Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Transferases
Reexamination Certificate
2000-01-21
2002-10-29
Prouty, Rebecca E. (Department: 1652)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Transferases
C435S193000, C435S015000, C435S016000, C435S320100, C536S023200
Reexamination Certificate
active
06471959
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of human transferases and to the use of these sequences in the diagnosis, treatment, and prevention of autoimmune/inflammatory, neurological, reproductive, and gastrointestinal disorders and cancer.
BACKGROUND OF THE INVENTION
Transferases, enzymes that catalyze group transfer reactions, are classified by the type of group transferred. One-carbon groups are transferred; for example, methyltransferases transfer methyl groups from S-adenosyl-methionine to substrates. Nitrogenous groups are transferred; for example, aminotransferases transfer amino groups. Other groups transferred include aldehyde or ketone, acyl, glycosyl, alkyl and aryl other than methyl, phosphorus-containing, sulfur-containing, and selenium-containing groups.
The enzyme glutamine-phenylpyruvate aminotransferase, also known as glutanaine transaminase K (GTK), catalyzes several reactions with a pyridoxal phosphate cofactor. GTK catalyzes the reversible conversion of L-glutamine and phenylpyruvate to 2-oxoglutaramate and L-phenylalanine. L-methionine, L-histidine, and L-tyrosine can substitute for L-glutamine in this reaction. GTK also catalyzes the conversion of kynurenine to kynurenic acid. Kynurenic acid, a tryptophan metabolite, is an antagonist of the N-methyl-D-aspartate (NMDA) receptor in the brain and may exert a neuromodulatory function. Alteration of the kynurenine metabolic pathway may be among the causative factors leading to several neurological disorders. GTK also possesses cysteine conjugate &bgr;-lyase activity which is involved in the metabolism of halogenated xenobiotics conjugated to glutathione. GTK action on the cysteine conjugates of xenobiotics yields metabolites that are nephrotoxic in rats and neurotoxic in humans. The neurotoxicity may be related to the kynurenine aminotransferase activity of GTK. GTK is expressed in kidney, liver, and brain. Both cytosolic and mitochondrial forms exist. Human and rat GTK genes have been isolated which encode proteins of 422 and 423 amino acids respectively. Both human and rat GTKs contain a putative pyridoxal phosphate binding site. (ExPASy ENZYME: EC 2.6.1.64; Perry, S. J. et al. (1993) Mol. Pharmacol. 43:660-665; Perry, S. et al. (1995) FEBS Lett. 360:277-280; and Alberati-Giani, D. et al. (1995) J. Neurochem. 64:1448-1455.)
The enzyme kynurenine/a-aminoadipate aminotransferase (AadAT) catalyzes two reactions with a pyridoxal phosphate cofactor. AadAT catalyzes the reversible conversion of &agr;-aminoadipate and &agr;-ketoglutarate to &agr;-ketoadipate and L-glutamate. This conversion is involved in lysine metabolism. AadAT also catalyzes the transamination of kynurenine acid to kynurenic acid. As described above, kynurenic acid is an NMDA receptor antagonist. Both soluble and mitochondrial forms of AadAT have been purified. A soluble AadAT is expressed in rat kidney, liver, and brain. The rat AadAT nucleotide gene encodes a protein of 425 amino acids which contains a putative pyridoxal phosphate binding site. (Nakatani, Y. et al. (1970) Biochim. Biophys. Acta 198:219-228; Buchli, R. et al. (1995) J. Biol. Chem. 270:29330-29335.)
Protein-arginine methyltransferases catalyze the posttranslational methylation of arginine residues in proteins, resulting in the mono- and dimethylation of arginine on the guanidino group. Known substrates are histones, heterogeneous nuclear ribonucleoproteins (hnRNPs), and myelin basic protein. This otherwise unusual posttranslational modification is common in hnRNPs and may regulate their function. hnRNPs function in the nucleus in mRNA processing, splicing, and transport into the cytoplasm. Homologous protein-arginine methyltransferases that methylate hnRNPs have been cloned from yeast, rat, and man. These protein-arginine methyltransferases contain five sequence motifs, termed region I, post-region I, region II, region III, and post-region III, that may be involved in binding S-adenosyl-methionine. One human gene (HRMT1L1) encodes a 433 amino acid protein. The other human gene (HRMT1L2) may be alternatively spliced to yield three protein-arginine methyltransferases, of length 343, 347, and 361 amino acids respectively, with different amino termini. The protein encoded by the cloned rat protein-arginine methyltransferase gene (PRMT1) interacts with the TIS21 protein and the homologous BTG1 protein. The intermediate-early TIS21 protein is the product of a gene induced by treatment of cells with mitogens such as epidermal growth factor, and the-BTG1 protein is the product of a human gene located near a chromosome translocation breakpoint associated with chronic lymphocytic leukemia. The HRMT1L2 protein interacts with the cytoplasmic domain of the interferon receptor. This interaction suggests that protein methylation may be an important signaling mechanism for cytokine receptors (Lin, W.-J. et al..(1996) J. Biol. Chem. 271:15034-15044; Abramovich, C. et al. (1997) EMBO J. 16:260-266; and Scott, H. S. et al. (1998) Genomics 48:330-340.)
The discovery of new human transferases and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of autoimmune/inflammatory, neurological, reproductive, and gastrointestinal disorders and cancer.
SUMMARY OF THE INVENTION
The invention features substantially purified polypeptides, human transferases, referred to collectively as “HUTRAN” and individually as “HUTRAN-1”, “HUTRAN-2”, and “HUTRAN-3.” In one aspect, the invention provides a substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 (SEQ ID NO: 1-3) and fragments thereof.
The invention further provides a substantially purified variant having at least 90% amino acid identity to the amino acid sequences of SEQ ID NO:1-3 or to fragments of any of these sequences. The invention also provides an isolated and purified polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-3 and fragments thereof. The invention also includes an isolated and purified polynucleotide variant having at least 70% polynucleotide sequence identity to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3 and fragments thereof.
Additionally, the invention provides an isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3 and fragments thereof, as well as an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:1-3 and fragments thereof.
The invention also provides an isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID) NO:4, SEQ ID NO:5, and SEQ ID NO:6 (SEQ ID NO:4-6), and fragments thereof. The invention further provides an isolated and purified polynucleotide variant having at least 70% polynucleotide sequence identity to the polynucleotide sequence comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:4-6 and fragments thereof, as well as an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:4-6 and fragments thereof.
The invention further provides an expression vector containing at least a fragment of the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-3 and fragments thereof. In another aspect, the expression vector is contained within a host cell.
The invention also provides a method for producing a polypeptide comprising the amino
Bandman Olga
Corley Neil C.
Gorgone Gina A.
Guegler Karl J.
Hillman Jennifer L.
Incyte Genomics Inc.
Incyte Genomics, Inc.
Prouty Rebecca E.
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