Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.
Mol Biochem Parasitol 1989 Jan 01
PMID:De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum. 264 36

The folylpolyglutamate hydrolase activities of mouse liver, kidney, muscle and brain were examined by incorporation of methylenetetrahydrofolate polyglutamate reaction products into a stable ternary complex with tritiated fluorodeoxyuridylate and L. casei thymidylate synthetase. Complexes were separated electrophoretically on the basis of charge associated with the polyglutamyl moieties to determine distribution of chain lengths throughout the time course of the reaction. Tissue folylpolyglutamate hydrolase activities were allowed to utilize endogenous folylpolyglutamate as substrates by incubating crude tissue extracts at pH 7.4 ang pH 4.5. Kidney and muscle contained relatively reactive hydrolases which were capable of generating intermediates of essentially all chain lengths from folylpentaglutamate, the predominant endogenous species. The relatively low activity in brain also gave rise to all possible intermediates. Liver contained a high concentration of methylenetetrahydrofolate but little hydrolase activity. The activity present in liver gave rise to essentially no intermediates but yielded only the monoglutamate form of the cofactor. When purified lysosomal preparations from liver and kidney were allowed to react with synthetic folylpolyglutamates, the same specificity with regard to reaction products was observed as with endogenous substrates.
Mol Cell Biochem 1982 Mar 19
PMID:Comparison of folylpolyglutamate hydrolases of mouse liver, kidney, muscle and brain. 617 12

We have constructed two phage display libraries expressing N-terminal pIII fusions in M13 composed of 37 and 43 random amino acid domains, respectively. The D38 library expresses 37 random amino acids with a central alanine residue, and the DC43 library contains 43 random amino acids with a central cysteine flanked by two glycine residues, giving the displayed peptide the potential to form disulfide loops of various sizes. We demonstrate that the majority of random sequences in both libraries are compatible in pentavalent display with phage viability. The M13 phage display vector itself has been engineered to contain a factor Xa protease cleavage site to provide an alternative to acid elution during affinity selection. An in-frame amber mutation has been inserted between the pIII cloning sites to allow for efficient selection against nonrecombinant phage in the library. These libraries have been panned against mAb 7E11-C5, which recognizes the prostate-specific membrane antigen (PSM). Isolated phage display a consensus sequence that is homologous to a region in the PSM molecule.
Mol Divers 1996 May
PMID:Construction and screening of M13 phage libraries displaying long random peptides. 923 7

Glutamate carboxypeptidase II (GCP II) catalyzes the extracellular hydrolysis of the neuromodulator N-acetyl-aspartylglutamate to N-acetyl-aspartate and glutamate. GCP II also hydrolyzes gamma-glutamyl bonds in folylpolyglutamate. The predicted amino acid sequence of GCP II displays similarities to aminopeptidases from Streptomyces griseus and Vibrio proteolyticus, whose crystal structures have been determined. These aminopeptidases are cocatalytic zinc metallopeptidases belonging to the peptidase family M28. Specific zinc and substrate ligands have been proposed in GCP II based on the amino acid sequence alignment to these M28 family members. In the present study, site-directed mutagenesis has been used to test the assignment of these putative ligands in human GCP II. Substitutions to the five putative zinc ligands resulted in severely reduced enzyme activity, although mutant protein was expressed as demonstrated by immunoblot analysis. In addition, substitutions of amino acids near the putative zinc ligands have identified other specific residues important for enzyme structure and/or function. Substitutions to putative substrate ligands were less perturbing, and increases in Km were observed for substitutions that introduced a large charge perturbation (e.g., Lys to Glu). The results from substitutions at the proposed zinc and substrate ligands are consistent with the assignment of these residues and suggest that GCP II has a three-dimensional structure similar to other members of the peptidase family M28.
Mol Pharmacol 1999 Jan
PMID:Site-directed mutagenesis of predicted active site residues in glutamate carboxypeptidase II. 988 12

Prostate cancer continues to be the most common cancer and second leading cause of cancer-related death among men. The use of markers, particularly serum-based prostate specific antigen (PSA), has contributed to the rapid rise in diagnosed cases in the late 1980s and early 1990s, but new diagnostic and possible therapeutic markers are needed and are currently being evaluated. One of these, prostate-specific membrane antigen (PSMA), is an approximately 100-kDa type II transmembrane protein originally thought to be highly selectively expressed in all types of prostatic tissue, with expression being upregulated in androgen-depleted or androgen-independent states. The radioimmunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11 is currently being used to diagnose prostate cancer metastasis and recurrence. In addition, Phase I and II trials have started utilizing PSMA in different therapeutic ways, with promising results. Recent exciting work has demonstrated PSMA expression in endothelial cells of vessels restricted to the tumor-associated neovasculature. This finding expands the possible beneficial uses of PSMA, as new anti-PSMA mAbs continue to be developed.
Mol Urol 1999
PMID:Prostate-Specific Membrane Antigen: Much More Than a Prostate Cancer Marker. 1085 38

New diagnostic tools are needed for the early detection of prostatic cancer. The molecular detection of prostate cancer cells in ejaculates was evaluated using complementary PCR-based methods. LNCaP cells, a cell line derived from prostatic carcinoma, were spiked into normal seminal ejaculates and the prostatic epithelial component of the specimens was isolated by immunomagnetic bead sorting, using a monoclonal antibody to prostate-specific membrane antigen (PSMA). Ejaculates from nine patients with a recent diagnosis of prostate cancer were processed in a similar fashion, using LNCaP-spiked aliquots as an internal positive control. Telomerase expression was evaluated by the telomeric repeat amplification protocol (TRAP) and glutathione S-transferase gene promoter (GSTP1) hypermethylation was evaluated by methylation-sensitive restriction endonuclease digestion and PCR amplification. Telomerase activity was detected in LNCaP cells recovered from normal seminal ejaculates but was not found in all nine samples from patients with prostate cancer. The sensitivity of GSTP1 analysis was similar to telomerase analysis for the detection of LNCaP cells from normal ejaculate samples but was positive in ejaculates from four out of nine patients with prostate cancer. GSTP1 DNA methylation status is more sensitive than telomerase analysis for the detection of malignant cells in seminal ejaculates from patients with prostate cancer.
Mol Cell Probes 2000 Aug
PMID:Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. 1097 Jul 25

