Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of an orally active inhibitor (UK 79300) of the neutral metalloendopeptidase EC 3.4.24.11 were investigated in six healthy male volunteers maintained on a constant diet (150 mmol sodium/day and 80 mmol potassium/day). Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours). The endopeptidase inhibitor enhanced plasma concentrations of atrial natriuretic factor in association with suppression of both plasma renin activity and aldosterone concentrations. Twenty-four-hour urinary excretion of sodium was doubled by UK 79300, and the urinary excretion rates of phosphorus, atrial natriuretic factor immunoreactivity, and cyclic guanosine monophosphate were also significantly enhanced, whereas urinary aldosterone excretion was halved. The profile of biological effects closely paralleled those previously reported with low dose infusions of atrial natriuretic factor in humans and animals. Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action.
Hypertension 1990 Sep
PMID:Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects. 214 60

The cell-surface neutral endopeptidase 3.4.24.11 (NEP) activity of the common acute lymphoblastic leukaemia antigen (CALLA) cleaves diverse peptide mediators at specific sites and it has been postulated that it regulates immune responses. The concentration of NEP was quantified in detergent extracts of synovial tissues by the percentage hydrolysis of [3H-D-Ala]-Leu enkephalin/hr/100 mg of tissue. The synovial tissue concentration of NEP was higher in all patients with rheumatoid arthritis (n = 7; group mean +/- SD = 29.4 +/- 20.2%), and was higher with degenerative joint disease (n = 6 of 8; group mean +/- SD = 11.9 +/- 10.4%) than with traumatic arthropathy (n = 3; 1.1 +/- 0.7%). The lack of direct relationship between synovial tissue NEP concentration and leukocytic infiltration suggests that the cellular source of NEP may be synoviocytes or fibroblasts, and that NEP may have distinctive pathogenetic roles in human arthritis.
Immunology 1990 Sep
PMID:Elevated synovial tissue concentration of the common acute lymphoblastic leukaemia antigen (CALLA)-associated neutral endopeptidase (3.4.24.11) in human chronic arthritis. 214 13

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.
Am J Hypertens 1990 Sep
PMID:The atriopeptidase inhibitor UK 69,578 increases atrial natriuretic factor and causes a natriuresis in normal humans. 214 71

Atrial natriuretic factor (ANF) is a peptide hormone secreted by the heart that is degraded in vivo by endopeptidase 24:11 (atriopeptidase). UK 69,578 is a novel atriopeptidase inhibitor that raises plasma levels of ANF in animals and normal volunteers, with associated diuresis and natriuresis. This study examines the effects of UK 69,578 in patients with mild heart failure. UK 69,578 was administered as an intravenous infusion over 20 min in a placebo-controlled, cross-over study to six patients with stable (NYHA Class 2) chronic heart failure. The atriopeptidase inhibitor was well tolerated and no side effects were encountered. Mean baseline plasma ANF was elevated at 88 pg/mL (normal less than 50), and increased 2- to 5-fold after UK 69,578 administration. Plasma ANF did not change significantly following placebo. There was a marked diuresis after UK 69,578 compared to placebo. Urinary sodium excretion doubled for 4 to 6 h, but there was no significant rise in potassium excretion. There was no increase in plasma active renin concentration during the study period. Noninvasive hemodynamic monitoring revealed no significant changes in heart rate, systemic arterial blood pressure, or echocardiographic left ventricular dimensions. However, invasive measurements using a Swan-Ganz catheter demonstrated falls in mean right atrial and pulmonary artery wedge pressures after UK 69,578. There was no change in cardiac output. Thus, inhibition of endopeptidase 24:11 by UK 69,578 results in significant elevation of plasma ANF, with associated diuresis, natriuresis and venodilatation. The compound was well tolerated in these patients with mild chronic heart failure.
Am J Hypertens 1990 Sep
PMID:Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure. 214 74

