Glutamate Carboxypeptidase II
Carboxypeptidases
Antigens, Surface
Organophosphorus Compounds
Folic Acid
Tromethamine
Carboxypeptidase H
Carboxypeptidase B
Carboxypeptidases A
Isolation and expression of novel human glutamate carboxypeptidases with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl peptidase IV activity. (1/231)
Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. The gene coding for human prostate-specific membrane antigen, a marker of prostatic carcinomas, and its rat homologue glutamate carboxypeptidase II have recently been shown to possess such NAALADase activity. In contrast, a closely related member of this gene family, rat ileal 100-kDa protein, possesses a dipeptidyl peptidase IV activity. Here, we describe the cloning of human ileal 100-kDa protein, which we have called a NAALADase- "like" (NAALADase L) peptidase based on its sequence similarity to other members of this gene family, and its inability to hydrolyze NAAG in transient transfection experiments. Furthermore, we describe the cloning of a third novel member of this gene family, NAALADase II, which codes for a type II integral membrane protein and which we have localized to chromosome 11 by fluorescent in situ hybridization analysis. Transient transfection of NAALADase II cDNA confers both NAALADase and dipeptidyl peptidase IV activity to COS cells. Expression studies using reverse transcription-polymerase chain reaction and Northern blot hybridization show that NAALADase II is highly expressed in ovary and testis as well as within discrete brain areas. (+info)Purification, cDNA cloning, and expression of a new human blood plasma glutamate carboxypeptidase homologous to N-acetyl-aspartyl-alpha-glutamate carboxypeptidase/prostate-specific membrane antigen. (2/231)
We describe the identification, cDNA cloning, and biochemical characterization of a new human blood plasma glutamate carboxypeptidase (PGCP). PGCP was co-purified from human placenta with lysosomal carboxypeptidase, cathepsin A, lysosomal endopeptidase, cathepsin D, and a gamma-interferon-inducible protein, IP-30, using an affinity chromatography on a Phe-Leu-agarose column. A PGCP cDNA was obtained as an expressed sequence tag clone and completed at 5'-end by rapid amplification of cDNA ends polymerase chain reaction. The cDNA contained a 1623-base pair open reading frame predicting a 541-amino acid protein, with five putative Asn glycosylation sites and a 21-residue signal peptide. PGCP showed significant amino acid sequence homology to several cocatalytic metallopeptidases including a glutamate carboxypeptidase II also known as N-acetyl-aspartyl-alpha-glutamate carboxypeptidase or as prostate-specific membrane antigen and expressed glutamate carboxypeptidase activity. Expression of the PGCP cDNA in COS-1 cells, followed by Western blotting and metabolic labeling showed that PGCP is synthesized as a 62-kDa precursor, which is processed to a 56-kDa mature form containing two Asn-linked oligosaccharide chains. The mature form of PGCP was secreted into the culture medium, which is consistent with its intracellular localization in secretion granules. In humans, PGCP is found principally in blood plasma, suggesting a potential role in the metabolism of secreted peptides. (+info)Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. (3/231)
Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was initially characterized by the monoclonal antibody (mAb) 7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and prostate cancer as well as in several extraprostatic tissues. Recent evidence suggests that PSMA is also expressed in tumor-associated neovasculature. We examined the immunohistochemical characteristics of 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA. Using the streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer cell lines and various fresh-frozen benign and malignant tissue specimens. In the latter, we compared the localization of the anti-PSMA mAbs to that of the anti-endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted strongly with the neovasculature of a wide spectrum of malignant neoplasms: conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5 of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5 cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6 cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti-PSMA mAbs to tumor-associated neovasculature was confirmed by CD34 immunohistochemistry in sequential tissue sections. Normal vascular endothelium in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases) but not with the neoplastic cells of any other tumor type, including those of benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1 hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5 of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7 cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently expressed in the neovasculature of a wide variety of malignant neoplasms and may be an effective target for mAb-based antineovasculature therapy. (+info)Prostate-specific membrane antigen is produced in tumor-associated neovasculature. (4/231)
Prostate-specific membrane antigen (PSMA), a type II transmembrane protein, was originally thought to be strictly expressed in prostatic tissue, but recent studies have demonstrated PSMA protein expression in nonprostatic tumor neovasculature as well. Using immunohistochemistry, reverse transcription-PCR assays, and in situ hybridization, we have demonstrated PSMA mRNA transcripts and protein expression in the endothelium of tumor-associated neovasculature of multiple nonprostatic solid malignancies. In addition, we found no PSMA mRNA or protein expression in the vascular endothelial cells of corresponding benign tissue examples. Our findings expand the possible therapeutic role of PSMA and establish it as a unique biomarker specifically produced and expressed by tumor-associated neovasculature but not produced or expressed by normal vessels. (+info)PSMA mimotope isolated from phage displayed peptide library can induce PSMA specific immune response. (5/231)
Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed predominantly in prostate secretory acinar epithelium and prostate cancer cells as well as in several extraprostatic tissues. Mouse monoclonal antibody 4G5 specific to the extracellular domain of PSMA was used to screen two phage displayed peptide libraries (9aa linear and 9aa cys library). Three 4G5-reactive phagotopes were identified. Sequence analysis of isolated clones demonstrated that the interaction motif "VDPA/SK" has high homology to 719-725aa on PSMA. Immunohistochemical staining of the prostate cancer sample with the PSMA-mimic phagotope (mimotope) immunized serum antibodies demonstrate that the mimotope isolated from the phage displayed peptide libraries can induce PSMA specific immune response in vivo. (+info)Prostate-specific membrane antigen levels in sera from healthy men and patients with benign prostate hyperplasia or prostate cancer. (6/231)
Prostate-specific membrane antigen (PSMA) serum levels have been proposed to be of prognostic significance in patients with advanced prostate disease. The objective of the present study was to confirm PSMA serum expression by Western blot techniques, to determine whether such data could assist in the differentiation of benign from malignant prostatic disease, and to determine the suitability of serum PSMA measurements in predicting recurrent or progressive prostate malignancies. We measured PSMA, a transmembrane glycoprotein identified in prostate epithelial cells, in the sera of 236 normal individuals and cancer patients by Western blot analysis. Within the normal male population, PSMA levels increase with age and were found to be significantly elevated in subjects more than 50 years of age when compared to those of younger men. We did not confirm previous reports that serum PSMA measurements could distinguish late-stage prostate carcinoma from early-stage prostate carcinoma, nor did we find PSMA to be more effective than prostate-specific antigen in monitoring prostate cancer patient prognosis. Furthermore, we found elevated serum PSMA in healthy females, and, similar to the healthy male population, the levels increased with age, with the highest levels found in the sera from breast cancer patients. These latter observations further support that PSMA is not a specific biomarker for prostate cancer and that a variety of normal and diseased tissue may contribute to the serum levels of PSMA. (+info)Dendritic cell-based immunotherapy of prostate cancer: immune monitoring of a phase II clinical trial. (7/231)
We assessed both non- and peptide-specific immune responses in prostate cancer patients before and after immunotherapy with dendritic cells exogenously pulsed with the prostate-specific membrane antigen-derived peptides, PSM-P1 and PSM-P2. For all subjects, we observed that clinical responses were strongly associated with two indicators of immunocompetence: skin test responses to recall antigens and cytokine secretion by T cells after nonspecific stimulation. In a subset of responders, we observed cytokine secretion or cytotoxicity against the immunizing peptides or an immunodominant epitope from an influenza recall antigen. The clinical results support the use of monitoring for overall immunocompetence to help determine why a patient has or has not responded to therapy. Moreover, it could be useful as an inclusion criterion to select those more likely to benefit from treatment. (+info)The development of biologic end points in patients treated with differentiation agents: an experience of retinoids in prostate cancer. (8/231)
The evaluation of new therapies in prostate cancer requires unique end points for agents with diverse mechanisms of action. Because retinoic acid may have a confounding effect on prostate-specific antigen, we incorporated a pathological end point into the outcome assessment of two sequential clinical trials using all-trans-retinoic acid (ATRA) and the combination of 13-cis-retinoic acid and IFN-2a (cRA inverted question markIFN). Pre- and posttherapy tumor biopsy specimens were studied for histological changes, apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), and proliferation index (Ki67). Prostate-specific membrane antigen (PSMA) expression was also evaluated using two different monoclonal antibodies to its intracellular domain (Cytogen 7E11 and Hybritech PM2). Fourteen patients with androgen-independent disease were treated with ATRA (50 mg/m2 p.o. every 8 h daily) and 16 androgen-independent and 4 androgen-dependent patients were treated with cRA inverted question markIFN (10 mg/kg/day cRA plus 3, 6, or 9 million units daily IFN). Both therapies were well tolerated, with fatigue and cheilitis being the most common adverse events. Clinical activity, assessed by radiographs and serum prostate-specific antigen, was minimal, and the majority of patients progressed within 3 months. One patient with androgen-dependent disease had prolonged stabilization for >1 year. The majority of cases (95%) showed no gross histological changes and no difference in apoptotic or proliferative indices. Increased PSMA immunoreactivity was seen in seven of nine (78%) cases using PM2 antibody and in two of nine (22%) cases using the 7E11 antibody. Although antitumor effects were modest, the results suggest a role for retinoids in modulating the expression of PSMA on prostate cancer cells. (+info)Glutamate carboxypeptidase II, also known as prostate-specific membrane antigen (PSMA) or N-acetylated-alpha-linked acidic dipeptidase (NAALADase), is a type II transmembrane glycoprotein enzyme. It is primarily expressed in the prostate epithelium, but can also be found in other tissues such as the kidney, brain, and salivary glands.
