Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Transferase other than ribonuclease
Reexamination Certificate
2000-01-12
2002-03-26
Achutamurthy, Ponnathapura (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Transferase other than ribonuclease
C435S320100, C435S183000, C435S253300, C435S254110, C435S419000, C435S325000, C536S023100, C536S023200
Reexamination Certificate
active
06361985
ABSTRACT:
BACKGROUND OF THE INVENTION
Glycosyltransferase molecules transfer carbohydrate molecules to glycoproteins during biosynthesis. Members of this family have also been detected on the cell surface where they are thought to be involved in varying aspects of cell-cell interactions. This family includes carbohydrate transferring enzymes, such as sialyltransferases and fucosyltransferases, and galactosyltransferases. During the formation of O-linked glycoproteins and the modification of N-linked ones, each sugar transfer is catalyzed by a different type of glycosyltransferase. Each glycosyltransferase enzyme is specific for both the donor sugar nucleotide and the acceptor molecule.
Galactosyltransferases promote the transfer of an activated galactose residue in UDP-galactose to the monosaccharide N-acetylglucosamine. This transfer is a step in the biosynthesis of the carbohydrate portion of galactose-containing glycoproteins, such as oligosaccharides and glycolipids, in animal tissues. One subgroup of the galactosyltransferases is the beta-1,3-galactosyltransferases, which are characterized by the elongation of type I oligosaccharide chains. Additionally, the beta-1,3-galactosyltransferases are found on glycoproteins and glycolipids, are important precursors of blood group antigens, and are present in soluble oligosaccharides of human milk. Similar to other members of galactosytransferases, the beta-1,3-galactosyltransferases require a divalent cation (Mn
2+
) to function. The beta-1,3-galactosyltransferases seem to have restricted tissue distributions.
Some galactosyltransferases are found in the Golgi apparatus. These Golgi-localized enzymes have structure similarity: a short N-terminal domain that faces the cytosol, a single transmembrane &agr; helix, and a large C-terminal domain that faces the Golgi lumen and that contains the catalytic site. The transmembrane &agr; helix is necessary and sufficient to restrict the enzyme to the Golgi. Of the beta-1,3-galactosyltransferase family, two members (See Amado, M. et al.,
J. Biol. Chem.
273, 21: 12770-12778, 1998) have been predicted to have two potentially different initiation codons, resulting in two different N-terminal cytoplasmic domains.
Additionally, galactosyltransferases have been shown to be expressed on the cell surface, where their function is theorized to participate in cellular interactions, perhaps as receptors, or receptor-like complementary molecules as well as secreted ligands. As a cell surface carbohydrate, galactosyltransferases have been implicated in varied biology such as cell migration, contact inhibition, tissue interactions, neuronal specificity, fertilization, embryonic cell adhesions, limb bud morphogenesis, mesenchyme development, immune recognition, growth control, and tumor metastasis. See, for example, Shur, B. D.,
Mol Cell Bioc.
61:143-158, 1984.
The failure of tumor cell-tumor cell adhesion is believed to be a contributing factor in tumor metastases. See, for example, Zetter,
Cancer Biolog,
4: 219-29, 1993. Metastases, in turn, are generally associated with poor prognosis for cancer treatment. The metastatic process involves a variety of cellular events, including angiogenesis, tumor cell invasion of the vascular or lymphatic circulation, tumor cell arrest at a secondary site; tumor cell passage across the vessel wall into the parenchymal tissue, and tumor cell proliferation at the secondary site. Thus, both positive and negative regulation of adhesion are necessary for metastasis. That is, tumor cells must break away from the primary tumor mass, travel in circulation and adhere to cellular and/or extracellular matrix elements at a secondary site. Molecules capable of modulating cell-cell and cell-matrix adhesion are therefore sought for the study, diagnosis, prevention and/or treatment of metastases.
Beta-1,3-galactosyltransferases have limited homology to each other. In contrast to other glycosyltransferases, they do not appear to be localized to the same chromosomes. Additionally, a member of this family has recently been identified in Drosophila. This molecule, Brainiac (brn), also known as a Neurogenic Secreted Signaling Peptide (NSSP), is involved in contact and adhesion between germ-line and follicle cells (Amado, M. et al.,
J. Biol. Chem.
273, 21: 12770-12778, 1998). Germline Brainiac activity has been shown to be essential for development of follicular epithelium (Goode, S. et al.,
Dev. Biol.
