New feature of angiotensin-converting enzyme: carbohydrate-recognizing domain

Кост, О. А.; Bovin, Nicolai V.; Chemodanova, Elena E.; Nasonov, V. V.; Orth, T.A.

doi:10.1002/1099-1352(200011/12)13:6<360::aid-jmr508>3.0.co;2-k

Cited by 32 publications

(21 citation statements)

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“…We next assessed the role of the putative carbohydrate recognition domain (Kost et al, 2003), a lectin-like structure residing within the N-terminal portion of somatic ACE, in enzyme dimerization. Because ACE dimer formation in vitro in inverse micelles has been reported to be inhibited by galactose and other carbohydrates (Kost et al, 2000), we incubated ACE-overexpressing porcine aortic endothelial cells with 10 M galactose, 10 M glucose, or 10 M mannitol (as an osmotic control) for 30 min, before the addition of 100 nM ramiprilat for 2 min. The basal or ramiprilat-induced dimerization of ACE in endothelial cells was not influenced by either galactose, glucose, or mannitol (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Other forms of human somatic ACE exist, such as an immature form found in intracellular compartments (ϳ170 kDa) and a soluble form (ϳ175 kDa) found in the plasma representing a C-terminally truncated form of the enzyme that is generated by the proteolytic cleavage of its stalk region and the subsequent release from the plasma membrane . Aggregates of ACE that might reflect enzyme dimers and/or higher oligomers have been found during purification of ACE from human lung (Nishimura et al, 1977) as well as in in vitro experiments by using inverse micelles and ACE-expressing COS cells (Kost et al, 2000(Kost et al, , 2003.…”

Section: Discussionmentioning

confidence: 98%

“…Somatic ACE contains 17 potential sites for N-glycosylation, mainly of the complex type (Das and Soffer, 1975). Because ACE dimerization has been attributed to interactions between its carbohydrate side chains and a carbohydrate recognition domain at its N domain that are sensitive to treatment with galactose (Kost et al, 2000), we tested the effects of galactose, glucose, or mannitol on either the basal or the ramiprilat-induced dimerization of ACE, but we were unable to find any significant interference with ACE dimerization. It has also been suggested that monoclonal antibody 9B9 directed to the putative carbohydrate recognition domain region can interfere with ACE self-association (Kost et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin-Converting Enzyme (ACE) Dimerization Is the Initial Step in the ACE Inhibitor-Induced ACE Signaling Cascade in Endothelial Cells

Kohlstedt

Gershome²,

Friedrich³

et al. 2006

Mol Pharmacol

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The binding of angiotensin-converting enzyme (ACE) inhibitors to ACE initiates a signaling cascade that involves the phosphorylation of the enzyme on Ser1270 as well as activation of the c-Jun NH 2 -terminal kinase (JNK) and leads to alterations in gene expression. To clarify how ACE inhibitors activate this pathway, we determined their effect on the ability of the enzyme to dimerize and the role of ACE dimerization in the initiation of the ACE signaling cascade. In endothelial cells, ACE was detected as a monomer as well as a dimer in native gel electrophoresis and dimerization/oligomerization was confirmed using the split-ubiquitin assay in yeast. ACE inhibitors elicited a rapid, concentration-dependent increase in the dimer/ monomer ratio that correlated with that of the ACE inhibitorinduced phosphorylation of ACE. Cell treatment with galactose and glucose to prevent the putative lectin-mediated self-association of ACE or with specific antibodies shielding the N terminus of ACE failed to affect either the basal or the ACE inhibitor-induced dimerization of the enzyme. In ACE-expressing Chinese hamster ovary cells, ACE inhibitors elicited ACE dimerization and phosphorylation as well as the activation of JNK with similar kinetics to those observed in endothelial cells. However, these effects were prevented by the mutation of the essential Zn 2ϩ -complexing histidines in the C-terminal active site of the enzyme. Mutation of the N-terminal active site of ACE was without effect. Together, our data suggest that ACE inhibitors can initiate the ACE signaling pathway by inducing ACE dimerization, most probably via the C-terminal active site of the enzyme.Two isoforms of the angiotensin-converting enzyme (ACE) exist in mammals: somatic or tissue ACE and testicular ACE. These enzymes are both type I transmembrane proteins consisting of an extended extracellular domain and a short cytoplasmic tail and are derived from a single gene by virtue of alternative use of transcription initiation sites (Hubert et al., 1991). The extracellular portion of testicular ACE has one active site, whereas that of somatic ACE has two active sites (the N and C domains), each of which contains the amino acid sequence HEMGH that is crucial for Zn 2ϩ binding (Wei et al., 1991). Soluble forms of ACE can also be detected in plasma and other body fluids and are generated by the enzymatic cleavage of the C-terminal extracellular portion, in the socalled juxtamembrane stalk region. All of the ACE isoforms hydrolyze circulating peptides and catalyze the extracellular conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, which is a potent vasopressor. ACE also inactivates the vasodilator peptides bradykinin and kallidin, which are derived from kininogen by the action of kallikreins (for review, see Bernstein et al., 2005). Inhibition of ACE is expected to prevent the formation of angiotensin II and to potentiate the hypotensive response to bradykinin, which would lead to the lowering of blood pressure. Somatic ACE also...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin-Converting Enzyme (ACE) Dimerization Is the Initial Step in the ACE Inhibitor-Induced ACE Signaling Cascade in Endothelial Cells

