Human phospholipase A2 and related nucleic acid compounds

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase

Reexamination Certificate

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C435S198000, C435S252300, C435S320100, C435S069200, C536S023200, C530S350000

Reexamination Certificate

active

06242206

ABSTRACT:

BACKGROUND OF THE INVENTION
Inflammatory and degenerative disorders account for a significant number of debilitating diseases. Inflammatory states, such as arthritis, psoriasis, asthma, and possibly atherosclerosis, stem from inflammatory reactions in the joints, skin, and blood vessels. It is generally believed that a central role in the inflammatory reaction is the production of phospholipid metabolites called eicosanoids. The eicosanoids represent a family of important mediators such as the leukotrienes, prostaglandins, lipoxins, hydroxyeicosatetreanoic acid, and thromboxanes. It is believed that the generation of eicosanoids is -dependent on the availability of arachidonic acid which is liberated from phospholipids by the action of phospholipase A
2
(EC 3.1.1.4).
Phospholipase A
2
(PLA
2
) is the common name for phosphatide 2-acylhydrolase, which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides which results in the production of equimolar amounts of lysophospholipids and free fatty acids. see E. A. Dennis, TBE ENZYMES, Vol. 16, Academic Press, New York, (1983). Phospholipase A
2
enzymes are found in all living species and form a diverse family of enzymes. Over eighty phospholipase A2 enzymes have been structurally characterized, and they show a high degree of sequence homology. J. Chang, et al.,
Biochemical Pharmacology.
36:2429-2436, (1987); F. F. Davidson and E. A. Dennis,
Journal of Molecular Evolution,
31:228-238 (1990).
The best characterized varieties of PLA
2
enzyme are the secreted forms, which are released into the extracellular environment where they aid in the digestion of biological materials. The secreted forms have a molecular weight of about 12-15,000 (Davidson and Dennis, supra). In contrast, cytosolic phospholipases A
2
are found in small amounts within the cell and play a key role in the biosynthetic pathway leading to the formation of the platelet activating factors and the eicosanoids. R. M. Kramer, SIGNAL-ACTIVATED PHOSPHOLIPASES, (M. Liscontdi, ed. 1994) pp. 13-30; J. D. Sharp, et al.,
Journal of Biological Chemistry,
266:14850-14853 (1991).
The cytosolic phospholipases A
2
have a molecular weight of approximately 85,000 daltons. J. D. Clark, et al.,
Cell,
65:1043-1051 (1991). Free arachidonic acid is the rate limiting precursor for the production of eicosanoids and is liberated from its membrane phospholipid store by the action of cytosolic PLA
2
. E. A. Dennis,
Drug Development and Research,
10:205-220, (1987). The same enzymatic step also produces lysophospholipids which may be converted to platelet-activating factors. Thus, it is believed that cytosolic PLA
2
is central to the regulation of the biosynthetic pathways of potent lipid mediators of inflammation.
Recent studies have begun to indicate that a major component of the pathology of Alzheimer's disease is chronic inflammation. See, J. Schnabel,
Science,
260:1719-1720 (1993). Indeed, pathological investigations have demonstrated the presence of glial hyperactivity, acute phase proteins, and complement factors within affected areas of the brains of persons affected with Alzheimer's disease. Administration of nonsteroidal anti-inflammatory drugs appears to slow the advance of Alzheimer's disease. Id. Understanding this inflammatory component of Alzheimer's disease, therefore, will lead to advances in novel methods of treating patients suffering from this disease.
Due to the central role in the inflammatory component of Alzheimer's disease that appears to be played by cytosolic phospholipase A
2
, it is desirable to identify and characterize new inhibitors of this enzyme. The present invention provides a novel phospholipase A
2
, nucleic acids encoding this enzyme, and assays which may be employed to identify inhibitors having a therapeutic benefit.
SUMMARY OF THE INVENTION
This invention provides an isolated amino acid compound useful as a phospholipase A
2
, said compound comprising the amino acid sequence
Met Met Pro Ala Glu Arg Arg Leu Pro Leu Ser Phe Val Leu Asp Val
  1               5                  10                  15

Leu Glu Gly Arg Ala Gln His Pro Gly Val Leu Tyr Val Gln Lys Gln
             20                  25                  30

Cys Ser Asn Leu Pro Ser Glu Leu Pro Gln Leu Leu Pro Asp Leu Glu
         35                  40                  45

Ser His Val Pro Trp Ala Ser Glu Ala Leu Gly Lys Met Pro Asp Ala
     50                  55                  60

Val Asn Phe Trp Leu Gly Glu Ala Ala Ala Val Thr Ser Leu His Lys
65                  70                  75                  80

Asp His Tyr Glu Asn Leu Tyr Cys Val Val Ser Gly Glu Lys His Phe
                 85                  90                  95

Leu Phe His Pro Pro Ser Asp Arg Pro Phe Ile Pro Tyr Glu Leu Tyr
            100                 105                 110

Thr Pro Ala Thr Tyr Gln Leu Thr Glu Glu Gly Thr Phe Lys Val Val
        115                 120                 125

Asp Glu Glu Ala Met Glu Lys Ala Glu Val Ser Arg Thr Cys Leu Leu
    130                 135                 140

Thr Val Arg Val Leu Gln Ala His Arg Leu Pro Ser Lys Asp Leu Val
145                 150                 155                 160

Thr Pro Ser Asp Cys Tyr Val Thr Leu Trp Leu Pro Thr Ala Cys Ser
                165                 170                 175

His Arg Leu Gln Thr Arg Thr Val Lys Asn Ser Ser Ser Ser Val Trp
            180&emsp

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