Androgen deprivation induces substantial changes in the phenotype of prostate cancer that are accompanied by alterations in protein expression. Immunohistochemical studies allow precise cellular localization of such expression, thereby providing an understanding of the biochemical alterations caused by therapy. Expression of proteins may be increased (e.g., multiple growth factors, heat shock protein), decreased (e.g., microvessel density, proliferation markers, certain integrins), or remain unchanged (e.g., prostate specific antigen, prostatic acid phosphatase, prostate-specific membrane antigen, and other secretory proteins). Variations in immunoreactivity may be of prognostic value in some patients. This report summarizes the existing literature regarding changes in tissue expression of proteins, as determined by immunohistochemistry, and the clinical implications of these changes.
Mol Urol 2000
PMID:Immunohistochemical changes in prostate cancer after androgen deprivation therapy. 1106 63

C242-DM1 is a tumor-activated immunotoxin under development by GlaxoSmithKline plc (formerly SmithKline Beecham plc), under licence from ImmunoGen Inc, as a potential treatment for colon tumor. It consists of a colon cancer-specific humanized antibody, C242, conjugated to the maytansine derivative DM1. In preclinical studies, C242-DM1 caused complete tumor regression in animal models of both human pancreatic and non-small cell lung cancer (NSCLC) at non-toxic doses. C242-DM1 has also been evaluated in an immunoconjugate combination with J-591 (Cornell University). The J591-DM1 immunoconjugate demonstrated effective, antigen-specific delivery of a highly cytotoxic drug to PSMA-positive Pca cells in vitro and in vivo with low systemic toxicity. Results from studies in monkeys showed that C242-DM1 had no significant toxicity or side effects, when administered at doses higher than those that were previously shown to completely eradicate human colon tumors in mice [271420]. ImmunoGen acquired the right to evaluate, and an option to license, technology related to maytansines from Takeda. In February 1999, ImmunoGen and SmithKline Beecham signed a US $45 million development and commercialization agreement for C242-DM1 [313493]. In August 1997, Immunogen received an SBIR grant to advance development of huC242-DM1 [258356]. EP-00425235, held by ImmunoGen, covers conjugated forms of ansamitocin (maytansine) derivatives. Takeda holds several patents for the production of ansamitocin and its analogs, the first one being JP-53124692.
Curr Opin Mol Ther 2001 Apr
PMID:Technology evaluation: C242-DM1, ImmunoGen Inc. 1133 34

Many researchers have investigated the expressions of candidates for a suitable reverse transcription nested polymerase chain reaction (RT-PCR) marker. But typically biomarkers often have false-positive results. We assessed whether epidermal growth factor receptor (EGFR), carcinoembryonic antigen (CEA) and prostate-specific membrane antigen (PSM) could be detected in 28 different types of normal human sources. Using RT-nested PCR assay, EGFR mRNA was also detected in various types of normal tissue, including pancreas, prostate and uterus. CEA was detected in various types of normal tissue, including prostate, uterus, bladder and spleen. PSM mRNA was also detected in various types of normal tissue, including kidney, liver, skeletal muscle, spleen, bladder and ovary. We report here that the expression of these biomarkers in normal cells might have induced false-positives, and that further enhancement of sensitivity might compromise specificity. Conversely, these biomarkers can be utilized for attempts to define micrometastases in various types of tumors whose cells express these tissue-specific genes.
Int J Mol Med 2002 Sep
PMID:Expression of molecular marker genes in various types of normal tissue: implication for detection of micrometastases. 1216 5

The expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA), two well characterized marker proteins, remains highly active in the hormone refractory stage of prostate cancer. In this study, an artificial chimeric enhancer (PSES) composed of two modified regulatory elements controlling the expression of PSA and PSMA genes was tested for its promoter activity and tissue specificity using the reporter system. As a result, this novel PSES promoter remained silent in PSA- and PSMA-negative prostate and non-prostate cancer cell lines, but mediated high levels of luciferase in PSA- and PSMA-expressing prostate cancer cell lines in the presence and absence of androgen. To determine whether PSES could be used for in vivo gene therapy of prostate cancer, a recombinant adenovirus, Ad-PSES-luc, was constructed. Luciferase activity in prostate cancer cell lines mediated by Ad-PSES-luc was 400- to 1000-fold higher than in several other non-prostate cell lines, suggesting the high tissue-specificity of the PSES promoter in an adenoviral vector. Finally, recombinant virus Ad-PSES-luc was injected into mice to evaluate the tissue-discriminatory promoter activity in an experimental animal. Unlike Ad-CMV-luc, the luciferase activity from systemic injection of Ad-PSES-luc was fairly low in all major organs. However, when injected into prostate, Ad-PSES-luc drove high luciferase activity almost exclusively in prostate and not in other tissues. Our results demonstrated the potential use of PSES for the treatment of androgen-independent prostate cancer patients.
Mol Ther 2002 Sep
PMID:Novel prostate-specific promoter derived from PSA and PSMA enhancers. 1223 Nov 79


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