Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Transferase other than ribonuclease
Reexamination Certificate
2002-03-12
2003-05-06
Hutson, Richard (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Transferase other than ribonuclease
C435S320100, C435S252300, C435S252330, C435S091100, C435S325000, C536S023100, C536S023200, C536S023500, C530S350000
Reexamination Certificate
active
06558935
ABSTRACT:
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of human transferase proteins and to the use of these sequences in the diagnosis, treatment, and prevention of cancer, developmental disorders, gastrointestinal disorders, genetic disorders, immunological disorders, neurological disorders, reproductive disorders, and smooth muscle disorders.
BACKGROUND OF THE INVENTION
Transferase Proteins
Transferases are enzymes that catalyze the transfer of molecular groups from a donor to an aceeptor molecule. The reaction may involve an oxidation, reduction, or cleavage of covalent bonds and is often specific to a substrate or to particular sites on a type of substrate. Transferase proteins participate in reactions essential to such functions as synthesis and degradation of cell components, and regulation of cell functions, including cell signaling, cell proliferation, inflammation, apoptosis, secretion and excretion. Transferases are involved in key steps in disease processes involving these functions. These enzymes are frequently classified according to the type of group transferred. For example, methyl transferases transfer one-carbon methyl groups, amino transferases transfer nitrogenous amino groups, and similarly denominated enzymes transfer aldehyde or ketone, acyl, glycosyl, alkyl or aryl, isoprenyl, saccharyl, phosphorous-containing, sulfur-containing, or selenium-containing groups, as well as small enzymatic groups such as Coenzyme A.
One example of a glycosyl transferase is O-linked N-acetylglucosamine (O-GlcNAc) transferase, an enzyme that catalyzes the reaction of monosaccharide N-acetylglucosamine linking to the hydroxyl group of a serine or threonine residue. O-GlcNAc and N-acetyl-&bgr;-D-glucosaminidase (O-GlcNAcase), regulate the attachment and removal, respectively, of O-GlcNAc from proteins in a manner analagous to regulation of protein phosphorylation by kinases and phosphotases. O-GlcNAc transferase has been localized primarily in the nucleus and the cytosol of cells and has been shown to play a role in several cellular systems such as transcription, nuclear transport, and cytoskeletal organization. O-GlcNAc transferase is a heterodimer consisting of two catalytic 110-kDa (p110) subunits and one 78-kDa (p78) subunit. The gene encoding this enzyme is highly conserved. The amino terminus of the p110 subunit has homology to the tetratricopeptide repeat (TPR) motif while the carboxyl terminus has no significant homology (Kreppel, L. K. et al. (1997) J. Biol. Chem. 272:9308-9315). Proteins containing the TPR motif interact through this TPR domain to form regulatory complexes. TPR motifs are believed to play a role in modulation of cellular processes such as cell cycle, transcription, and protein transport (Das, A. K. et al. (1998) EMBO J 17:1192-1199).
The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a purine salvage enzyme that catalyzes the conversion of hypoxanthine and guanine to their respective mononucleotides. HGPRT is ubiquitous, is known as a ‘housekeeping’ gene, and is frequently used as an internal control for reverse transcriptase polymerase chain reactions. There is a serine-tyrosine dipeptide that is conserved among all members of the HGPRT family and is essential for the phosphoribosylation of purine bases(Jardim, A. and Ullman, B. (1997) J. Biol. Chem. 272:8967-8973). A partial deficiency of HGPRT can lead to overproduction of uric acid, causing a severe form of gout. An absence of HGPRT causes Lesch-Nyhan syndrome, characterized by hyperuricaemia, mental retardation, choreoathetosis, and compulsive self-mutilation (Sculley, D. G. et al. (1992) Hum Genet 90:195-207).
