Identification of human prostaglandin E synthase:: A microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target

被引:854
作者
Jakobsson, PJ [1 ]
Thorén, S
Morgenstern, R
Samuelsson, B
机构
[1] Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden
[2] Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden
关键词
D O I
10.1073/pnas.96.13.7220
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Human prostaglandin (PG) E synthase (EC 5.3.99.3) is a member of a recently recognized protein superfamily consisting of membrane associated proteins involved in eicosanoid and glutathione metabolism (the MAPEG family). Previous designations of the protein are PIG12 and MGST1-L1. PGE synthase was expressed in Escherichia coli, and both cytosolic and membrane fractions were prepared. Western blot analysis specifically detected a 15- to 16-kDa protein in the membrane fraction. Both fractions were incubated with prostaglandin H-2 in the presence or absence of reduced glutathione, The membrane but not the cytosolic fraction was found to possess high glutathione-dependent PGE synthase activity (0.25 mu mol/min/mg). The human tissue distribution was analyzed by Northern blot analysis. High expression of PGE synthase mRNA was detected in A549 and HeLa cancer cell lines. Intermediate level of expression was demonstrated in placenta, prostate, testis, mammary gland, and bladder whereas lon mRNA expression was observed in several other tissues. A549 cells have been used as a model system to study cyclooxygenase-2 induction by IL-1 beta, If A549 cells were grown in the presence of IL-1 beta, a significant induction of the PGE synthase was observed by Western blot analysis. Also, Western blot analysis specifically detected a 16-kDa protein in sheep seminal vesicles. In summary, we have identified a human membrane bound PGE synthase. The enzyme activity is glutathione-dependent, and the protein expression is induced by the proinflammatory cytokine IL-1 beta, PGE synthase is a potential novel target for drug development.
引用
收藏
页码:7220 / 7225
页数:6
相关论文
共 32 条
  • [1] Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2
    Brock, TG
    McNish, RW
    Peters-Golden, M
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (17) : 11660 - 11666
  • [2] Burgess JR, 1997, BIOCHEM MOL BIOL INT, V41, P217
  • [3] Cyclooxygenase in biology and disease
    Dubois, RN
    Abramson, SB
    Crofford, L
    Gupta, RA
    Simon, LS
    Van De Putte, LBA
    Lipsky, PE
    [J]. FASEB JOURNAL, 1998, 12 (12) : 1063 - 1073
  • [4] DUCHESNE MJ, 1978, PROSTAG OTH LIPID M, V15, P19, DOI 10.1016/S0090-6980(78)80003-3
  • [5] Fersht A., 1985, ENZYME STRUCTURE MEC
  • [6] DETECTION AND ISOLATION OF AN ENDOPEROXIDE INTERMEDIATE IN PROSTAGLANDIN BIOSYNTHESIS
    HAMBERG, M
    SAMUELSS.B
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1973, 70 (03) : 899 - 903
  • [7] ISOLATION AND STRUCTURE OF 2 PROSTAGLANDIN ENDOPEROXIDES THAT CAUSE PLATELET-AGGREGATION
    HAMBERG, M
    SVENSSON, J
    WAKABAYASHI, T
    SAMUELSSON, B
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1974, 71 (02) : 345 - 349
  • [8] HAMBERG M, 1967, J BIOL CHEM, V242, P5336
  • [9] BIOSYNTHESIS OF PROSTAGLANDIN-E1 BY HUMAN SEMINAL-VESICLES
    HAMBERG, M
    [J]. LIPIDS, 1976, 11 (03) : 249 - 250
  • [10] Prostaglandin synthase 2
    Herschman, HR
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1996, 1299 (01): : 125 - 140