Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1997-04-01
2000-10-24
Nashed, Nashaat
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435 41, 435193, 43525233, 435325, 4353201, 536 232, 536 235, C12P 1700, C07H 2104
Patent
active
061365726
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to DNA sequences that code for kynurenine aminotransferase.
BACKGROUND OF THE INVENTION
The enzyme kynurenine aminotransferase (known in the art as KAT) catalyzes the biosynthesis of kynurenic acid (KYNA) from kynurenine (KYN) and is singularly responsible for the regulation of extracellular KYNA concentrations in the brain (J. Neurochem., 57:533-540 (1991)).
KYNA is an effective excitatory amino acid (EAA) receptor antagonist with a particularly high affinity to the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor complex (J. Neurochem., 52:1319-1328 (1989)). As a naturally occurring brain metabolite (J. Neurochem., 51:177-180 (1988); and Brain Res., 454:164-169 (1988)), KYNA probably serves as a negative endogenous modulator of cerebral glutamatergic function (Ann. N.Y. Acad. Sci., 648:140-153 (1992)).
EAA receptors and in particular NMDA receptors are known to play a central role in the function of the mammalian brain (Watkins et al, In: The NMDA Receptor, page 242, (1989), Eds., Oxford University Press, Oxford). For example, NMDA receptor activation is essential for cognitive processes, such as, for example, learning and memory (Watkins et al, In: The NMDA Receptor, Eds., pages 137-151, (1989), Oxford University press, Oxford) and for brain development (Trends Pharmacol. Sci., 11:290-296 (1990)).
It follows that a reduction in NMDA receptor function will have detrimental consequences for brain physiology and, consequently, for the entire organism. For example, the decline in the number of NMDA receptors which occurs in the aged brain (Synapse, 6:343-388 (1990)) is likely associated with age-related disorders of cognitive functions.
In the brain, KYNA concentrations and the activity of KYNA's biosynthetic enzyme KAT show a remarkable increase with age (Brain Res., 558:1-5, (1992); and Neurosci. Lett., 94:145-150 (1988)). KAT inhibitors, by providing an increase of the glutamatergic tone at the NMDA receptor, could therefore be particularly useful in situations where NMDA receptor function is insufficient and/or KAT activity and KYNA levels are abnormally enhanced. Hence they could be particularly useful in the treatment of the pathological consequences associated with the aging processes in the brain which are, for example, cognitive disorders including, e.g., attention and memory deficits and vigilance impairments in the elderly.
KAT inhibitors may also be useful in the treatment of perinatal brain disorders which may be related to irregularities in the characteristic region specific pattern of postnatal KAT development (Baran et al, Dev. Brain Res., 74:283-286 (1993)).
In subcellular fractionation studies KAT activity was recovered in the cytosol and in mitochondria (J. Neurochem., supra).
Most nuclear-encoded precursors of mitochondrial proteins contain amino-terminal presequences (Pfanner et al, In: Current Topics in Bioenergetics, 15:177-219 (1987); Lee Ed., New York Academic Press; and Nicholson et al, In: Protein Transfer and Organelle Biogenesis, Das and Robins Eds., New York Academic Press (1988)). These presequences are required for the precursor to enter the mitochondrial matrix, where they are proteolytically removed (Hurt et al, FEBS Lett., 178:306 (1984); Horwich et al, EMBO J., 4:1129 (1985). This cleavage is not essential for completing import but is necessary for further assembly of the newly imported polypeptides into functional complexes (Zwizinski et al, J. Biol. Chem., 258:13340 (1983); Lewin et al, J. Biol. Chem., 258:6750 (1983); Ou et al, J. Biochem., 100:1287 (1986)). Precursor targeting sequences differ considerably in their structures. One of the few common themes is the high content of positively charged amino acids and of hydroxylated amino acids. Presequences may form an amphipathic structure in the form of either .alpha.-helices or .beta.-sheets (von Heijne et al, EMBO J., 5:1335 (1986); Roise et al, EMBO J., 5:1327 (1986); and Vassarotti et al, EMBO J., 6:705 (1987)). Despite the large variability
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Perry et al. "Molecular cloning and expression of a cDNA from human kidney . . . " FEBS Lett. 360, Mar. 6, 1995.
Perry et al., "Isolation and Expression of cDNA . . . " Molecular Pharm.., 43:660-665 (1993).
Baran et al., "Purification and Characterization . . . " J. Neurochemistry, 62:730-738 (1994).
Okuno et al., "Measurement of Rat Brain . . . " J. Neurochemistry, 57:533-540 (1991).
Alberati-Giani et al., "Cloning and Characterization . . . " J. Neurochemistry 64:1448-1455 (1995).
Mosca et al., "Molecular cloning of rat kynurenine . . . " FEBS Letters, 353:21-24 (1994).
Perry et al., "Molecular cloning and expression of a cDNA . . . " FEBS Letters 360:277-280, (1995).
Malherbe et al., "Identification of mitochondrial form of kynurenine . . . " FEBS Letters 367:141-144, (1995).
Benatti Luca
Breton Jerome
Mosca Monica
Okuno Etsuo
Schwarcz Robert
Nashed Nashaat
Pharmacia & Upjohn S.p.A.
University of Maryland at Baltimore
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