Polyprenyl transferases catalyze the addition of polyprenyl groups to molecules. For example, the enzyme 1,4-dihydroxy-2-napthoate octaprenyltransferase catalyzes the conversion of the soluble 1,4-dihydroxy-2-napthoic acid (DHNA) to the membrane-bound demethylmenaquinone by attaching a 40-C side chain to DHNA, a key step in the biosynthesis of menaquinone (vitamin K2). This octaprenyltransferase is a membrane protein in
Escherichia coli
that is necessary for the synthesis of menaquinone (Suvarna, K. et al. (1998) J. Bacteriol. 180:2782-2787). Quinones, in many cases, take part in the oxidation-reduction cycles essential to living organisms (Morrison, R. T. and Boyd, R. N. (1987)
Organic Chemistry
, Allyn and Bacon, Inc., Newton, Mass., pp. 1092-1093). Other octaprenyltransferase have been shown to allow the synthesis of quinones under anaerobic conditions and, therefore, may play a role in anaerobic metabolism (Alexander, K. and Young, I. G. (1978) Biochemistry 17:4750-4755).
The synthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) requires two enzymes, adenosine triphosphate (ATP) sulfurylase and adenosine 5′-phosphosulfate (APS) kinase. ATP sulfurylase catalyzes the formation of APS from ATP and free sulfate. APS kinase phosphorylates APS to produce PAPS, the sole source of donor sulfate in higher organisms. In bacteria, fungi, yeast, and plants, these two enzymes are separate polypeptides. In animals, ATP sulfurylase and APS kinase are present in a single protein. The bifunctional enzyme found in mammals shows extensive homology to known sequences of both ATP sulfurylases and APS kinases. APS kinase peptide sequences are well conserved and contain an ATP-GTP binding motif (P-loop) flanked by cysteine residues and a PAPS-dependent enzyme motif. ATP sulfurylase peptide sequences have a PP-motif found in ATP sulfurylases and PAPS reductases (Rosenthal, E. and Leustek, T. (I995) Gene 165:243-248; Li, H. et al. (1995) J. Biol. Chem. 270:29453-29459; Deyrup, A. T. et al. (1998) J. Biol. Chem. 273:9450-9456; Bork, P. and Koonin, E. V. (1994) Proteins 20:347-355).
The enzyme phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the methylation of phosphatidylethanolamine. Hepatocytes in the liver synthesize phosphatidylcholine (PC) by stepwise methylation of phosphatidylethanolamine and have abundant activity for PEMT. Other cells and tissues express minimal activities for PEMT. All mammalian cells, including hepatocytes, synthesize PC from choline via the CDP-choline pathway. Evidence suggests that one function of hepatic PEMT is to maintain PC synthesis and generate choline when dietary supply of choline is insufficient, as occurs during pregnancy, lactation, or starvation (Walkey, C. J. et al. (1998) J. Biol. Chem. 273:27043-27046). Forms of PEMT may also play a role in hepatocyte proliferation and liver cancer (Walkey, C. J. et al. (1999) Biochim. Biophys. Acta 1436:405-412). In the brain, decreased PEMT activity has been associated with Alzheimer's disease (Guan, Z. Z. et al. (1999) Neurochem. Int. 34:41-47).
Sulfotransferase enzymes catalyze the transfer of sulfur-containing groups to molecules. For example, HNK-1 sulfotransferase (HNK-1ST) forms the HNK-1 carbohydrate epitope by adding a sulfate group to glycoproteins and glycolipids. The HNK-1 epitope was discovered by an antibody against human natural killer cells and is found in neural adhesion molecules, including N-CAM and myelin-associate glycoprotein. The HNK-1 carbohydrate epitope was recognized to have functional significance as an auto-antigen involved in peripheral demyelinative neuropathy. The HNK-1ST is a type II membrane protein with a consensus sequence shared by Golgi-associated sulfotransferases. The human and rat HNK-1STs share 90% homology in amino acid sequence. Human HNK-1ST was predominantly detected in fetal brain and in adult brain, testis, and ovary. (See Ong, E. et al. (1998) J. Biol. Chem. 273:5190-5195.)
Camnitine palmitoyitransferase I (CPT I) is an enzyme that catalyzes the transfer of fatty acyl groups from coenzyme A to carnitine, the rate-determining step in mitochondrial fatty acid &bgr;-oxidation (a major source of energy production in the cell). CPT I has two structural genes (&agr; and &bgr;) that are differentially expressed in tissues that utilize fatty, acids as fuel. The &agr; structure is expressed most highly in
Azimzai Yalda
Baughn Mariah R.
Corley Neil C.
Guegler Karl J.
Hillman Jennifer L.
Hutson Richard
Incyte Genomics Inc.
Incyte Genomics, Inc.
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