered (≤13%) the S-configuration at C-15. These results establish a previously unrecognized role for Ser-530 and Val-349 in maintaining the correct S stereochemistry of the carbon-15 hydroxyl group during prostaglandin synthesis. The findings may also explain the absolute conservation of Ser-530, the target of aspirin, throughout the families of cyclooxygenase enzymes.
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影响因子：
56.9
作者：
Malkowski, MG;Ginell, SL;Garavito, RM
通讯作者：
Garavito, RM
DOI：
10.1016/s0021-9258(17)36820-5
发表时间：
1994-05
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Lecomte;O. Laneuville;Chuan Ji;D L DeWitt;William L. Smith
通讯作者：
M. Lecomte;O. Laneuville;Chuan Ji;D L DeWitt;William L. Smith
培养上皮细胞中药理学上独特的前列腺素 H 合酶的鉴定。
DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Holtzman,MJ;Turk,J;Shornick,LP
通讯作者：
Shornick,LP
DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Shimokawa,T;Smith,WL
通讯作者：
Smith,WL