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)

Stabilization of biologically active conformations of native peptides by cyclization or introduction of hindering residues led to peptidominetics endowed with high affinity and selectivity for one class of receptors and able to cross the blood brain barrier. This is the case of BUBU, Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu) and BUBUC, Tyr-D-Cys-(OtBu)-Gly-Phe-Leu-Thr(OtBu) for the opioid delta receptors and of BC 254, Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-PheNH2 and of BC 264, Boc-Tyr(SO3H)gNle-mGly-Trp-MeNle-Asp-PheNH2 for central CCK-B receptors. Inhibition of metabolizing peptidases such as aminopeptidase N and endopeptidase 24.11 (NEP) for enkephalins and of NEP and ACE for atrial natriuretic peptide and angiotensin I by mixed inhibitors such as kelatorphan and RB 101 or ES14, rationally designed by taking into account the structural differences in the active site of these zinc-metallopeptidases, led to potent analgesics devoid of the major morphine side effects or to new antihypertensives.
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PMID:Peptidomimetics as receptors agonists or peptidase inhibitors: a structural approach in the field of enkephalins, ANP and CCK. 132 Apr 19

Dried bonito (Katsuobusi), a Japanese traditional seasoning made of bonito muscle was hydrolyzed by various proteases and the inhibitory activity of the hydrolyzates for angiotensin I-converting enzyme (ACE) [EC 3.4.15.1] was measured. Among the digests, thermolysin digest showed the most potent inhibitory activity. Eight inhibitory peptides were isolated from the digest using HPLC. The amino acid sequences of inhibitory peptides were Ile-Lys-Pro-Leu-Asn-Tyr, Ile-Val-Gly-Arg-Pro-Arg-His-Gln-Gly, Ile-Trp-His-His-Thr, Ala-Leu-Pro-His-Ala, Phe-Gln-Pro, Leu-Lys-Pro-Asn-Met, Ile-Tyr, and Asp-Tyr-Gly-Leu-Tyr-Pro. By searching for the sequence homology in many proteins, four of them were found in the primary structure of actin. Asp-Met-Ile-Pro-Ala-Gln-Lys was obtained from the boiling water extract of dried bonito and this peptide was found in the primary structure of creatine kinase. Fragments of these peptides were prepared by further enzymatic digestion or chemical synthesis and their ACE-inhibitory activities were measured. Among them, Ile-Lys-Pro, Ile-Trp, Leu-Lys-Pro, and Leu-Tyr-Pro had higher inhibitory activity than their parental peptides. Ile-Lys-Pro suppressed the hypertensive activity of angiotensin I.
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PMID:Peptide inhibitors for angiotensin I-converting enzyme from thermolysin digest of dried bonito. 136 54

In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function.
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PMID:Angiotensin II inhibits cortical cholinergic function: implications for cognition. 169 79

The endothelial angiotensin I-converting enzyme (ACE) is organized in two large homologous domains, each bearing a putative active site. However, only one of these sites is probably involved in catalyzing the conversion of angiotensin I into angiotensin II. The testicular form of ACE is equally active, encoded by the same gene, but translated from a shorter mRNA. Molecular cloning of the human testicular ACE cDNA indicates that the mRNA codes for 732 residues (vs 1306 in endothelium). The testicular transcript corresponds to the 3' half of the endothelial transcript and encodes one of the two homologous domains of endothelial ACE, preceded by a short specific sequence. This 5' specific sequence contains 228 nucleotides and encodes 67 amino acids, including the putative signal peptide followed by a serine/threonine-enriched region, presumably glycosylated. The testicular transcript corresponds to the ancestral, non-duplicated form of the ACE gene. Since the carboxyl-terminal domain of the endothelial ACE is expressed in the testicular enzyme, it is likely that it bears the active site in both forms.
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PMID:The testicular transcript of the angiotensin I-converting enzyme encodes for the ancestral, non-duplicated form of the enzyme. 254 53

