Abstract
Substance P (SP1-11) was exposed to a continuous flux of superoxide () or hydroxyl radicals (.OH) in a hypoxanthine (HX)/xanthine oxidase (86 mU) system in the presence of 1 mM deferoxamine and 40 mM D-mannitol or 50 μM FeCI3. 6H2O and 50 μM EDTA, respectively. caused fragmentation between the Phe7 and Phe8, whereas .OH induced cleavage also between the Phe8 and Gly9. Reactive oxygen species H2O2 and HCIO did not cause fragmentation, but modification of the amino acid side chains and/or aggregation with altered hydrophobicity in reverse phase high performance liquid chromatography compared to native SP1-11. Furthermore, exposure of SP1-11 to phorbol myristate acetate preactivated neutrophils resuited in products similar to those observed upon exposure to superoxide or hydroxyl radicals in a cell-free HX/xanthine oxidase system. This study suggests that, in contrast to rigid proteins, fragmentation is relatively easily induced in a small peptide like SP1-11, perhaps due to strain on the peptide and t-carbon bonds caused by the movable, random coil configuration acquired by SP1-11 in an aqueous solution. Oxidative modification might modulate paracrine actions of SP1-11 at site of inflammation.
Highlights
Substance P (SPl-11) is an undecapeptide, which consists of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 .1 SP1-11 has been localized to small unmyelinated, slowly conducting C-type polymodal nociceptors.[2]
During ischaemia xanthine dehydrogenase is proteolytically cleaved to xanthine oxidase by an enzyme activated by Ca2+ efflux from mitochondria
If instead of oxygen derived free radicals (ODFR), SP>I was exposed to reactive oxygen species RiO2 (1 and 0.1 mM) or HC10, fragmentation was not observed, but rather modification of the amino acid s:,de chains and/or aggregation: H202 and HC10 induced the formation of oxidation products with retention times 33.13min and 32.04 min, respectively
Summary
Substance P (SPl-11) is an undecapeptide, which consists of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 .1 SP1-11 has been localized to small unmyelinated, slowly conducting C-type polymodal nociceptors.[2]. During reperfusion xanthine oxidase will catalyse the conversion of HX to xanthine and further to uric acid (Equation 1, see below), with bimolecular oxygen acting as an electron acceptor in both reactions. It seems, that released at a site of inflammation, will be exposed to degradative enzymes and to various reactive oxygen species. That released at a site of inflammation, will be exposed to degradative enzymes and to various reactive oxygen species This prompted us to study the possible effect of such compounds on substance P in vitro
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