PubMed · 1168790
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T Tomoda, H Yamaguchi, N Kaneda. 1975. [Amine decomposition by enterobacteria].. https://pubmed.ncbi.nlm.nih.gov/1168790/
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The reaction mechanism of Yersinia pestis arginine decarboxylase has been investigated using a series of substrate, product, and inhibitors. Using single wavelength stopped-flow spectroscopy, novel mechanistic features were noted in the presence of the product, agmatine. By focusing on the excitation and emission wavelengths of the geminal diamine intermediate, we were able to monitor the formation and decay of two different geminal diamine species. Experiments revealed that the enzyme exists in two different conformational states--one that binds ligand and one that does not. The on and off rates for the conversion between the two conformational states was determined to be 390 s-1 and 880 s-1, respectively. The KD for agmatine binding was 6 mM. In addition, experiments revealed a pH-dependent conversion between two states of the enzyme. The deprotonated form of the enzyme binds ligand more slowly than the protonated form. The rates for the formation of the geminal diamine and external aldimine in this pathway were determined to be 25 and 4 s-1, respectively. There is also a slow interconversion between the protonated and deprotonated enzymes that has a pKa of approximately 8.0. Finally, the formation of the geminal diamine was determined to be Mg2+-dependent.
Agmatine (decarboxylated arginine) is an endogenous amine found in the CNS that antagonizes NMDA receptors and inhibits nitric oxide synthase. Intrathecally administered agmatine inhibits hyperalgesia evoked by inflammation, nerve injury and intrathecally administered NMDA. These actions suggest an antiglutamatergic neuromodulatory role for agmatine in the spinal cord. Such a function would require a mechanism of regulated clearance of agmatine such as neuronal or glial uptake. Consistent with this concept, radiolabeled agmatine has been shown to accumulate in synaptosomes, but the mechanism of this transport has not been fully characterized. The present study describes an agmatine uptake system in spinal synaptosomes that appears driven by a polyamine transporter. [(3)H]Agmatine uptake was Ca(2+), energy and temperature dependent. [(3)H]Agmatine transport was not moderated by L-arginine, L-glutamate, glycine, GABA, norepinephrine or serotonin. In contrast, [(3)H]agmatine uptake was concentration dependently inhibited by unlabeled putrescine and by unlabeled spermidine (at significantly higher concentrations). Similarly, [(3)H]putrescine uptake was inhibited in a concentration-dependent manner by unlabeled agmatine and spermidine. The polyamine analogs paraquat and methylglyoxal bis (guanylhydrazone) inhibited, whereas the polyamine transport enhancer difluoromethylornithine increased, [(3)H]agmatine transport. Taken together, these results suggest that agmatine transport into spinal synaptosomes may be governed by a polyamine transport mechanism.
Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or l-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular l-citrulline concentrations, an indirect sign of NO production since equal amounts of l-citrulline and NO are produced from l-arginine. l-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or l-NAME (100 mg/kg i.p.) in control rats. Both agmatine and l-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. l-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and l-NAME treatments significantly suppressed the increase in l-citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of l-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance.