DNA sequences for matrix metalloproteases, their production and

Details DNA sequences for matrix metalloproteases, their production and DNA sequences for matrix metalloproteases, their production and

1996-11-20

2000-09-05

Prouty, Rebecca E.

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

435212, 435226, 435325, 435410, 43525233, 4353201, 536 231, 536 232, 536 235, C07H 2104, C12N 950

Patent

active

061141593

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The invention relates to DNA sequences for human matrix metalloproteases as well as to homologous sequences derived therefrom. It furthermore relates to the proteins and protein variants, coded by the DNA sequences, their expression, preparation and utilization. Areas of application are molecular biological, medical and pharmaceutical research, medical diagnosis and therapy and the pharmaceutical and biotechnological industry.
Matrix metalloproteases hydrolyze proteins of the extracellular matrix. They change the matrix structure and effect cell-matrix interactions. The matrix metalloproteases include collagenases, gelatinases, stromelysins and metalloelastases [1]. The following are some of the physiological processes, in which the enzymes participate: ovulation [2], embryo implantation in the uterus [3], cell migrations and tissue inversions during embryo genesis [4], involution of the mammary gland [5] and of the uterus [6] and angiogenesis [7]. Matrix metalloproteases play an important role in wound healing and scar formation [8], in metastasizing of tumors cells [9, 10], in rheumatic arthritis and osteoarthritis [11, 12] and in periodontal diseases [13].
All matrix metalloproteases contain a Zn.sup.2+ ion in the active center. The activation of the matrix metalloproteases, synthesized in the form of inactive proenzymes, requires the dissolution of a bond between the Zn.sup.2+ ion in the active center and a Cys group in the N-terminal propeptide of matrix metalloproteases (cysteine switch) [14]. Matrix metalloproteases consist of several protein domains, which exhibit homology among members of the protease family [1, 14]. Whereas the protease matrilysin consists only of a propeptide and of the amino acid sequence of the catalytic domain, other matrix metalloproteases contain, in addition, a hemopexin-like sequence of about 200 amino acids. The gelatinases A and B contain additional amino acid sequences. Known human matrix metalloproteases, their molecular weights and their preferred substrates are listed in Table 1.


TABLE 1 ______________________________________ MATRIX METALLOPROTEASES Protease M.sub.r (kDa) Substrate ______________________________________ Interstitial 54.1 Collagen I, II, III Collagenase (MMP-1) Neutrophilic 53.4 Collagen I, II, III Collagenase (MMP-5) Gelatinase A 73.9 Collagen IV, V, VII (MMP-2) Gelatin, Elastin Gelatinase B 78.4 Collagen IV, V (MMP-9) Gelatin, Elastin Stromelysin 1 54 Proteoglycans, (MMP-3) Fibronectin, Laminin, Gelatin, Collagen II, IV, V, IX Stromelysin 2 54.1 Proteoglycans, (MMP-10) Fibronectin, Laminin, Gelatin, Collagen II, IV, V, IX Matrilysin 29.7 Proteoglycans, (MMP-7) Fibronectin, Gelatin, Elastin Stromelysin 3 54.6 Metalloelastase 54 Fibronectin, Elastin ______________________________________
The different matrix metalloproteases are distinguished not only by a characteristic, macromolecular specificity for matrix proteins. Their activity is controlled on different molecular and cellular level: factors, cytokines, polypeptide hormones, prostaglandins, glucocorticoids, estrogen, progesterone and other effectors [1, 14]. respective propeptides [16] or by oxidation [17]. such as TIMP-I, TIMP-2 and TIMP-3 (TIMP=Tissue Inhibitor of Matrix Metalloproteases) [16].
Matrix metalloproteases are being investigated intensively because of their important physiological functions and their role in the pathogenesis of diseases. There is interest in finding and characterizing further matrix metalloproteases.


SUMMARY OF THE INVENTION

It is an object of the present invention to make accessible novel and previously unknown human matrix metalloproteases for medical research, diagnosis and therapy. The task consists of identifying and isolating DNA sequences for matrix metalloproteases and of characterizing the proteins coded by the DNA sequences.
Novel matrix metalloproteases are discovered by the following method. In sequences of known matrix metallo

REFERENCES:
Basset et al. "A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas" Nature 348, 699-704, Dec. 1990.
Sato et al. "A matrix metalloproteinase expressed on the surface of invasive tumour cells" Nature 370, Jul. 1994.
Matrisian, et al. The Matrix-Degrading Metalloproteinase, BioEssays, 14:7, 455-463, 1992.
Will, et al. cDNA Sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment, Eur. J. Biochem. 231:3, 602-608, 1995.

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