178:35-50, 1996). Additionally, brn is required continuously throughout oogenesis, beginning in the germarium at the time that follicle cells envelop the oocyte-nurse cell complex and continuing stages when the eggshell is produced. The expression of brn in the germline continuously throughout oogenesis is consistent with brn's role in developing the follicular epithelium around each germline cyst, as well as for dorsal-ventral patterning of the follicular epithelium during later phases of oogenesis. See Goode, S. et al.,
Development.
116: 177-192, 1992.
A deficiency of beta-1,3-galactosyltransferase enzymes has been noticed in the Tn-syndrome. This syndrome is a rarely acquired disorder affecting all hemopoietic lineages, and is characterized by the expression of the Tn and the sialosyl-Tn antigens on the cell surface. The Tn is &agr;N-acetylgalactosamine linked O-glycosidically to threonine or serine residues of membrane proteins. These antigens bind naturally occurring serum antibodies thereby leading to mild hemolytic anemia and pronounced thrombopenia. Thus, the blood cells in the Tn-syndrome are expected to carry less sialic acid if galactose can not be transferred to N-Acetylgalactosamine. The expression of Tn and sialosyl-Tn antigens as a consequence of incomplete or disordered gylcan biosynthesis has been recognized as a cancer-associated phenomenon. Tn and sialosyl-Tn antigens are among the most investigated cancer-associated carbohydrate antigens.
The present invention provides such polypeptides for these and other uses that should be apparent to those skilled in the art from the teachings herein.
SUMMARY OF THE INVENTION
Within one aspect, the invention provides an isolated polypeptide comprising residues 114 to 370 of SEQ ID NO:2. Within an embodiment, the isolated polypeptide comprises residues 114 to 378 of SEQ ID NO:2. Within another embodiment, the isolated polypeptide comprises residues 50 to 378 of SEQ ID NO:2. Within another embodiment, the isolated polypeptide comprises residues 26 to 378 of SEQ ID NO:2. Within another embodiment, the isolated polypeptide comprises residues 1 to 378 of SEQ ID NO:2.
Within another aspect, the invention provides an isolated polypeptide selected from the group consisting of: a) a polypeptide comprising residues 1 to 25 of SEQ ID NO:2; b) a polypeptide comprising residues 26 to 49 of SEQ ID NO:2; c)a polypeptide comprising residues 50 to 113 of SEQ ID NO:2; d) a polypeptide comprising residues 114 to 370 of SEQ ID NO:2; e) a polypeptide comprising residues 371 to 378 of SEQ ID NO:2; and f) a polypeptide comprising residues 1 to 378 of SEQ ID NO:2.
Within another aspect, the invention provides an isolated polynucleotide encoding a polypeptide wherein the polypeptide comprises residues 114 to 370 of SEQ ID NO:2. Within another embodiment, the isolated polynucleotide comprises residues 114 to 378 of SEQ ID NO:2. Within another embodiment, the isolated polynucleotide comprises residues 50 to 378 of SEQ ID NO:2. Within another embodiment, the isolated polynucleotide comprises residues 26 to 378 of SEQ ID NO:2. Within another embodiment, the isolated comprises residues 1 to 378 of SEQ ID NO:2.
Within another aspect, the invention provides an isolated polynucleotide encoding a polypeptide molecule wherein the polypeptide is selected from the group consisting of: a) a polypeptide comprising residues 1 to 25 of SEQ ID NO:2; b) a polypeptide comprising residues 26 to 49 of SEQ ID NO:2; c) a polypeptide comprising residues 50 to 113 of SEQ ID NO:2; d) a polypeptide comprising residues 114 to 370 of SEQ ID NO:2; e) a polypeptide comprising re
Conklin Darrell C.
Gao Zeren
Jaspers Stephen R.
Yamamoto Gayle
Achutamurthy Ponnathapura
Adams Robyn
Kerr Kathleen
ZymoGenetics Inc.
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