Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotension II is the effector molecule of the renin-angiotensin system. Therefore, agents directed at the receptor that mediates its actions are likely to represent the most physiologically specific inhibitors of the system. We suggest here an approach to such drugs based on an operational analogy between peptidases and peptide hormone receptors and on the development of inhibitors of angiotensin-converting enzyme. The rationale that led to captopril, enalapril, and related inhibitors of this peptidase required identification of its cognitive and functional properties, i.e., what amino acid sequences it preferentially recognizes and its Zn2+ -dependent dipeptidyl carboxypeptidase activity. Purification of the enzyme was necessary to obtain this information. We speculate that this type of information may be equally useful for developing a receptor antagonist. As progress toward this objective, we describe briefly purification of rabbit hepatic angiotensin II receptor using chemical and immunoaffinity ligands. We hope to determine the cognitive and functional properties of this purified protein, i.e., what residues it preferentially recognizes in defined peptides and the molecular mechanism by which binding of ligand is transduced into a cellular response.
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PMID:Angiotensin receptor is a desirable locus for physiologically specific inhibition of the renin-angiotensin system. 241 17

Evidence for effects of angiotensin converting enzyme (ACE) on isolated human glomeruli was provided using specific binding of tritium-labeled ramiprilat, a potent inhibitor of ACE. [3H]ramiprilat bound to isolated glomeruli, depending on time and temperature, displaying a KD of 3.8 nmol/L and a Bmax of 853 fmol/mg protein. Specific binding represented more than 90% of total binding. Dissociation occurred rapidly after dilution of the sample with incubation buffer or after addition of an excess of unlabeled inhibitor. Binding of [3H]ramiprilat was also inhibited by increasing concentrations of enalaprilat, another ACE inhibitor. ACE is a zinc-containing enzyme. Addition of EGTA to the assay, which chelates zinc ions, completely prevented binding. This was reversed by divalent Zn2+ and Ca2+ ions, but not by magnesium. Binding of [3H]ramiprilat to isolated glomeruli was maximal at pH 8, which also is optimal for ACE activity. The binding of [3H]ramiprilat to isolated human glomeruli is specific, and resembles the characteristics which have been found earlier for enzyme activity of ACE. Thus, binding of [3H]ramiprilat to isolated glomeruli can be assumed to be directed to ACE.
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PMID:High-affinity binding of the converting enzyme inhibitor, ramiprilat, to isolated human glomeruli. 247 98

The effect of zinc depletion and of additional angiotensin I-converting enzyme (ACE) inhibitor treatment was studied on ACE in aortic and other tissues, in plasma and on systolic blood pressure of the rat. Zinc deprivation significantly reduced plasma zinc concentration, plasma and testicular ACE activities and blood pressure, but stimulated aortic ACE while lung values remained constant. Zinc deficiency combined with ACE inhibition further suppressed plasma ACE and stimulated the aortic enzyme earlier. Zinc repletion experiments (in vitro) suggest the existence of a feedback mechanism controlling ACE synthesis depending on plasma ACE activity.
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PMID:Effect of zinc depletion on angiotensin I-converting enzyme in arterial walls and plasma of the rat. 254 44

1. The three dimensional requirements for inhibition of ACE (angiotensin converting enzyme) were investigated in order to facilitate design of a more potent and selective antihypertensive agent. 2. All compounds designed possessed a bicyclic unit incorporating carboxylate and amidic carbonyl groups together with a thiol-bearing side chain. 3. NMR spectroscopy of the bicyclic units and molecular mechanics calculations enabled the possible positions of the thiol group to be studied. 4. Determination of the positions of the thiol group conferring best inhibition in the active site of ACE permitted the probable location of the active site zinc ion to be identified. The intention was to replace the thiol side chain with a homophenylalanine unit to bind to the zinc ion and also to occupy the S1 site which fits the Phe8 side chain of angiotensin I. 5. Examination of a torsional angle psi in a compound possessing poor inhibitory potency indicated correspondence to a high energy conformation of alanylproline. The bicyclic unit was modified to incorporate a seven-instead of a six-membered ring to bring psi into the range of an accessible conformation of alanylproline. The corresponding IC50 resulting indicated that psi was closer to that of the active conformations of enalaprilat and captopril. 6. Removal of one carbonyl improved the ACE inhibitory potency further. 7. The postulated active conformation of cilazaprilat is presented.
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PMID:Chemical design of cilazapril. 254 50

A change has been made in the commonly used lisinopril affinity gel procedure for purifying angiotensin converting enzyme. The new method greatly decreases the time required and greatly increases the yield of pure enzyme. All of the enzyme in various bovine tissues was extracted with 0.5% triton X-100 and applied to the affinity column; 70% was trapped and all of the trapped enzyme was released as the apoenzyme by EDTA. The holoenzyme was recovered by dialysis against zinc containing buffer. The turnover numbers were precisely the same for enzyme from lung, atrium, kidney, striatum and blood. The tissue concentrations of ACE were very different but the final specific activities were the same.
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PMID:Purification of bovine angiotensin converting enzyme. 255 Jul 12

