Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for...
Patent
1997-09-16
1999-09-07
Hobbs, Lisa
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
435 6, 435440, 5303871, C12N 900, C12N 1500, C12Q 168, C07K 1600
Patent
active
059486570
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to newly identified polynucleotides and polypeptides, and their production and uses, as well as their variants, agonists and antagonists, and their uses. In particular, in these and in other regards, the invention relates to novel polynucleotides and polypeptides of the tRNA synthetase family, hereinafter referred to as "tRNA synthetase".
BACKGROUND OF THE INVENTION
It is particularly preferred to employ Staphylococcal genes and gene products as targets for the development of antibiotics. The Staphylococci make up a medically important genera of microbes. They are known to produce two types of disease, invasive and toxigenic. Invasive infections are characterized generally by abscess formation effecting both skin surfaces and deep tissues. S. aureus is the second leading cause of bacteremia in cancer patients. Osteomyelitis, septic arthritis, septic thrombophlebitis and acute bacterial endocarditis are also relatively common. There are at least three clinical conditions resulting from the toxigenic properties of Staphylococci. The manifestation of these diseases result from the actions of exotoxins as opposed to tissue invasion and bacteremia. These conditions include: Staphylococcal food poisoning, scalded skin syndrome and toxic shock syndrome.
The tRNA synthetases have a primary role in protein synthesis according to the following scheme: ##EQU1## in which AA is an amino acid.
Inhibition of this process leads to a reduction in the levels of charged tRNA and this triggers a cascade of responses known as the stringent response, the result of which is the induction of a state of dormancy in the organism. As such selective inhibitors of bacterial tRNA synthetase have potential as antibacterial agents. One example of such is mupirocin which is a selective inhibitor of isoleucyl tRNA synthetase. Isolation of tRNA synthetase allows for the identification and analysis of potential antibacterial targets to facilitate screening for antibacterial compounds.
Isoleucyl tRNA synthetase, isolated from Staphylococcus aureus, has already been described (Chalker, A., F., Ward, J., M., Fosberry, A., P. and Hodgson, J., E. 1994 Gene 141: 103-108).
Clearly, there is a need for factors that may be used to screen compounds for antibiotic activity and which factors may also be used to determine their roles in pathogenesis of infection, dysfunction and disease. There is a need, therefore, for identification and characterization of such factors and their antagonists and agonists which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptides of the invention have amino acid sequence homology to a known phenylalanyl tRNA synthetase protein.
SUMMARY OF THE INVENTION
It is an object of the invention to provide polypeptides that have been identified as novel tRNA synthetase polypeptides by homology between the known amino acid sequence or sequences of other proteins such as phenylalanyl tRNA synthetase protein.
It is a further object of the invention to provide polynucleotides that encode tRNA synthetase polypeptides, particularly polynucleotides that encode the polypeptide herein designated tRNA synthetase.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises a region encoding phenylalanyl tRNA synthetase
In another particularly preferred embodiment of the invention there is a novel phenylalanyl tRNA synthetase protein from Staphylococcus aureus ID NO: 4!, or a variant of either sequence.
In accordance with this aspect of the invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressible by the Staphylococcus aureus WCUH 29 strain contained in NCIMB Deposit No. 40771.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding tRNA synthetase, particularly Staphylococcus aureus tRNA synthetase, including mRNAs, cDNAs, genomic DNAs. Further embodiments of this aspect of the invention include b
REFERENCES:
Kron, et al., "An immunodominant antigen of Brugia malayi is an asparaginyl-tRNA synthetase", FEBS Letters, 374 pp. 122-124 (1995).
Chalker, et al., "Analysis and toxic overexpression in Escherichia coli of a staphylococcal gene encoding isoleucyl-tRNA synthetase", Gene, 141, pp. 103-108 (1994).
Nilsen, et al., "Cloning and characterization of a potentially protective antigen in lymphatic filariasis", Proc. Natl. Acad. Sci. USA, 85, pp. 3604-3607 (1988).
Beresten, et al., "Molecular and cellular studies of tryptophanyl-tRNA synthetase using monoclonal antibodies", Eur. J. Biochem, 184, pp. 575-581 (1989).
Calendar, et al., "Purification and Physical Characterization of Tyrosyl Ribonucleic Acid Synthetases from Escherichia coli and Bacillus subtilis", Biochemistry, 5, No. 5, pp. 1681-1690 (1966).
Hennecke, et al., Immunochemical Studies on Phenylalanyl-tRNA Synthetase from Escherichia coli, Hoppe-Seyler's Zeitschrift Fur Physiologische Chemie, 358, pp. 197-208 (1977).
Brakhage, et al., "Structure and nucleotide sequence of the Bacillus subtilis phenylalanyl-tRNA synthetase genes", EMBL Sequence Database, Accession No. X53057, (Nov. 1990).
Brakhage, et al., "Structure and nucleotide sequence of the Bacillus subtilis phenylalanyl-tRNA synthetase genes", Biochimie, 72, pp. 725-734 (1990).
Hodgson John Edward
Lawlor Elizabeth Jane
Gimmi Edward R.
Hobbs Lisa
Jackson Arthur E.
King William T.
SmithKline Beecham Plc
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