Angiotensin-Converting Enzyme Inhibitors: Biochemical Properties and Biological Action

Ondetti, Miguel A.; Cushman, David; Soffer, Richard L.

doi:10.3109/10409238409108720

Cited by 76 publications

(30 citation statements)

References 130 publications

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“…From these results, it can be concluded that TeTx L chain exhibits a thioldependent zinc endopeptidase activity. However, specific inhibitors of other zinc endopeptidases, such as captopril or trandolaprilate for angiotensinconverting enzyme (Ondetti et al, 1984), phosphoramidon for thermolysin and thiorphan or RB 104 (Fournit-Zaluslu et al, 1992) for neutral endopeptidase 24.11 (for a review see Roques et al, 1993), are completely devoid of inhibitory activity. Even a stimulatory action is found for the mercaptoinhibitors captopril and thiorphan (fivefold and twofold respectively) due certainly to their thiol-associated reducing properties.…”

Section: Resultsmentioning

confidence: 99%

Solid‐phase synthesis, conformational analysis and in vitro cleavage of synthetic human synaptobrevin II 1–93 by tetanus toxin L chain

Cornille

Goudreau

Ficheux

et al. 1994

European Journal of Biochemistry

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A 93-residue peptide corresponding to the cytosolic domain of a human vesicle associated membrane protein (VAMP or synaptobrevin) has been prepared by solid-phase peptide synthesis in order to investigate the proteolytic activity of the tetanus toxin light chain (TeTx L chain). This protein has been recently reported to inactivate the neuronal rat synaptobrevin I1 by proteolysis. We show in this study that the synthetic human synaptobrevin I1 1-93 (Syb I1 1-93) as well as an Nterminus-shortened 69-residue peptide were cleaved selectively at the Gln76-Phe77 peptide bond by TeTx L chain while shorter peptides were not. A Michaelis constant K , = 192 & 2 pM and a catalytic constant k,,, = 0.5 min-I were found for the 93-residue peptide. A neutral optimum pH for the cleavage rate, an inhibition by preincubation of the toxin with well known nonspecific inhibitors of metallopeptidases as well as a zinc-dependent enzyme activity suggest that TeTx belongs to the zinc endopeptidase family. Moreover an activation by reducing agents and an inhibition by cysteine-modifying chemical reagents indicate a critical thiol dependency. Among several specific inhibitors of zinc endopeptidases tested, none could inhibit TeTx L chain even at high concentration. Structural studies by 600-MHz 'H-NMR showed that in water or dimethylsulfoxide the peptide Syb I1 1-93 and shorter fragments did not present well definkd conformations. Nevertheless protein-protein interactions have been shown for the peptides Syb I1 1-93 and 25-93 but not for Syb I1 51-93, a fragment not cleaved by TeTx L chain.Tetanus is a mammalian disease generated by the infection of a wound by the anaerobic bacillus Clostridium tetani. Clinically, this is manifested by a spastic paralysis induced by prevention of inhibitory neurotransmitter (4-aminobutyric acid and glycine) release in the central nervous system (for reviews see:

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Section: Resultsmentioning

confidence: 99%

Solid‐phase synthesis, conformational analysis and in vitro cleavage of synthetic human synaptobrevin II 1–93 by tetanus toxin L chain

Cornille

Goudreau

Ficheux

et al. 1994

European Journal of Biochemistry

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“…We made early but unsuccessful attempts to produce tripeptide analogue inhibitors of ACE by substituting onto sulfhydryl or carboxylic acid prototypes a phenylalkyl side chain that might mimic the corresponding residue of an antepenultimate aromatic amino acid in a substrate. Our observation that substituted glutaryl proline derivatives were equal to or better than the corresponding succinyl prolines was one of the starting points for the development by the Merck group 17 of the next major class of specific ACE inhibitors, a series of tripeptide analogue inhib-itors, including enalapril and lisinopril, that were reported in 1980. Later, tripeptide analogue inhibitors with hydroxyphosphinyl zinc ligands were developed at Squibb; and these, like all of the other clinically important ACE inhibitors, are structurally related to the tripeptide sequence Phe-Ala-Pro.…”

Section: History Of the Design Of Captopril And Related Inhibitors Ofmentioning

confidence: 99%

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

1991

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“…Protein concentration was determined by the method of Bradford. Inhibition studies for ACE activity were performed after preincubation with 1 pM enalaprilat (a gift from Merck Sharp and Dohme) (Ondetti and Cushman, 1984). ACE mRNA characterization by reverse transcriptase polymerase chain reaction (RT-PCR) amplification Total human lung RNA was prepared by the guanidinium thiocyanate CsCl method (Chirgwin et al, 1979).…”

Section: Ace Assay In Transformed Endothelial Cellsmentioning

confidence: 99%

Cell adhesion markers are expressed by a stable human endothelial cell line transformed by the SV40 large T antigen under vimentin promoter control

Vicart

Testut

Schwartz

et al. 1993

Journal Cellular Physiology

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Markers of endothelium have been studied in a new endothelial cell line derived from human umbilical cord vein cells by microinjection of a recombinant gene that includes a deletion mutant of the human vimentin gene regulatory region controlling the large T and small t antigen coding region of the SV40 virus. In culture, this immortalized venous endothelial cell line (IVEC) demonstrated morphological characteristics of endothelium; uptake of acetylated low density lipoprotein and presence of the Factor VIII-related antigen. Treatment of IVEC cells with Interleukin-1 beta (IL-1 beta) at 10 U.ml-1 activates the expression of cell adhesion molecules such as endothelial leucocyte adhesion molecule (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), as observed in primary culture. Prostacyclin secretion was induced in the IVEC cells by 100 nM PMA treatment and thrombin at 0.5 U/ml. Angiotensin converting enzyme (ACE) activity detected in IVEC cells was present but lower than ACE activity in primary endothelial cells and was completely blocked by enalaprilat (1 microM), a specific ACE inhibitor. The presence of ACE mRNA was also demonstrated in IVEC cells by RT-PCR amplification. Our data demonstrate that endothelial cells immortalized by use of this recombinant gene retain the morphological organization and numerous differentiated properties of endothelium.

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Angiotensin-Converting Enzyme Inhibitors: Biochemical Properties and Biological Action

Cited by 76 publications

References 130 publications

Solid‐phase synthesis, conformational analysis and in vitro cleavage of synthetic human synaptobrevin II 1–93 by tetanus toxin L chain

Solid‐phase synthesis, conformational analysis and in vitro cleavage of synthetic human synaptobrevin II 1–93 by tetanus toxin L chain

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

Cell adhesion markers are expressed by a stable human endothelial cell line transformed by the SV40 large T antigen under vimentin promoter control

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