We have generated in vitro lymphokine-activated killer (LAK) cells from healthy donors by stimulating their mononuclear leukocytes with recombinant interleukin-2 (rIL-2) (100 U/ml). After 6 days in culture, the lytic properties of the LAK cells were analyzed in the 51Cr-release assay by utilizing a target panel of 6 paired lines consisting of an Epstein-Barr virus (EBV)-positive Burkitt's lymphoma (BL) cell line and an EBV-transformed lymphoblastoid cell line (LCL) from the same donor, the Raji BL line and the natural killer (NK) cell-sensitive K562 line. The patterns of lysis showed that the LAK cells discriminated between two categories of BL cell lines. Group I/II BL tumor cells which expressed the common acute lymphoblastic leukemia antigen (CALLA), the BL-associated glycolipid antigen (BLA) and phenotypically resembled biopsy cells were strongly lysed whereas group III BL cells which had assumed an LCL-like phenotype during culture and lacked the CALLA and BLA surface markers were only poorly lysed. The LCL targets were generally resistant to lysis but the K562 cell line was particularly sensitive. The outcome of cell depletion and monoclonal antibody (MAb) studies indicated that the LAK cell populations were phenotypically and functionally heterogeneous and consisted of at least 2 subpopulations of effector cells; a tumor-specific component and an NK-cell-mediated component.
Int J Cancer 1990 Sep 15
PMID:Lymphokine-activated killer (LAK) cells discriminate between Epstein-Barr virus (EBV)-positive Burkitt's lymphoma cells. 216 43

To examine whether the norpA (no receptor potential A) gene encodes a phosphoinositide-specific phospholipase C (PLC) in the eye of Drosophila, a major PLC in the extract from normal Drosophila heads, which was absent in the extract from norpA mutant heads, and purified and its partial amino acid sequences were determined. The purification of the major PLC in KCl extract from normal Drosophila heads was achieved by sequential column chromatography on DEAE-Sepharose CL-6B, Mono Q, Superose 12, Mono S, second Mono S, and second Mono Q, followed by column chromatography on Superose 12 in the presence of 1% sodium cholate. The enzyme thus purified was found to be homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular weight of the enzyme was estimated to be 98,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified enzyme hydrolyzed both phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP2). Interestingly, the calcium and pH requirements for activation of the crude enzyme (KCl extract) were quite different from those of partially purified enzyme (active fraction from second Mono Q column). The maximal activity for PIP2 hydrolysis was observed at calcium concentrations between 10(-7) and 10(-5) M for both the crude and partially purified enzymes. On the other hand, the activity for PI hydrolysis of the crude enzyme increased with increasing calcium concentrations, while that of the partially purified enzyme reached a maximum at calcium concentrations between 10(-6) and 10(-4) M, and decreased at millimollar concentration. The pH dependences for PI hydrolysis of the crude enzyme and the partially purified enzyme were similar. The crude enzyme hydrolyzed PIP2 over a broad pH range from 6 to 8.5, while the activity of the partially purified enzyme monotonously increased with increasing pH. The partial amino acid sequences were determined by treating the purified enzyme with endopeptidase Lys-C; the resultant peptide fragments were purified on a high performance liquid chromatography-reverse phase column and then sequenced with sequencer. The obtained sequences were found to be a part of the deduced amino acid sequences of cDNA which was suggested to be norpA gene.
J Biol Chem 1990 Sep 05
PMID:Purification and partial amino acid sequences of phosphoinositide-specific phospholipase C of Drosophila eye. 216 93

Four Epstein-Barr virus-positive lymphoblastoid cell lines (LCL) were successfully infected in vitro with immunodeficiency virus type 1 (HIV-1) as demonstrated by reverse transcriptase activity and p24 HIV antigen in culture supernatants, positive cell staining for gag-encoded HIV proteins, presence of viral HIV genome by Southern blot analysis and ulstrastructural observations. In addition, both HIV-1-infected B cells and their supernatants efficiently transactivated the chloramphenicol acetyl transferase reporter gene which is under the control of the HIV-1 long terminal repeat. The LCL cells displayed long-term HIV-1 infection and production, but no cytopathic effects were observed. Cytofluorimetric analysis did not detect membrane CD4 presence in the LCL cells before and after HIV-1 infection; moreover, a minute amount of CD4 mRNA was observed only in one of the LCL. A monoclonal antibody specific for the viral binding site of the CD4 molecule delayed, but did not block, HIV-1 infection of the LCL cells. Following HIV-1 infection, changes in LCL phenotype were observed, consisting of a decrease in CD23- and CD39-positive cells, and a concomitant increase of cells with surface CD10 and Bac-1. Furthermore, HIV-1-infected LCL cells did not grow in tight clumps, as usually observed in uninfected LCL, but as disperse suspensions, and formed more agar colonies than control LCL. However, despite this apparent acquisition of a malignant-like phenotype, c-myc proto-oncogene rearrangement was not detected. The appearance of cells with new characteristics did not seem due to clone selection by HIV-1 infection, since all the LCL conserved their clonotypic pattern of IgH chain rearrangement. The acquisition of malignant-like features by HIV-infected B cells might be clinically significant in terms of the pathogenesis of non-Hodgkin's B cell lymphomas, which occur frequently in AIDS patients.
Eur J Immunol 1990 Sep
PMID:Infection of Epstein-Barr virus-transformed lymphoblastoid B cells by the human immunodeficiency virus: evidence for a persistent and productive infection leading to B cell phenotypic changes. 217 Jan 47

