Arginase II

Details Arginase II Arginase II

2000-04-03

2001-11-13

Schwartzman, Robert A. (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S007100

Reexamination Certificate

active

06316199

ABSTRACT:

This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human Arginase II.
BACKGROUND OF THE INVENTION
Clinically significant hyperargininemia results from mutations in the Type I arginase gene (Arginase I) (Cederbaum S D, et al., 1979, Pediat Res 13:827-833; Cederbaum S., et al., 1977, J. Pediatr 90:569-573; Michel V V, et al., 1978, Clin Genet 13:61-67) which is predominantly expressed in the liver and red blood cells (Gasiorowska I, et al., 1970, Biochim Biophys Acta 17:19-30; Hermann B G and Frischauf A-M., 1987, Meth Enzymol 152: 180-183; Spector E B, et al., 1982, Biochem Med 28:165-175.) Arginase I deficient patients present with spasticity, growth retardation, progressive mental impairment and episodic hyperammonemia (Cederbaum S D, et al., 1979, Pediat Res 13:827-833; Cederbaum S D, et al., 1977, J. Pediatr 90:569-573; Thomas K R and Capecchi M R, 1987, Cell 51:503-512.) Although significantly devastating, Arginase I deficiency has a milder clinical phenotype than other urea cycle disorders. It has been proposed that the presence of a second isoform of arginase might be responsible for this milder presentation (Grody W W., et al., 1989, J Clin Invest 83:602-609; Grody W W, et al., 1993, Hum Genet 91:1-5) The existence of an extra-urea cycle form of arginase (Arginase II), which localizes to the mitochondria (Wissmann P B, et al., 1994, Am J Hum Genet 55:A139), has been demonstrated utilizing various non-cross reacting antibodies to Arginase I and Arginase II (Spector E B, et al., 1983, Pediatr Res 17:941-941). In patients deficient in type I arginase activity, a compensatory up regulation of Arinase II has been observed (Gasiorowska I et al., 1970, Biochim Biophys Acta 17:19-30; Hermann B G, et al., 1987, Meth Enzymol 152:180-183). Using these antibodies, it has been established that Arginase II is expressed predominantly in the kidney, but is also found in the brain, activated macrophage, the gastrointestinal tract and in the lactating mammary gland (Spector E B, et al., 1983, Pediatr Res 17:941-944.) Arginase II is not expressed at a significant level in the liver or red blood cells. In addition to a hypothetical role in the production of proline and glutamate it has been postulated that Arginase II may play an important role in nitric oxide biosynthesis through the production of ornithine as a precursor of glutamate (Mezl V A, et al., 1977, Biochem J 164:105-113; Wang W W, et al., 1995, Biochem Biophys Res Comm 210:1009-1016.) It is because of the many potential extra-urea cycle, metabolic roles of Arginase II and its up regulation in the hyperargininemnic patient, with its implications for gene therapy, that cloning of the Arginase II gene is important. Many different techniques have been utilized to isolate the gene for Arginase II. The presence of six highly conserved regions in the protein, present in the arginases of most species examined, has been critical to the discovery process (Johnson J L, et al., 1984, J Neurochem 43:1123-1126; Ikeda Y, et al., 1987, Arch Biochem Biophys 252:662-674.)
SUMMARY OF THE INVENTION
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as novel Arginase II by homology between the amino acid sequence set out in
FIGS. 2A
,
2
B and
2
C and known amino acid sequences of other proteins such as Type I arginase and agmatinase.
It is a further object of the invention, moreover, to provide polynucleotides that encode Arginase II, particularly polynucleotides that encode the polypeptide herein designated Arginase II.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises the region encoding human Arginase II in the sequence set out in
FIGS. 2A
,
2
B and
2
C or in the cDNA in ATCC deposit No. 75,656, deposited Jan. 26, 1994 (referred to herein as the deposited clone).
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human Arginase II, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention, biologically, diagnostically, clinically or therapeutically useful variants, analogs or derivatives thereof, or fragments thereof, including fragments of the variants, analogs and derivatives.
Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of human Arginase II.
It also is an object of the invention to provide Arginase II polypeptides, particularly human Arginase II polypeptides, to treat diseases associated with or caused by a defect in the Arginase II gene or Arginase II gene expression, such as, for example, urea cycle diseases, hypertension, hypotension, episodic hyperammonemia, defects in biosynthesis of proline, glutamate, nitric oxide and ornithine, as well as hyperargininemia and its related spasticity, growth retardation, and progressive mental impairment, and prostate disease, particularly prostate cancer, prostatitis and benign prostatic hyperplasia or hypertrophy, and also prostate damage, kidney disease, and kidney damage.
In accordance with another object of the invention is a method of using Arginase II to control nitric oxide formation in an individual having a need to control such formation.
In accordance with yet another object of the invention is a method of treating systemic hypotension caused by sepsis or cytokines using Arginase II alone or in combination with an alpha sub-1 adrenergic agonist.
Another object of the invention is a method to deplete systemic arginine levels in an individual having a need for a depletion of such levels.
In accordance with this aspect of the invention there are provided novel polypeptides of human origin referred to herein as Arginase II as well as biologically, diagnostically or therapeutically useful fragments, variants and derivatives thereof, variants and derivatives of the fragments, and analogs of the foregoing.
Among the particularly preferred embodiments of this aspect of the invention are variants of human Arginase II encoded by naturally occurring alleles of the human Arginase II gene.
It is another object of the invention to provide a process for producing the aforementioned polypeptides, polypeptide fragments, variants and derivatives, fragments of the variants and derivatives, and analogs of the foregoing.
In a preferred embodiment of this aspect of the invention there are provided methods for producing the aforementioned Arginase II polypeptides comprising culturing host cells having expressibly incorporated therein an exogenously-derived human Arginase II-encoding polynucleotide under conditions for expression of human Arginase II in the host and then recovering the expressed polypeptide.
In accordance with another object the invention there are provided products, compositions, processes and methods that utilize the aforementioned polypeptides and polynucleotides for research, biological, clinical and therapeutic purposes, inter alia.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods, inter alia, for, among other things: assessing Arginase II expression in cells by determining Arginase II polypeptides of Arginase II-encoding mRNA; in a sample from a host organism having or suspected of having a disease associated with or caused by a defect in the Arginase II gene or Arginase II gene expression, such as, for example, urea cycle diseases, hypertension, hypotension, episodic hyperammonemia, defects in biosynthesis of proline, glutamate, nitric oxide and ornithine, as we

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