PSMA plays a role in the regulation of glutamate metabolism by cleaving N-acetylaspartylglutamic acid (NAAG) to produce N-acetylaspartate (NAA) and glutamate. It has been identified as a useful biomarker for prostate cancer, with increased expression associated with more aggressive tumors.
In addition to its enzymatic activity, PSMA has been shown to have other functions, including involvement in cellular signaling pathways and regulation of angiogenesis. As a result, it is being investigated as a potential therapeutic target for the treatment of prostate cancer and other malignancies.
Carboxypeptidases are a group of enzymes that catalyze the cleavage of peptide bonds at the carboxyl-terminal end of polypeptides or proteins. They specifically remove the last amino acid residue from the protein chain, provided that it has a free carboxyl group and is not blocked by another chemical group. Carboxypeptidases are classified into two main types based on their catalytic mechanism: serine carboxypeptidases and metallo-carboxypeptidases.
Serine carboxypeptidases, also known as chymotrypsin C or carboxypeptidase C, use a serine residue in their active site to catalyze the hydrolysis of peptide bonds. They are found in various organisms, including animals and bacteria.
Metallo-carboxypeptidases, on the other hand, require a metal ion (usually zinc) for their catalytic activity. They can be further divided into several subtypes based on their structure and substrate specificity. For example, carboxypeptidase A prefers to cleave hydrophobic amino acids from the carboxyl-terminal end of proteins, while carboxypeptidase B specifically removes basic residues (lysine or arginine).
Carboxypeptidases have important roles in various biological processes, such as protein maturation, digestion, and regulation of blood pressure. Dysregulation of these enzymes has been implicated in several diseases, including cancer, neurodegenerative disorders, and cardiovascular disease.
Surface antigens are molecules found on the surface of cells that can be recognized by the immune system as being foreign or different from the host's own cells. Antigens are typically proteins or polysaccharides that are capable of stimulating an immune response, leading to the production of antibodies and activation of immune cells such as T-cells.
Surface antigens are important in the context of infectious diseases because they allow the immune system to identify and target infected cells for destruction. For example, viruses and bacteria often display surface antigens that are distinct from those found on host cells, allowing the immune system to recognize and attack them. In some cases, these surface antigens can also be used as targets for vaccines or other immunotherapies.
In addition to their role in infectious diseases, surface antigens are also important in the context of cancer. Tumor cells often display abnormal surface antigens that differ from those found on normal cells, allowing the immune system to potentially recognize and attack them. However, tumors can also develop mechanisms to evade the immune system, making it difficult to mount an effective response.
Overall, understanding the properties and behavior of surface antigens is crucial for developing effective immunotherapies and vaccines against infectious diseases and cancer.
A dipeptide is a type of molecule that is formed by the condensation of two amino acids. In this process, the carboxyl group (-COOH) of one amino acid combines with the amino group (-NH2) of another amino acid, releasing a water molecule and forming a peptide bond.
The resulting molecule contains two amino acids joined together by a single peptide bond, which is a type of covalent bond that forms between the carboxyl group of one amino acid and the amino group of another. Dipeptides are relatively simple molecules compared to larger polypeptides or proteins, which can contain hundreds or even thousands of amino acids linked together by multiple peptide bonds.