The effects of angiotensin I and II on basal potassium-induced release of [3H]acetylcholine were investigated in slices of rat entorhinal cortex. Potassium (10-25 mM) produced a concentration-dependent increase in the release of [3H]acetylcholine in the presence of extracellular calcium. Angiotensin II (10(-9)-10(-5) M) (but not angiotensin I) reduced the potassium-induced release of [3H]acetylcholine in a concentration-related manner to 60% of control levels, but did not effect basal tritium release. The effect of angiotensin II was antagonised by [1-sarcosine, 8-threonine] angiotensin II, an angiotensin II receptor antagonist, but not by agents acting on alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine or 5-hydroxytryptamine receptors nor by the angiotensin converting enzyme (ACE) inhibitor SQ 29852. The results indicate that angiotensin II acting via an angiotensin II receptor can inhibit the release of [3H]acetylcholine in slices of the rat entorhinal cortex. It is hypothesised that the ability of ACE inhibitors to facilitate cognitive processes may be related to a reduced availability of angiotensin II.
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PMID:Angiotensin II inhibits the release of [3H]acetylcholine from rat entorhinal cortex in vitro. 276 77

A glutamic acid residue at the active site of bovine lung angiotensin I-converting enzyme, a zinc-metallo peptidyl dipeptidase, was esterified with p-[N,N-bis(chloroethyl)amino]phenylbutyryl-L-[U-14C]proline (chlorambucyl-L-[U-14C]-L-proline), an affinity label for this enzyme (Harris, R.B., and Wilson, I.B. (1983) J. Biol. Chem. 258, 1357-1362). The radiolabeled enzyme was digested with BrCN and only 1 of the 30 cleavage peptides resolved by reverse-phase high performance liquid chromatography (HPLC) contained the bound radiolabel. This active-site peptide (Mr = 16,000) was digested with trypsin and the labeled peptide formed (T-2) was further degraded with thermolysin. The thermolytic peptides were resolved by reverse-phase HPLC. Only 1 of the 5 peptides obtained (Th-1, Mr = 1290) contained the bound radiolabel. Th-1 (12 residues) was subjected to manual Edman degradation and the following partial sequence was determined: H2N-Phe-Thr-Glu-Leu-Ala-Asp-Ser-Glu... The radiolabel was released at cycle 3 and the amount recovered was equivalent to the amount of phenylthiohydantoin-Glu detected on HPLC. Thus, glutamic acid is esterified with chlorambucyl-L-[U-14C]proline in confirmation of our earlier findings. The sequence determined is homologous in 5 residues with the corresponding sequences of bovine carboxypeptidase A and B, two other mammalian zinc proteases. There is little sequence homology with thermolysin, a bacterial zinc protease that also contains an essential active-site glutamic acid residue.
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PMID:Sequencing of an active-site peptide of angiotensin I-converting enzyme containing an essential glutamic acid residue. 285 12

The mRNA encoding angiotensin I-converting enzyme, a zinc-metallo dipeptidyl carboxyhydrolase, has been identified in extracts prepared from bovine lung tissue. Bovine lung poly(A) + mRNAs were subjected to electrophoresis and northern blot hybridization analysis using a radiolabeled synthetic 24-deoxyoligonucleotide probe complementary to eight codons for amino acids at the active-site of the enzyme (Harris, R.B. & Wilson, I.B., J. Biol. Chem. 260, 2208-2211, 1985). This amino acid sequence contains the catalytic glutamic acid residue. A single RNA species (approximately equal to 4 kb) was detected which is 1 kb larger than predicted from the molecular weight of the enzyme. The excess nucleic acid composition may be due to leader and/or trailer sequences or the RNA may encode a high molecular weight precursor form of the enzyme. We have cloned an EcoR1-HindIII digest fragment (1400 bp) of the duplex cDNA derived from the bovine lung converting enzyme poly(A) + mRNA and also Bal31 deletion fragments generated from the 1400 bp clone. Several of the Bal31 clones contain the active-site sequence codons of the enzyme and the complete cDNA sequence of one of these (72 bp) has been determined. We found the amino acid sequence at the active site to be -Phe-Thr-Glu-Leu-Ala-Asn-Ser-, containing the catalytic Glu residue. This sequence is identical with the sequence that we previously determined by manual Edman degradation analysis of the appropriate active-site peptide except that we now find Asn instead of Asp. We have sequenced 670 bp of the 1400 bp clone but have not yet overlapped the active-site sequence.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hybridization and partial cDNA sequence analyses of bovine lung angiotensin I-converting enzyme. 288 36

