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Pyridoxal 5 Phosphate Decarboxylates Angiotensin II: Putative Mechanism for Generation of Angiotensin A
Author(s) -
Stoyell-Conti Filipe Fernandes,
Chabbra Alesa,
Perry Richard,
Speth Robert C.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07034
Subject(s) - chemistry , angiotensin ii , renin–angiotensin system , receptor , angiotensin iii , medicine , enzyme , alanine , endocrinology , decarboxylation , biochemistry , angiotensin ii receptor type 1 , amino acid , biology , blood pressure , catalysis
In 2007, a new renin‐angiotensin system (RAS) peptide, Angiotensin A (Ang A; Ala‐Arg‐Val‐Tyr‐Ile‐His‐Pro‐Phe) was discovered, which differs from Angiotensin II (Ang II; Asp‐Arg‐Val‐Tyr‐Ile‐His‐Pro‐Phe) by having alanine (Ala) in position one instead of aspartic acid (Jankowski et al., 2007). Previous studies have shown that Ang A has a higher affinity for angiotensin II receptor type 2 (AT2R) compared to Ang II. It is important to note that AT2R counter‐regulates the adverse effects of angiotensin II receptor type 1 (AT1R). In addition, data from our lab shows that Ang A is ~17‐fold less potent than Ang II at AT1R. Together these observations suggest that Ang A may be less harmful to the cardiovascular system compared to Ang II. Alamandine (Ala‐Arg‐Val‐Tyr‐Ile‐His‐Pro) can be derived from Ang A through enzymatic hydrolysis by angiotensin‐converting enzyme 2 (ACE2) and other carboxypeptidases. Alamandine may also be produced from Ang‐(1‐7) by decarboxylation of the Asp 1 residue (Lautner et al., 2013). Alamandine is reported to be ~1000‐fold more potent than Ang‐(1‐7) at counteracting the AT1R mediated adverse effects of Ang II by activating Mas and MrgD receptors (Tetzner et al., 2018). Pyridoxal 5 Phosphate (P5P), the active form of vitamin B6, can promote non‐enzymatic reactions such as decarboxylation and transamination. We hypothesized that P5P could decarboxylate Asp of Ang II to form Ang A. To test this hypothesis, we incubated a mixture containing Ang II (1 mM), P5P (3 mM), and 3‐(N‐morpholino)propanesulfonic acid, MOPS) buffer (100 mM) at pH 7.4 and a temperature of 37 °C for 24 hours. High performance liquid chromatography‐mass spectrometry (HPLC‐MS) analysis of the reaction mixture produced ion signals at m/z 335 and m/z 502 corresponding to [Ang II – CO 2 + 3H] 3+ and [Ang II – CO 2 + 2H] 2+ , respectively. The mass spectra and retention times for these ions are similar to an Ang A standard. These preliminary results suggests that P5P converts Ang II to Ang A via decarboxylation of Asp. Further studies are underway to confirm the site of decarboxylation.