Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Oxidoreductase
Reexamination Certificate
2001-07-10
2004-01-13
Prouty, Rebecca E. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Oxidoreductase
C435S320100, C435S252300, C435S325000, C536S023200, C536S023500
Reexamination Certificate
active
06677144
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of enzyme proteins that are related to the pyruvate dehydrogenase enzyme subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel peptides and proteins that effect protein phosphorylation and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.
BACKGROUND OF THE INVENTION
Many human enzymes serve as targets for the action of pharmaceutically active compounds. Several classes of human enzymes that serve as such targets include helicase, steroid esterase and sulfatase, convertase, synthase, dehydrogenase, monoxygenase, transferase, kinase, glutanase, decarboxylase, isomerase and reductase. It is therefore important in developing new pharmaceutical compounds to identify target enzyme proteins that can be put into high-throughput screening formats. The present invention advances the state of the art by providing novel human drug target enzymes related to the pyruvate dehydrogenase subfamily.
Pyruvate Dehydrogenase Complex, E1 Subunit
The novel human protein, and encoding gene, provided by the present invention is related to the pyruvate dehydrogenase E1-alpha precursor protein (see De Meirleir et al.,
J. Biol. Chem.
263 (4), 1991-1995 (1988)). The pyruvate dehydrogenase (PDH) complex is comprised of a plurality of each of three different enzymes: pyruvate decarboxylase (E1), dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3). Each of these three different enzymes is comprised of multiple subunits; the E1 enzyme is a heterotetramer consisting of two alpha and two beta subunits. The E1-alpha subunit contains the E1 active site and is therefore critical for the functioning of the PDH complex. PDH plays an important role in all metabolically active tissues; however, it plays a particularly critical role in the brain since the brain normally obtains all its energy from aerobic oxidation of glucose.
Genetic defects in the PDH complex are the main cause of lactic acidosis, particularly in children. Furthermore, in the majority of cases, the specific genetic defects leading to lactic acidosis are in the E1-alpha subunit. PDH deficiency due to genetic defects can cause fatal lactic acidosis in newborns and chronic neurological dysfunction and neurodegeneration with gross structural abnormalities in the CNS. PDH deficiency is one of the most common pathologies of mitochondrial energy metabolism. It is common for even heterozygous females to show severe clinical symptoms.
For a further review of the PDH complex, particularly PDH-E 1 and the PDH-E1-alpha subunit, see:
1. Bindoff, L. A.; Birch-Machin, M. A.; Farnsworth, L.; Gardner-Medwin, D.; Lindsay, J. G.; Turnbull, D. M. Familial intermittent ataxia due to a defect of the E1 component of pyruvate dehydrogenase complex. J. Neurol. Sci. 93: 311-318, 1989. PubMed ID: 2592988; 2. Blair, H. J.; Reed, V.; Laval, S. H.; Boyd, Y. The locus for pyruvate dehydrogenase E1 alpha-subunit (Pdhal) lies between Plp and Amg on the mouse X chromosome. Mammalian Genome 4: 230-233, 1993. PubMed ID: 7684627; 3. Borglum, A. D.; Flint, T.; Hansen, L. L.; Kruse, T. A. Refined localization of the pyruvate dehydrogenase E1-alpha gene (PDHA1) by linkage analysis. Hum. Genet. 99: 80-82, 1997. PubMed ID: 9003499; 4. Brown, G. K.; Haan, E. A.; Kirby, D. M.; Scholem, R. D.; Wraith, J. E.; Rogers, J. G.; Danks, D. M. ‘Cerebral’ lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Europ. J. Pediat. 147: 10-14, 1988. PubMed ID: 3123240; 5. Brown, G. K.; Otero, L. J.; LeGris, M.; Brown, R. M. Pyruvate dehydrogenase deficiency. J. Med. Genet. 31: 875-879, 1994. PubMed ID: 7853374; 6. Brown, R. M.; Dahl, H.-H. M.; Brown, G. K. An homologous locus to the human X-linked pyruvate dehydrogenase E1-alpha subunit gene is located at the distal end of the mouse X chromosome. (Abstract) Cytogenet. Cell Genet. 