Abstract
Felinine is a unique sulfur-containing amino acid found in the urine of domestic cats and select members of the Felidae family. Research over the past 50 years has led to the conclusion that felinine must be synthesized in the kidney, as free felinine is not present in the blood or tissues of cats. We propose that felinine is present in the blood as gamma-glutamylfelinylglycine, a glutathione conjugate. To test our hypothesis [35S]cysteine was administered intraperitoneally to one entire male cat, and two radiolabeled fractions were isolated from the blood. We showed that the amounts of both fractions in serum were linked to the gender of the cat, with entire males expressing significantly higher levels compared with castrated males, entire females, or spayed females. Both fractions were characterized using amino acid analysis with one fraction (S18), containing an equimolar ratio of Cys, Glu, and Gly, while fraction S16 was found to contain Cys, plus free amino acids. Nanospray mass spectrometry confirmed the sequence of fraction S18 as being gamma-glutamylfelinylglycine and conclusively proving that felinine is present in the blood of cats as part of a larger molecule, thereby questioning the current theory that felinine is synthesized in the kidney.
Highlights
Felinine is a sulfur-containing amino acid that has been found in the urine of certain members of Felidae
The remaining two radioactive peaks, which eluted at ϳ16.5% (S16) and 21.5% (S18) of the gradient contained between 1–9% and 2–10% of the radioactivity in the serum sample, respectively. These two 35S-containing peaks S16 and S18 were identified as possible candidates for the felinine-containing peptide and were subjected to further analysis by amino acid analysis, mass spectrometry, and amino acid sequencing
This study has shown that intraperitoneal administration of [35S]cysteine to an entire male cat results in the incorporation of the 35S moiety into material found in three serum peaks separated by reversed-phase High Performance Liquid Chromatography (HPLC): the injection peak, S16, and S18
Summary
We propose felinine arises from a conjugation reaction between the cysteine in glutathione (GSH) and IPP to form the tripeptide ␥-glutamylfelinylglycine, rather than free felinine being formed from free cysteine and IPP This mechanism would be similar to that described for the formation of isovalthine, another unusual sulfur amino acid that has been isolated from the urine of domestic cats, lions, and humans suffering from hypothyroidism and hypercholesterolemia [14]. In the case of the ␥-glutamylfelinylglycine conjugate, following formation in tissues such as the liver the peptide could be transported via the blood to the kidney, where free felinine could be liberated by the actions of ␥-glutamyltransferase and aminopeptidase M and be excreted in the urine. Our hypothesis would explain the absence of free felinine in the blood of domestic cats
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