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- Name help_outline [Pyr1]apelin-13 Identifier CHEBI:147415 Charge 2 Formula C69H110N22O16S InChIKeyhelp_outline GGMAXEWLXWJGSF-PEWBXTNBSA-P SMILEShelp_outline C([C@H](CC1=CC=CC=C1)NC(=O)[C@H]2N(CCC2)C([C@H](CCSC)NC(=O)[C@H]3N(CCC3)C(=O)CNC([C@H](CCCC[NH3+])NC([C@H](CC4=CN=CN4)NC([C@H](CO)NC([C@H](CC(C)C)NC([C@H](CCCNC(=[NH2+])N)NC(=O)[C@H]5N(CCC5)C([C@H](CCCNC(=[NH2+])N)NC([C@H]6NC(=O)CC6)=O)=O)=O)=O)=O)=O)=O)=O)(=O)[O-] 2D coordinates Mol file for the small molecule Search links Involved in 1 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (Beilstein: 3587155; CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,048 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline [Pyr1]apelin-12 Identifier CHEBI:147416 Charge 2 Formula C60H101N21O15S InChIKeyhelp_outline RDEHKCXWTDAMPV-SLUWFFAESA-P SMILEShelp_outline [O-]C(=O)[C@H]1N(CCC1)C([C@H](CCSC)NC(=O)[C@H]2N(CCC2)C(=O)CNC([C@H](CCCC[NH3+])NC([C@H](CC3=CN=CN3)NC([C@H](CO)NC([C@H](CC(C)C)NC([C@H](CCCNC(=[NH2+])N)NC(=O)[C@H]4N(CCC4)C([C@H](CCCNC(=[NH2+])N)NC([C@H]5NC(=O)CC5)=O)=O)=O)=O)=O)=O)=O)=O 2D coordinates Mol file for the small molecule Search links Involved in 1 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline L-phenylalanine Identifier CHEBI:58095 Charge 0 Formula C9H11NO2 InChIKeyhelp_outline COLNVLDHVKWLRT-QMMMGPOBSA-N SMILEShelp_outline [NH3+][C@@H](Cc1ccccc1)C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 72 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
| RHEA:63604 | RHEA:63605 | RHEA:63606 | RHEA:63607 | |
|---|---|---|---|---|
| Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
| UniProtKB help_outline |
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Publications
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Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.
Wang W., McKinnie S.M., Farhan M., Paul M., McDonald T., McLean B., Llorens-Cortes C., Hazra S., Murray A.G., Vederas J.C., Oudit G.Y.
Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analo ... >> More
Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. << Less
Hypertension 68:365-377(2016) [PubMed] [EuropePMC]
This publication is cited by 1 other entry.
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[Pyr1]Apelin-13(1-12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13.
Yang P., Kuc R.E., Brame A.L., Dyson A., Singer M., Glen R.C., Cheriyan J., Wilkinson I.B., Davenport A.P., Maguire J.J.
<b>Aims:</b> Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> in human cardiovascular tissues and to confirm it retains significant biological activity f ... >> More
<b>Aims:</b> Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> in human cardiovascular tissues and to confirm it retains significant biological activity for the apelin receptor <i>in vitro</i> and <i>in vivo</i>. The minimum active apelin fragment was also investigated. <b>Methods and Results:</b> [Pyr<sup>1</sup>]apelin-13 incubated with recombinant human ACE2 resulted in de novo generation of [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> identified by mass spectrometry. Endogenous [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> was detected by immunostaining in human heart and lung localized to the endothelium. Expression was undetectable in lung from patients with pulmonary arterial hypertension. In human heart [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> (pK<sub>i</sub> = 8.04 ± 0.06) and apelin-13(F13A) (pK<sub>i</sub> = 8.07 ± 0.24) competed with [<sup>125</sup>I]apelin-13 binding with nanomolar affinity, 4-fold lower than for [Pyr<sup>1</sup>]apelin-13 (pK<sub>i</sub> = 8.83 ± 0.06) whereas apelin-17 exhibited highest affinity (pK<sub>i</sub> = 9.63 ± 0.17). The rank order of potency of peptides to inhibit forskolin-stimulated cAMP was apelin-17 (pD<sub>2</sub> = 10.31 ± 0.28) > [Pyr<sup>1</sup>]apelin-13 (pD<sub>2</sub> = 9.67 ± 0.04) ≥ apelin-13(F13A) (pD<sub>2</sub> = 9.54 ± 0.05) > [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> (pD<sub>2</sub> = 9.30 ± 0.06). The truncated peptide apelin-13(R10M) retained nanomolar potency (pD<sub>2</sub> = 8.70 ± 0.04) but shorter fragments exhibited low micromolar potency. In a β-arrestin recruitment assay the rank order of potency was apelin-17 (pD<sub>2</sub> = 10.26 ± 0.09) >> [Pyr<sup>1</sup>]apelin-13 (pD<sub>2</sub> = 8.43 ± 0.08) > apelin-13(R10M) (pD<sub>2</sub> = 8.26 ± 0.17) > apelin-13(F13A) (pD<sub>2</sub> = 7.98 ± 0.04) ≥ [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> (pD<sub>2</sub> = 7.84 ± 0.06) >> shorter fragments (pD<sub>2</sub> < 6). [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> and apelin-13(F13A) contracted human saphenous vein with similar sub-nanomolar potencies and [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> was a potent inotrope in paced mouse right ventricle and human atria. [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> elicited a dose-dependent decrease in blood pressure in anesthetized rat and dose-dependent increase in forearm blood flow in human volunteers. <b>Conclusions:</b> We provide evidence that ACE2 cleaves [Pyr<sup>1</sup>]apelin-13 to [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> and this cleavage product is expressed in human cardiovascular tissues. We have demonstrated biological activity of [Pyr<sup>1</sup>]apelin-13<sub>(1-12)</sub> at the human and rodent apelin receptor <i>in vitro</i> and <i>in vivo</i>. Our data show that reported enhanced ACE2 activity in cardiovascular disease should not significantly compromise the beneficial effects of apelin based therapies for example in PAH. << Less