Kohlstedt

Gershome²,

Friedrich³

et al. 2006

Mol Pharmacol

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“…Glycosidic α (2)(3)(4)(5)(6)(7)(8) bond in disialic and trisialic acid derivatives was characterized by downfield position of H-8 and H-9 (>4.0 ppm) as compared to Neu5Ac [12,15]. The synthesized sialosides were used for characterization of siglecs [16] and other carbohydrate-binding proteins [17,18].…”

Section: Introductionmentioning

confidence: 99%

Koenigs-Knorr Glycosylation with Neuraminic Acid Derivatives

Pazynina

Nasonov

Belyanchikov

et al. 2010

International Journal of Carbohydrate Chemistry

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Earlier we reported a convenient and efficient method of preparing α2-6 sialooligosaccharides in conditions of Koenigs-Knorr reaction. The use of Ag 2 CO 3 allowed carrying out α2-6 sialylation of galacto-4,6-diol of mono-and disaccharides with chloride of acetylated N-acetylneuraminic acid methyl ester as glycosyl donor. In this study we applied this approach to other derivatives of neuraminic acid, namely, Neu5Gc, 9-deoxy-9-NAc-Neu5Ac, Neu5Acα2-8Neu5Ac, and Neu5Acα2-8Neu5Acα2-8Neu5Ac as glycosyl donors; eight compounds were synthesized: Neu5Gcα-O(CH 2 ) 3 NH 2 (8), Neu5Gcα2-6Galβ1-4GlcNAcβ-O(CH 2 ) 3 NH 2 (10), 9-deoxy-9-NAc-Neu5Ac-O(CH 2 ) 3 NH 2 (15), 9-deoxy-9-NAc-Neu5Acα2-6Galβ1-4GlcNAcβ-O(CH 2 ) 3 NH 2 (17), Neu5Acα2-8Neu5Acα-O(CH 2 ) 3 NH 2 (23) Neu5Acα2-8Neu5Acα-OCH 3 (24), Neu5Acα2-8Neu5Acα-OCH 2 (p-C 6 H 4 )NHCOCH 2 NH 2 (25), and Neu5Acα2-8Neu5Acα2-8Neu5Acα-O(CH 2 ) 3 NH 2 (32). These sialosides were used for characterization of siglecs and other carbohydrate-binding proteins.

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“…Park et al [6] recently discussed the effectiveness of chitooligosaccharides for ACE inhibition while Huang et al [7] have reported improved ACE inhibitory activity of chitooligosaccharides by carboxyl modification. Interestingly, the existence of carbohydrate-binding center on ACE has been proposed recently [8,9]. While many carbohydrate-peptide conjugates are reported to display a wide variety of potent biological activities of therapeutic value [10][11][12], use of amino acid esters of carbohydrates as inhibitors of ACE has not been reported so far.…”

Section: Introductionmentioning

confidence: 99%