15 cases of HCL were studied with a panel of monoclonal antibodies against different leukocyte antigens. A B-cell phenotype different from that of B-CLL was observed (CD10-, CD19+, CD20+, CD21-, CD22+, CD37+, CD38-, FMC7+, LN1+, PCA-1+, BLy7+ and CD5-). As expected, CD11c and CD25 were positive and, in addition, a My7 and My9 positivity in varying degree was noted. 3 weeks of in vitro incubation did not significantly alter the phenotype. We conclude that HCL exhibits a unique phenotype among chronic B-cell leukemias, which is closer to the plasma cell stage of differentiation than that of B-CLL. The BLy7 monoclonal antibody seems to be a promising marker for HCL.
Eur J Haematol 1990 Sep
PMID:Immunophenotype of hairy-cell leukemia. 222 30

The proinsulin-insulin system provides a general model for the proteolytic processing of polypeptide hormones. Two proinsulin-specific endopeptidases have been defined, a type I activity that cleaves the B-chain/C-peptide junction (Arg31-Arg32) and a type II activity that cleaves the C-peptide/A-chain junction (Lys64-Arg65). These endopeptidases are specific for their respective dibasic target sites; not all such dibasic sites are cleaved, however, and studies of mutant proinsulins have demonstrated that additional sequence or structural features are involved in determining substrate specificity. To define structural elements required for endopeptidase recognition, we have undertaken comparative 1H NMR and photochemical dynamic nuclear polarization (photo-CIDNP) studies of human proinsulin, insulin, and split proinsulin analogues as models of prohormone processing intermediates. The overall conformation of proinsulin is observed to be similar to that of insulin, and the connecting peptide is largely unstructured. In the 1H NMR spectrum of proinsulin significant variation is observed in the line widths of insulin-specific amide resonances, reflecting exchange among conformational substates; similar exchange is observed in insulin and is not damped by the connecting peptide. The aromatic 1H NMR resonances of proinsulin are assigned by analogy to the spectrum of insulin, and assignments are verified by chemical modification. Unexpectedly, nonlocal perturbations are observed in the insulin moiety of proinsulin, as monitored by the resonances of internal aromatic groups. Remarkably, these perturbations are reverted by site-specific cleavage of the connecting peptide at the CA junction but not the BC junction. These results suggest that a stable local structure is formed at the CA junction, which influences insulin-specific packing interactions. We propose that this structure (designated the "CA knuckle") provides a recognition element for type II proinsulin endopeptidase.
Biochemistry 1990 Sep 11
PMID:NMR and photo-CIDNP studies of human proinsulin and prohormone processing intermediates with application to endopeptidase recognition. 225 1

On the basis of the identity of a segment of the amino acid sequence within the active site of the bacterial enzyme thermolysin and the mammalian enzyme neutral endopeptidase 24.11, the possible involvement of valine-573 of neutral endopeptidase 24.11 in substrate binding was investigated. Valine-573 was changed to leucine and to alanine by site-directed mutagenesis. The effect of these mutations on inhibitor binding and substrate catalysis was examined with a series of compounds containing variable P'1 residues. With a small P'1 residue such as alanine, both mutant enzymes exhibited kinetic properties essentially the same as the wild-type enzyme. However, with larger P'1 residues such as phenylalanine, tyrosine, and leucine, the Val573Leu mutant showed a 24-100-fold decrease in inhibitor affinity. Similarly substrates containing bulky P'1 residues showed a 10-40-fold decrease in Vmax with little change in Km. In contrast, the Val573Ala mutant showed only modest changes in terms of inhibitor binding or substrate turnover. These results support the proposed role of valine-573 as a part of the hydrophobic binding pocket, S'1 binding subsite, of neutral endopeptidase 24.11.
Biochemistry 1990 Sep 04
PMID:Use of site-directed mutagenesis to identify valine-573 in the S'1 binding site of rat neutral endopeptidase 24.11 (enkephalinase). 226 63


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