Dipeptides have a variety of biological functions in the body, including serving as building blocks for larger proteins and playing important roles in various physiological processes. Some dipeptides also have potential therapeutic uses, such as in the treatment of hypertension or muscle wasting disorders.
Organophosphorus compounds are a class of chemical substances that contain phosphorus bonded to organic compounds. They are used in various applications, including as plasticizers, flame retardants, pesticides (insecticides, herbicides, and nerve gases), and solvents. In medicine, they are also used in the treatment of certain conditions such as glaucoma. However, organophosphorus compounds can be toxic to humans and animals, particularly those that affect the nervous system by inhibiting acetylcholinesterase, an enzyme that breaks down the neurotransmitter acetylcholine. Exposure to these compounds can cause symptoms such as nausea, vomiting, muscle weakness, and in severe cases, respiratory failure and death.
Folic acid is the synthetic form of folate, a type of B vitamin (B9). It is widely used in dietary supplements and fortified foods because it is more stable and has a longer shelf life than folate. Folate is essential for normal cell growth and metabolism, and it plays a critical role in the formation of DNA and RNA, the body's genetic material. Folic acid is also crucial during early pregnancy to prevent birth defects of the brain and spine called neural tube defects.
Medical Definition: "Folic acid is the synthetic form of folate (vitamin B9), a water-soluble vitamin involved in DNA synthesis, repair, and methylation. It is used in dietary supplementation and food fortification due to its stability and longer shelf life compared to folate. Folic acid is critical for normal cell growth, development, and red blood cell production."
Tromethamine is a chemical compound with the formula (CH2OH)3CNH2. It is also known as tris(hydroxymethyl)aminomethane or THAM. Tromethamine is a tertiary amine that acts as a buffer, maintaining a stable pH in various solutions.
In medical terms, tromethamine is used as a medication to correct acid-base imbalances in the body. It works by binding hydrogen ions and converting them into water and carbon dioxide, which can then be eliminated from the body. Tromethamine is often used in critically ill patients who have severe metabolic acidosis, a condition characterized by an excess of acid in the body that can lead to organ dysfunction and failure.
Tromethamine is available as a sterile solution for injection or as a powder to be reconstituted with sterile water for injection. It may also be used as an additive to intravenous fluids to help maintain a stable pH. Common side effects of tromethamine include local irritation at the injection site, nausea, vomiting, and headache.
Carboxypeptidase H is also known as carboxypeptidase E or CPE. It is an enzyme that plays a role in the processing and activation of neuropeptides, which are small protein-like molecules that function as chemical messengers within the nervous system. Carboxypeptidase H/E is responsible for removing certain amino acids from the end of newly synthesized neuropeptides, allowing them to become biologically active. It is widely expressed in the brain and other tissues throughout the body.
Carboxypeptidase B is a type of enzyme that belongs to the peptidase family. It is also known as carboxypeptidase B1 or CpB. This enzyme plays a crucial role in the digestion of proteins by cleaving specific amino acids from the carboxyl-terminal end of polypeptides.
Carboxypeptidase B preferentially removes basic arginine and lysine residues from protein substrates, making it an essential enzyme in various physiological processes, including blood clotting, hormone processing, and neuropeptide metabolism. It is synthesized as an inactive zymogen, procarboxypeptidase B, which is converted to its active form upon proteolytic activation.
In addition to its physiological functions, carboxypeptidase B has applications in research and industry, such as protein sequencing, peptide synthesis, and food processing.
Carboxypeptidases A are a group of enzymes that play a role in the digestion of proteins. They are found in various organisms, including humans, and function to cleave specific amino acids from the carboxyl-terminal end of protein substrates. In humans, Carboxypeptidase A is primarily produced in the pancreas and secreted into the small intestine as an inactive zymogen called procarboxypeptidase A.
Procarboxypeptidase A is activated by trypsin, another proteolytic enzyme, to form Carboxypeptidase A1 and Carboxypeptidase A2. These enzymes have different substrate specificities, with Carboxypeptidase A1 preferentially cleaving aromatic amino acids such as phenylalanine and tyrosine, while Carboxypeptidase A2 cleaves basic amino acids such as arginine and lysine.
Carboxypeptidases A play a crucial role in the final stages of protein digestion by breaking down large peptides into smaller di- and tripeptides, which can then be absorbed by the intestinal epithelium and transported to other parts of the body for use as building blocks or energy sources.
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