Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Isomerase
Patent
1995-12-28
1998-09-29
Wax, Robert A.
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Isomerase
4353201, 435325, 4352523, 514 44, 536 232, 935 22, A01N 4304, C12N 990, C12N 500, C07H 2104
Patent
active
058145095
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a polypeptide having an amino acid sequence of human-originated prostacyclin synthase (hereinafter referred to as PGIS), a DNA encoding same, a vector containing said DNA, a host cell transformed with said vector and a method for preparing human-originated PGIS comprising culturing said host cell. The present invention also relates to an antibody having a reactivity with said PGIS or its fragment. Moreover, the present invention relates to a pharmaceutical composition comprising said DNA or a vector containing said DNA, a method for promoting the production of prostaglandin I.sub.2 and a method for the treatment of the diseases induced by a low production of prostaglandin I.sub.2.
BACKGROUND ART
PGIS is mainly contained in microsomal fractions of vascular endothelial cells, and is an enzyme that catalyzes synthesis of prostaglandin I.sub.2 (hereinafter referred to as PGI.sub.2), that is, conversion of prostaglandin H.sub.2 (hereinafter referred to as PGH.sub.2) to PGI.sub.2.
PGI.sub.2 synthesized by this enzyme has potent platelet aggregation-inhibitory action and vascular smooth muscle-relaxing action. On the other hand, platelets contain thromboxane A.sub.2 (hereinafter referred to as TXA.sub.2) having strong platelet aggregation action and vascular smooth muscle-contracting action, and the both substances act Journal of Pharmacology, vol. 76, p 3 (1982)!.
Cardiovascular diseases such as myocardial infarction, thrombosis and arteriosclerosis, which are among the adult diseases, have recently been considered to be caused by the imbalance in the vascular production of PGI.sub.2 and TXA2, particularly, insufficient vascular function due to low production of PGI.sub.2 (ibid.).
For the therapeutic treatment of the diseases presumably induced by the low production of PGI.sub.2, PGI.sub.2 may be supplemented as a pharmaceutical product from the outside of the body. However, PGI.sub.2 is chemically extremely unstable to the extent that a practical use of PGI.sub.2 itself as a pharmaceutical product may be unrealizable. In view of such situation, for example, stable PGI.sub.2 analogs such as blood coagulation inhibitor or vasodilator are under development.
The homeostasis in human and other animals which is inherently based on the balance between PGI.sub.2 and TXA2 may possibly destroyed by the administration of stable PGI.sub.2 analogs. That is, administration of stable PGI.sub.2 analogs in large amounts is associated with a risk of lowering the responsiveness of cells to PGI.sub.2, thus impairing its capability of responding to PGI.sub.2 when such responsiveness is in
For correcting the imbalance between PGI.sub.2 and TXA.sub.2 and attempting the recovery of normal functions of the vascular system in an expectation of therapeutic effect over thrombosis and the like, chemically stable analogs may be used. Alongside therewith, moreover, elucidation of physicochemical property and biological property of PGIS, clarification of the relations between PGIS production and PGI.sub.2 production while using said PGIS or DNA encoding PGIS as a research sample, and development of said PGIS or DNA encoding PGIS as pharmaceutical products to regulate the production of PGI.sub.2 are considered to be important and significant for the treatment of the above-said various diseases caused by the imbalance between PGI.sub.2 and TXA.sub.2.
Conventionally, there has been reported the tissue distribution of PGIS, namely, its presence in vascular endothelial cells, non-vascular smooth Prostaglandin, Thromboxane, and Leukotriene Research, vol. 11, pp. 87-92 (1983) and J. Biol. Chem., vol. 258, No. 9, pp. 5922-5926 (1983)!. Meanwhile, isolation and purification of PGIS from porcine and bovine have Environmental Implications, pp. 103-106 (1982); bovine: J. Biol. Chem., vol. 258, No. 9, pp. 3285-3293 (1983)! and N-terminal amino acid sequence and partial downstream amino acid sequence of bovine PGIS have been Research, vol. 17, pp. 29-33 (1987) and Biochemical and Biophysical Research Com
REFERENCES:
Bimodal Distribution of the Prostaglandin I.sub.2 Synthase Antigen in Smooth Muscle Cells, W. Smith et al, The Journal of Biological Chemistry, pp. 5922-5926, dtd. 1983.
Purification, Quantitation, and Localization of PGI.sub.2 Synthase Using Monoclonal Antibodies, W. Smith et al, pp. 87-92, dtd. 1983.
Eighth Gaddum Memorial Lecture University of London Institute of Education Dec. 1980, Biological Importance of Prostacyclin, S. Moncada, pp. 1-31, dtd 1982.
Agonist-Specific Desensitization of PGI.sub.2 -Stimulated Cyclic AMP Accumulation by PGE.sub.1 In Human Foreskin Fibroblasts, R. Gorman et al, pp. 3-17, dtd. 1980.
Cytochrome P-450, Biochemistry, Biophysics and Environmental Implications, Proceedings of the 4th International Conference on Cytochrome P-450 held in Kuopio, Finland, May 31-Jun. 3, 1982, E. Hietanen et al, eds., pp. 103-106, dtd. 1982.
Purification of Prostacyclin Synthase from Bovine Aorta By Immunoaffinity Chromatography, D. DeWitt et al, The Journal of Biological Chemistry, pp. 3285-3293, dtd. Mar. 1983.
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Molecular Cloning and Chracterization of Bovine Prostacyclin Synthase, Biochemical and Biophysical Research Communications, B. Pereira et al, pp. 59-65, dtd. 1994.
Ngo et al. (1994) Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox. In: The Protein Folding Proble and Tertiary Structure Prediction, Eds. Merz et al., Birkhauser, Boston, MA, pp. 491-495, Jan. 1994.
Stole Einar
Wax Robert A.
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