ARO1 multifunctional polypeptide of Candida albicans

Details ARO1 multifunctional polypeptide of Candida albicans ARO1 multifunctional polypeptide of Candida albicans

2000-10-10

2002-02-12

Prouty, Rebecca E. (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

C435S232000, C435S190000, C435S194000

Reexamination Certificate

active

06346405

ABSTRACT:

This invention relates, in part, to newly identified polynucleotides and polypeptides; variants of these polynucleotides and polypeptides; processes for making these polynucleotides and these polypeptides, and their variants; agonists and antagonists of the polypeptides; and uses of these polynucleotides, polypeptides, variants, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of arom, hereinafter referred to as “ARO1” and “ARO1”.
BACKGROUND OF THE INVENTION
It is particularly preferred to employ candidal genes and gene products as targets for the development of antifungals. Candida spp. make up a medically important genus of microbes. They are known to produce two main types of infection, superficial infections of the mucosa and skin, and systemic infections, particularly in immuno-compromised patients, characterized by dissemination to the body tissues with poor prognosis without intervention.
C. albicans
is the principal species causing candida infections
The frequency of
Candida albicans
infections has risen dramatically in the past 20 years. This has been attributed to an increasing population of people with weakened immune systems and the use of broad spectrum antibacterials and more interventional surgical practices. The amoury of good antifingal agents is small and resistance to existing agents is an emerging problem. This has created a demand for both new antifingal agents and diagnostic tests for this organism.
Fungi like bacteria and plants, but unlike mammals, are able to synthesize the aromatic amino acids phenylalanine, tyrosine and tryptophan. In fungi, a single polypeptide, the arom multifunctional enzyme, catalyses five consecutive reactions of the central aromatic biosynthetic pathway (Lambert et al. (1985). The 3-dehydroquinate synthase activity of the pentafunctional arom enzyme complex of
Neurospora crassa
is Zn
2+
-dependent.
Biochemical Journal
226:817-29. Duncan et al. (1987). The pentafunctional arom enzyme of
Saccharomyces cerevisiae
is a mosaic of monofinctional domains.
Biochemical Journal
246:375-86.). Inhibition of any step catalyzed by this enzyme will prevent the synthesis of aromatic amino acids, p-aminobenzoic acid (precursor for folate) and ubiquinone. These essential metabolites are in limiting concentrations in mammalian tissues and thus inhibition of this enzyme is a valid antifingal strategy.
Clearly, there is a need for factors that may be used to screen compounds for antifungal activity and which 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 which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptide of the present invention has the conserved residues, and have amino acid sequence homology to known arom multifunctional protein protein.
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 ARO1 peptides by homology between the amino acid sequence set out in Table 2 and known amino acid sequences of other proteins such as
Saccharomyces cerevisiae
ARO1 protein.
It is a further object of the invention, moreover, to provide polynucleotides that encode ARO1 polypeptides, particularly polynucleotides that encode the polypeptide herein designated ARO1.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises the region encoding ARO1 polypeptides in the sequence set out in Table 1 [SEQ ID NO:1], or a variant thereof.
In another particularly preferred embodiment of the present invention there is a novel arom multifunctional protein protein from
Candida albicans
comprising the amino acid sequence of Table 2 [SEQ ID NO:2], or a variant thereof.
In accordance with this aspect of the present invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressible by the strain
Candida albicans
SC5314 contained in ATCC Deposit No. PTA-567.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding ARO1, particularly Candida ARO1, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention include biologically, diagnostically, prophylactically, clinically or therapeutically useful variants thereof, and compositions comprising same.
In accordance with another aspect of the present invention, there is provided the use of a polynucleotide of the invention for therapeutic or prophylactic purposes, in particular genetic immunization.
Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of ARO1 and polypeptides encoded therefrom.
In accordance with this aspect of the invention there are provided novel polypeptides of Candida referred to herein as ARO1 as well as biologically, diagnostically, prophylactically, clinically or therapeutically useful fragments, variants thereof, and compositions comprising same.
Among the particularly preferred embodiments of this aspect of the invention are variants of ARO1 polypeptide encoded by naturally occurring alleles of the ARO1 gene.
In a preferred embodiment of this aspect of the invention there are provided methods for producing the aforementioned ARO1 polypeptides.
In accordance with yet another aspect of the present invention, there are provided inhibitors to such polypeptides, useful as antifungal agents, including, for example, antibodies.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods, inter alia: assessing ARO1 expression; to treat, for example, candidosis (candidiasis), for example, superficial candidosis; candidosis of the oropharynx, such as, oral thrush (acute pseudomembraneous candodisis), denture stomatitis, angular choilitis (pelèche),
Candida leukoplakia
(chronic hyperplastic candidosis), midline glossitis (median rbomboid glossitis, glossal central papillary atrophy, “antibiotic sore tongue”, acute atrophic candidosis), and miscellaneous forms of oral candidosis; candidosis of the genitalia, such as, vulvovaginal candidosis (vaginal thrush,
Candida colpitis
), and candidosis of the penis (
Candida balanitis, balanoposthitis
and
urethritis
); candidosis of the skin, nails and other external sites, such as,
Candida intertrigo, napkin
(diaper)
dermatitis, Candida onychia
and
paronychia,
candidosis of the external ear, and miscellaneous cutaneous forms of candidosis; chronic mucocutaneous candidosis; systemic candidosis; candidosis of the gastrointestinal tract, such as, esophageal candidosis, gastric candidosis, candidosis of the intestine,
Candida cholecystitis,
and the “autobrewery syndrome” (“meitei-sho”); candidosis of the Urinary Tract, such as, renal candidosis (
Candida pyelonephritis
), candidosis of the urinary bladder (
Candida cystitis
),
Candida urethritis
and
prostatitis;
cardiovascular Candida infections, such as,
candida endocarditis,
and
myocarditis; Candida endocariditis, Candida myocarditis
and
pericarditis, Candida phlebitis
and
thruombophlebitis;
Candida infections of the eye, such as,
Candida endophthalmitis,
Candida infections of the cornea and conjuctiva, and candidosis of the lacrimal sacs (dacryocystitis); candidosis of the central nervous system;
Candida meningitis,
cerebral candidosis, and candidosis of the inner ear; Candida infections of bones and joints;
Candida peritonitis,
hepatitis and miscellaneous other forms of systemic candidosis, such as,
Candida peritonitis, Candida hepatitis
and
splenitis, Candida pancreatitis,
Congenital and intrauterine candidosis (
Candida chorioamnionitis
and
funisitis
); disseminated candidosis, such as, in neonates, young infants, and heroin addicts; Candida allergy, such as,

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