Serotonin catabolism and the formation and fate of 5-hydroxyindole thiazolidine carboxylic acid.
Serotonin (5-HT) functions as a neurotransmitter and neuromodulator in both the central and enteric nervous systems of mammals. The dynamic degradation of 5-HT metabolites in 5-HT-containing nervous system tissues is monitored by capillary electrophoresis with wavelength-resolved laser-induced native fluorescence detection in an effort to investigate known and novel 5-HT catabolic pathways. Tissue samples from wild type mice, genetically altered mice, Long Evans rats, and cultured differentiated rat pheochromocytoma PC-12 cells, are analyzed before and after incubation with excess 5-HT. From these experiments, several new compounds are detected. One metabolite, identified as 5-hydroxyindole thiazoladine carboxylic acid (5-HITCA), has been selected for further study. In 5-HT-incubated central and enteric nervous system tissue samples and differentiated PC-12 cells, 5-HITCA forms at levels equivalent to 5-hydroxyindole acetic acid, via a condensation reaction between L-cysteine and 5-hydroxyindole acetaldehyde. In the enteric nervous system, 5-HITCA is detected without the addition of 5-HT. The levels of L-cysteine and homocysteine in rat brain mitochondria are measured between 80 and 140 microm and 1.9 and 3.4 microm, respectively, demonstrating that 5-HITCA can be formed using available, free L-cysteine in these tissues. The lack of significant accumulation of 5-HITCA in the central and enteric nervous systems, along with data showing the degradation of 5-HITCA into 5-hydroxyindole acetaldehyde, suggests that an equilibrium coupled to the enzyme, aldehyde dehydrogenase type 2, prevents the accumulation of 5-HITCA. Even so, the formation of 5-HITCA represents a catabolic pathway of 5-HT that can affect the levels of 5-HT-derived compounds in the body.
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Leah N
LN
Squires
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Jennifer A
JA
Jakubowski
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Jeffrey N
JN
Stuart
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Stanislav S
SS
Rubakhin
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Nathan G
NG
Hatcher
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Won-Suk
WS
Kim
Department of Molecular Pharmacology and Toxicology, Pharmaceutical Sciences Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089.
Kevin
K
Chen
Department of Molecular Pharmacology and Toxicology, Pharmaceutical Sciences Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089.
Jean C
JC
Shih
CNRS, Unité Mixte de Recherche 146, Institut Curie, 91405 Orsay, France.
Isabelle
I
Seif
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801. Electronic address: jsweedle@uiuc.edu.
Jonathan V
JV
Sweedler
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D007211:Indoles / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020318:Rats, Long-Evans; D012701:Serotonin / Q000737:chemistry* / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*; D053778:Thiazolidines
D007211:Indoles; D013844:Thiazoles; D053778:Thiazolidines; C059687:2-(3'-(5'-hydroxyindolyl)methyl)-1,3-thiazolidine-4-carboxylic acid; D012701:Serotonin; D008995:Monoamine Oxidase