51: 970, 1989.; 7. Brown, R. M.; Dahl, H.-H. M.; Brown, G. K. X-chromosome localization of the functional gene for the E1-alpha subunit of the human pyruvate dehydrogenase complex. Genomics 4: 174-181, 1989. PubMed ID: 2737678; 8. Brown, R. M.; Dahl, H.-H. M.; Brown, G. K. Regional localization of the X-linked human pyruvate dehydrogenase E1-alpha subunit gene. (Abstract) Cytogenet. Cell Genet. 51: 970, 1989.; 9. Brown, R. M.; Otero, L. J.; Brown, G. K. Transfection screening for primary defects in the pyruvate dehydrogenase E1-alpha subunit gene. Hum. Molec. Genet. 6: 1361-1367, 1997. PubMed ID: 9259285; 10. Chun, K.; MacKay, N.; Petrova-Benedict, R.; Robinson, B. H. Mutations in the X-linked E1-alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. Hum. Molec. Genet. 2: 449-454, 1993. PubMed ID: 8504306; 11. Chun, K.; MacKay, N.; Petrova-Benedict, R.; Robinson, B. H. Pyruvate dehydrogenase deficiency due to a 20-bp deletion in exon 11 of the pyruvate dehydrogenase (PDH) E1-alpha gene. Am. J. Hum. Genet. 49: 414-420, 1991. PubMed ID: 1907799; 12. Dahl, H.-H. M. Pyruvate dehydrogenase E1-alpha deficiency: males and females differ yet again. Am. J. Hum. Genet. 56: 553-557, 1995. PubMed ID: 7887408; 13. Dahl, H.-H. M.; Brown, G. K. Pyruvate dehydrogenase deficiency in a male caused by a point mutation (F205L) in the E1-alpha subunit. Hum. Mutat. 3: 152-155, 1994. PubMed ID: 8199595; 14. Dahl, H.-H. M.; Brown, G. K.; Brown, R. M.; Hansen, L. L.; Kerr, D. S.; Wexler, I. D.; Patel, M. S.; De Meirleir, L.; Lissens, W.; Chun, K.; MacKay, N.; Robinson, B. H. Mutations and polymorphisms in the pyruvate dehydrogenase E1-alpha gene. Hum. Mutat. 1: 97-102, 1992. PubMed ID: 1301207; 15. Dahl, H.-H. M.; Hansen, L. L.; Brown, R. M.; Danks, D. M.; Rogers, J. G.; Brown, G. K. X-linked pyruvate dehydrogenase E1-alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J. Inherit. Metab. Dis. 15: 835-847, 1992. PubMed ID: 1293379; 16. Dahl, H.-H. M.; Maragos, C.; Brown, R. M.; Hansen, L. L.; Brown, G. K. Pyruvate dehydrogenase deficiency caused by deletion of a 7-bp repeat sequence in the E1-alpha gene. Am. J. Hum. Genet. 47: 286-293, 1990. PubMed ID: 2378353; 17. de Meirleir, L.; Lissens, W.; Vamos, E.; Liebaers, I. Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the E1-alpha subunit. Hum. Genet. 88: 649-652, 1992. PubMed ID: 1551669; 18. De Meirleir, L.; Specola, N.; Seneca, S.; Lissens, W. Pyruvate dehydrogenase E1-alpha deficiency in a family: different clinical presentation in two siblings. J. Inherit. Metab. Dis. 21: 224-226, 1998. PubMed ID: 9686362; 19. de Meirleir, L. J.; Lissens, W.; Vamos, E.; Liebaers, I.; Pyruvate dehydrogenase deficiency due to a mutation of the E1-alpha subunit. J. Inherit. Metab. Dis. 14: 301-304, 1991. PubMed ID: 1770778; 20. Endo, H.; Hasegawa, K.; Narisawa, K.; Tada, K.; Kagawa, Y.; Ohta, S. Defective gene in lactic acidosis: abnormal pyruvate dehydrogenase E1 alpha-subunit caused by a frame shift. Am. J. Hum. Genet. 44: 358-364, 1989. PubMed ID: 2537010; 21. Endo, H.; Miyabayashi, S.; Tada, K.; Narisawa, K. A four-nucleotide insertion at the E1-alpha gene in a patient with pyruvate dehydrogenase deficiency. J. Inherit. Metab. Dis. 14: 793-799, 1991. PubMed ID: 1779625; 22. Fitzgerald, J.; Wilcox, S. A.; Graves, J. A. M.; Dahl, H.-H. M. A eutherian X-linked gene, PDHA1, is autosomal in marsupials: a model for the evolution of a second, testis-specific variant in eutherian mammals. Genomics 18: 636-642, 1993. PubMed ID: 8307573; 23. Hansen, L. L.; Brown, G. K.; Kirby, D. M.; Dahl, H.-H. M. Characterization of the mutations in three patients with pyruvate dehydrogenase E1-alpha deficiency. J. Inherit. Metab. Dis. 14: 140-151, 1991. PubMed ID: 1909401; 24. Harris, E. E.; Hey, J. X chromosome evidence for ancient human histories. Proc. Nat. Acad. Sci. 96: 3320-3324, 1999. PubMed ID: 10077682; 25. Ho, L.; Wexler, I. D.; Liu, T.-C.; Thekkumk
Beasley Ellen M.
DiFrancesco Valentina
Gong Fangcheng
Ketchum Karen A.
Applera Corporation
Celera Genomics
Karjala Justin D.
Prouty Rebecca E.
Steadman David J.
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