We have purified angiotensin-converting enzyme (ACE, EC 3.4.15.1) from rat brain corpus striatum and rat lung. The brain enzyme has Mr 165,000 by sodium dodecyl sulfate gel electrophoresis, whereas the lung enzyme is 175,000. This difference is not an artifact of preparation since mixture of the two tissues prior to purification results in isolation of two proteins with Mr 165,000 and 175,000. Separation of tryptic fragments of 125I-labeled lung and brain ACE by reverse-phase chromatography yields distinct but similar patterns. No differences between the native enzymes are detected in dansyl-tripeptide cleavage specificity, inhibitor profile, immunological properties, sucrose gradient sedimentation, or gel filtration of ACE from the two tissues. However, lung and brain ACE can be differentiated in their ability to cleave amidated peptides. Both lung and brain ACE cleave Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) via two pathways. In one pathway, ACE first releases Gly-Leu-Met-NH2 and then dipeptides sequentially from the carboxyl terminus. The other first produces Leu-Met-NH2, and then releases dipeptides to leave substance P 1-5. Lung ACE favors initial tripeptide release 3:1, while the striatal enzyme acts via the two pathways to a similar extent. Lung and striatal ACE also differ in their ability to degrade other amidated peptides. His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 (substance K) and bombesin are degraded by striatal but not lung ACE. Physalaemin and luteinizing hormone-releasing hormone are cleaved by both enzymes, while eledoisin, kassinin, thyrotropin-releasing hormone, and substance P 5-11 are not cleaved by either enzyme. Physalaemin is degraded more rapidly by the lung enzyme. The coincidence of an ACE isozyme with substance P and substance K in the descending striatonigral pathway and the unique ability of this isozyme to cleave substance P and substance K suggest that one or both of these peptides is a physiological substrate for striatonigral ACE.
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PMID:A rat brain isozyme of angiotensin-converting enzyme. Unique specificity for amidated peptide substrates. 299 Dec 65

Angiotensin-converting enzyme (ACE; dipeptidyl carboxypeptidase, EC 3.4.15.1) from monkey brain was partially purified 274-fold with 4.5% yield. The optimum pH of the enzyme was 8.2, and its Km was 3.3 mM, with hippuryl-His-Leu as the substrate in 300 mM NaCl. Its molecular weight (Mr) was estimated to be approximately 260,000 by gel filtration on Sephadex G-200. On high-performance liquid chromatographic analysis, ACE hydrolyzed neo-kyotorphin Thr-Ser-Lys-Tyr-Arg) with liberation of kyotorphin (Tyr-Arg), the [Met]enkephalin releaser. ACE also converted [Met]enkephalin-Arg6-Phe7 to [Met]enkephalin; then the enzyme slowly hydrolyzed the resulting [Met]enkephalin. The Km values of the enzyme for neo-kyotorphin and [Met]enkephalin-Arg6-Phe7 were 0.58 and 0.30 mM respectively. Thus, brain ACE may have a role in the formation of kyotorphin and [Met]enkephalin from their precursors but has little part in [Met]enkephalin degrading processes.
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PMID:Hydrolysis of neo-kyotorphin (Thr-Ser-Lys-Tyr-Arg) and [Met]enkephalin-Arg6-Phe7 by angiotensin-converting enzyme from monkey brain. 302 52

A glutamic acid residue at the active-site of bovine lung angiotensin I-converting enzyme was esterified with p-[N,N-bis-(chloroethyl)amino]phenylbutyryl-L-[U-14]-Proline (chlorambucyl-L-[U-14C]-L-Proline), an affinity label for this enzyme. The radiolabeled enzyme was digested with BrCN and only 1 of the 30 cleavage peptides resolved by reverse-phase HPLC contained the bound radiolabel. This active-site peptide (Mr approximately 16,000) was digested with trypsin, and the labeled peptide (T-2) was further degraded with thermolysin. The enzyme digest peptides were also resolved by reverse-phase HPLC. Only 1 of the 5 peptides obtained after thermolysin digestion (Th-1, Mr 1290) contained the bound radiolabel. Th-1 (12 residues) was subjected to manual Edman degradation and the following partial sequence was determined: H2N-Phe-Thr-Glu-Leu-Ala-Asp-Ser-Glu. The radiolabel was released at cycle 3 and the amount recovered was equivalent to the amount of PTH-Glu detected on HPLC. Thus, glutamic acid is esterified with chlorambucyl-L-[U-14C]-Proline which confirms our earlier findings. The sequence that we determined is homologous in five residues with the corresponding sequences of carboxypeptidase A and B, two other mammalian zinc-proteases. There is little sequence homology with thermolysin, a bacterial zinc-protease that also contains an essential active-site glutamic acid residue.
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PMID:Isolation and sequencing of an active-site peptide from angiotensin I-converting enzyme. 302 71


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