Angiotensin-converting enzyme (ACE; EC 3.4.15.1) is a zinc-containing dipeptidyl carboxypeptidase widely distributed in mammalian tissues and is thought to play a critical role in blood pressure regulation. Testis contains a unique, androgen-dependent ACE isozyme of unknown function. We have determined the cDNA sequence for human testicular ACE; it encodes a protein that is identical, from residue 37 to its C terminus, to the second half or C-terminal domain of the endothelial ACE sequence [Soubrier, F., Alhenc-Gelas, F., Hubert, C., Allegrini, J., John, M., Tregear, G. & Corvol, P. (1988) Proc. Natl. Acad. Sci. USA 85, 9386-9390]. The full-length human testis ACE cDNA was constructed from a composite of cloned cDNAs, obtained by a combination of (i) immunoscreening and hybridization screening of a human testicular cDNA library in lambda gt11 and (ii) hybridization screening of human testis cDNAs constructed with ACE-specific primers and amplified by the polymerase chain reaction. The protein sequence inferred consists of a 732-residue preprotein including a 31-residue signal peptide. The mature polypeptide has a molecular weight of 80,073. The testis enzyme contains the second of the two putative metal-binding sites (His-Glu-Met-Gly-His) identified in endothelial ACE. This indicates that the functionally active catalytic site is within the C-terminal domain of the endothelial enzyme, accounting for the previous finding that these two structurally dissimilar isozymes are virtually identical catalytically. Of 22 testis ACE cDNAs cloned and sequenced, 3 have unique 5' regions, consisting of inserted, deleted, or substituted sequences up to 328 base pairs long, which have apparently arisen by alternative pre-mRNA splicing.
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PMID:Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. 255 86

Taste and smell disturbances are infrequently reported adverse effects of treatment with captopril and are even less frequently reported with other ACE inhibitors. These adverse effects have been attributed to the chemical structure of the drugs used, although this relationship is the matter of some debate. A link between the taste disturbance associated with ACE inhibitors and changes in plasma zinc concentration has also been suggested, but again the evidence for this relationship is equivocal. One problem facing research in this area has been the lack of reliable assessment techniques for the quantitative evaluation of smell and taste function. Three quantitative methods for evaluating taste and smell function are described, together with the results of a pilot study aimed at evaluating the potential ease of application of these techniques in a larger group of patients. In this double-blind, crossover pilot study, 8-week treatment with lisinopril (20-40 mg once daily) was compared with captopril (25-50 mg twice daily) in 12 hypertensive patients. The two drugs produced similar falls in lying and standing blood pressure and neither drug produced a significant alteration in smell recognition, or olfactory or taste threshold. None of the minor changes observed appeared to correlate with either plasma zinc concentrations or intra-erythrocyte zinc levels. This study provides important observations on the use of these new techniques. Based on the wide variability of results obtained, the design of further clinical studies must address and overcome the many factors (age, sex, smoking, etc.) which may confound the study of drug effects on taste and smell.
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PMID:ACE inhibitors in hypertension: assessment of taste and smell function in clinical trials. 277 91

Zinc, the catalytically essential metal of angiotensin converting enzyme (ACE), has been replaced by cobalt(II) to give an active, chromophoric enzyme that is spectroscopically responsive to inhibitor binding. Visible absorption spectroscopy and magnetic circular dichroic spectropolarimetry have been used to characterize the catalytic metal binding site in both the cobalt enzyme and in several enzyme-inhibitor complexes. The visible absorption spectrum of cobalt ACE exhibits a single broad maximum (525 nm) of relatively low absorptivity (epsilon = 75 M-1 cm-1). In contrast, the spectra of enzyme-inhibitor complexes display more clearly defined maxima at longer wavelengths (525-637 nm) and of markedly higher absorptivities (130-560 M-1 cm-1). The large spectral response indicates that changes in the cobalt ion coordination sphere occur on inhibitor binding. Magnetic circular dichroic spectropolarimetry has shown that the metal coordination geometry in the inhibitor complexes is tetrahedral and of higher symmetry than in cobalt ACE alone. The presence of sulfur----cobalt charge-transfer bands in both the visible absorption and magnetic circular dichroic spectra of the cobalt ACE-Captopril complex confirm direct ligation of the thiol group of the inhibitor to the active-site metal.
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PMID:Electronic spectroscopy of cobalt angiotensin converting enzyme and its inhibitor complexes. 282 50

Angiotensin-converting enzyme (ACE) is an Zn(II)-containing dipeptidyl carboxypeptidase that converts angiotensin I to the potent vasoconstrictor, angiotensin II. Using oligonucleotide probes based on the amino acid sequence of mouse kidney ACE, cDNA encoding this protein has been isolated. One cDNA, ACE.31, encodes the N-terminal 332 amino acids of mouse ACE, a portion of the protein containing a putative 34-amino acid leader sequence and the N terminus of the mature protein. Northern analyses with cloned ACE cDNA revealed that both mouse kidney and lung express two ACE mRNAs, one of 4900 and another of 4150 bases. Southern analysis suggests that cDNA ACE.31 is the product of a single gene, and thus these data add evidence to the hypothesis that the converting enzymes produced by epithelial and endothelial cells are identical.
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PMID:The isolation of angiotensin-converting enzyme cDNA. 284 12

Forty-two patients with lung cancer and 72 healthy subjects were studied in order to determine a possible relationship between serum zinc and angiotensin-converting enzyme (ACE), a peptidyl dipeptide hydrolase. Serum zinc levels were 105 +/- 21 micrograms/dl in control subjects and 50 +/- 19 micrograms/dl in patients, and angiotensin-converting enzyme activity was 296 +/- 28 U/l in the former and 240 +/- 55 U/l in the latter using hippurylglycylglycine as a substrate. The findings obtained show that the decreased levels of angiotensin-converting enzyme may be related to decreased serum zinc levels and that the primary defect may be the zinc deficiency in these patients.
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PMID:Serum zinc and angiotensin-converting enzyme levels in patients with lung cancer. 285 86


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