1. Amino acids dilate resistance blood vessels of the perfused rat mesentery
O A al-Swayeh, P K Moore J Pharm Pharmacol. 1989 Oct;41(10):723-6. doi: 10.1111/j.2042-7158.1989.tb06351.x.
The vasodilator effect of several L-amino acids in the perfused, noradrenaline-preconstricted rat mesentery preparation has been investigated. N-alpha-Benzoyl-L-arginine ethyl ester (BAEE) (ED50, 1.4 +/- 0.09 mumol) and L-alanine methylester (ED50, 0.9 +/- 0.007 mumol) were the most potent although L-arginine methylester, hydroxamate and hydrochloride, N-alpha-benzoyl-L-arginine methyl ester (BAME), L-methionine methylester, L-lysine hydroxamate and L-glutamic acid methylester exhibited similar potency with ED50 values in the range 2.4-3.7 mumol. L-Homoarginine chloride was inactive at doses up to 20 mumols. D-Arginine hydrochloride and D-lysine hydroxamate were inactive at doses up to 50 mumols whilst D-methionine methylester (50 mumols) produced small falls in perfusion pressure in only 3 out of 7 preparations studied. Responses to BAEE, BAME, L-arginine hydrochloride, L-alanine methylester, L-methionine methylester, L-lysine hydroxamate and acetylcholine (but not nitroprusside) were significantly inhibited by CHAPS (4.7 mg mL-1, 30 s) de-endothelialization as well as pretreatment of mesentery preparations with gossypol (3 microM). Responses to BAEE, BAME, L-arginine hydrochloride, L-alanine methylester and acetylcholine were similarly selectively reduced by NDGA (10 microM) pretreatment. We propose that these L-amino acids exhibit vasodilator activity in the perfused rat mesentery by virtue of releasing endothelium-derived nitric oxide (EDNO).
2. Homocysteine sensitizes the mouse neuromuscular junction to oxidative stress by nitric oxide
John S Wang, Danica Bojovic, Yang Chen, Clark A Lindgren Neuroreport. 2018 Aug 15;29(12):1030-1035. doi: 10.1097/WNR.0000000000001073.
Homocysteine (HCY), a redox-active metabolite of the methionine cycle, is of particular clinical interest because of its association with various neurodegenerative diseases including amyotrophic lateral sclerosis. It has been previously established that HCY exacerbates damage to motor neurons from reactive oxygen species (ROS) such as hydrogen peroxide. To assess the role of HCY at the mammalian neuromuscular junction, neurotransmission was monitored by electrophysiology at the mouse epitrochleoanconeus muscle. Preparations were preincubated in HCY before inducing ROS and recordings were taken before and after ROS treatment. In this study, HCY was observed to sensitize the neuromuscular junction to ROS-induced depression of spontaneous transmission frequency, an effect we found to be mediated by a N-methyl-D-aspartate receptor (NMDAR) and nitric oxide (NO). The NMDAR antagonist D, L-2-amino-5-phosphonopentanoic acid prevented the HCY-induced sensitization to oxidative stress. Disrupting NO activity with either the nitric oxide synthase I antagonist Nω-nitro-L-arginine methyl ester hydrochloride or the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide potassium salt also prevented sensitization. Moreover, replacing HCY with the exogenous NO donor Diethylamine NONOate diethylammonium was sufficient to reconstitute the effects of HCY-induced sensitization to ROS. Interestingly, a novel secondary effect was observed where HCY itself depresses quantal content, an effect found to be mediated by NMDARs independently of nitric oxide and ROS. Collectively, these data present a novel model of two distinct pathways through which HCY alters neurotransmission at the neuromuscular junction. Characterizing HCY's mechanism of action is of particular clinical relevance as many treatments for amyotrophic lateral sclerosis are centered on mitigating HCY-induced pathologies.
3. Peptide coupling between amino acids and the carboxylic acid of a functionalized chlorido-gold(I)-phosphane
Margit Kriechbaum, Manuela List, Markus Himmelsbach, Günther J Redhammer, Uwe Monkowius Inorg Chem. 2014 Oct 6;53(19):10602-10. doi: 10.1021/ic5017142. Epub 2014 Sep 9.
We have developed a protocol for the direct coupling between methyl ester protected amino acids and the chlorido-gold(I)-phosphane (p-HOOC(C6H4)PPh2)AuCl. By applying the EDC·HCl/NHS strategy (EDC·HCl = N-ethyl-N'-(3-(dimethylamino)propyl)carbodiimide hydrochloride, NHS = N-hydroxysuccinimide), the methyl esters of l-phenylalanine, glycine, l-leucine, l-alanine, and l-methionine are coupled with the carboxylic acid of the gold complex in moderate to good yields (62-88%). All amino acid tagged gold complexes were characterized by (1)H and (13)C NMR spectroscopy and high-resolution mass spectrometry. As corroborated by measurement of the angle of optical rotation, no racemization occurred during the reaction. The molecular structure of the leucine derivative was determined by single-crystal X-ray diffraction. In the course of developing an efficient coupling protocol, the acyl chlorides (p-Cl(O)C(C6H4)PPh2)AuX (X = Cl, Br) were also prepared and characterized.
