Tryptophan metabolism, from nutrition to potential therapeutic applications

Tryptophan is an indispensable amino acid that should to be supplied by dietary protein. Apart from its incorporation into body proteins, tryptophan is the precursor for serotonin, an important neuromediator, and for kynurenine, an intermediary metabolite of a complex metabolic pathway ending with niacin, CO2, and kynurenic and xanthurenic acids. Tryptophan metabolism within different tissues is associated with numerous physiological functions. The liver regulates tryptophan homeostasis through degrading tryptophan in excess. Tryptophan degradation into kynurenine by immune cells plays a crucial role in the regulation of immune response during infections, inflammations and pregnancy. Serotonin is synthesized from tryptophan in the gut and also in the brain, where tryptophan availability is known to influence the sensitivity to mood disorders. In the present review, we discuss the major functions of tryptophan and its role in the regulation of growth, mood, behavior and immune responses with regard to the low availability of this amino acid and the competition between tissues and metabolic pathways for tryptophan utilization.

[1]  K. Eder,et al.  Studies on the tryptophan requirement of piglets , 2001, Archiv fur Tierernahrung.

[2]  P. McGuire,et al.  Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature , 2006, Psychopharmacology.

[3]  R. Pihl,et al.  Acute effect of altered tryptophan levels and alcohol on aggression in normal human males , 1995, Psychopharmacology.

[4]  D. Zuroff,et al.  The Effect of Tryptophan on Social Interaction in Everyday Life: A Placebo-Controlled Study , 2001, Neuropsychopharmacology.

[5]  M. Murray Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. , 2003, The Lancet. Infectious diseases.

[6]  S. Fujii,et al.  Induction of tryptophan 2,3-dioxygenase in the mouse endometrium during implantation. , 2000, Biochemical and biophysical research communications.

[7]  Joachim L. Schultze,et al.  IDO-expressing regulatory dendritic cells in cancer and chronic infection , 2008, Journal of Molecular Medicine.

[8]  W. Riedel,et al.  Effects of acute tryptophan depletion on memory, attention and executive functions: A systematic review , 2009, Neuroscience & Biobehavioral Reviews.

[9]  I. Bechmann,et al.  IDO expression in the brain: a double-edged sword , 2007, Journal of Molecular Medicine.

[10]  J. Bjork,et al.  Differential Behavioral Effects of Plasma Tryptophan Depletion and Loading in Aggressive and Nonaggressive Men , 2000, Neuropsychopharmacology.

[11]  B. Séve,et al.  Chronic lung inflammation affects plasma amino acid concentrations in pigs. , 2004, Journal of animal science.

[12]  D. Fuchs,et al.  Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. , 2005, Journal of affective disorders.

[13]  E. Pfefferkorn Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Markus Dietary Amino Acids and Brain Serotonin Function; Implications for Stress-Related Affective Changes , 2008, NeuroMolecular Medicine.

[15]  D. Fuchs,et al.  Monitoring tryptophan metabolism in chronic immune activation. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[16]  R. Schwarcz,et al.  Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO1 , 2006, The Journal of Immunology.

[17]  B. Westerink,et al.  Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein–carbohydrate mixture in the adult rat , 2004, Neurochemistry International.

[18]  J. Schmitt,et al.  Effects of tryptophan loading on human cognition, mood, and sleep , 2010, Neuroscience & Biobehavioral Reviews.

[19]  D. Munn,et al.  Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. , 2001, Journal of reproductive immunology.

[20]  B. Séve,et al.  Dietary tryptophan helps to preserve tryptophan homeostasis in pigs suffering from lung inflammation. , 2008, Journal of animal science.

[21]  R. Ball,et al.  Tryptophan requirement in young adult women as determined by indicator amino acid oxidation with L-[13C]phenylalanine. , 1998, The American journal of clinical nutrition.

[22]  T. Stone,et al.  Neurotoxicity of tryptophan metabolites. , 2007, Biochemical Society transactions.

[23]  B. Kerr,et al.  Dietary tryptophan effects on plasma and salivary cortisol and meat quality in pigs. , 2006, Journal of animal science.

[24]  Knox We,et al.  The hormonal control of tryptophan peroxidase in the rat. , 1955 .

[25]  P. Reeds,et al.  Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? , 1994, The Journal of nutrition.

[26]  M Diksic,et al.  Differences between males and females in rates of serotonin synthesis in human brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Fuchs,et al.  ENHANCED ENZYMATIC DEGRADATION OF TRYPTOPHAN BY INDOLEAMINE 2,3-DIOXYGENASE CONTRIBUTES TO THE TRYPTOPHAN-DEFICIENT STATE SEEN AFTER MAJOR TRAUMA , 2005, Shock.

[28]  Arjan Blokland,et al.  Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat , 2002, Journal of psychopharmacology.

[29]  Marco Leyton,et al.  The role of serotonin in human mood and social interaction Insight from altered tryptophan levels , 2002, Pharmacology Biochemistry and Behavior.

[30]  C. Firk,et al.  Mood and cortisol responses following tryptophan-rich hydrolyzed protein and acute stress in healthy subjects with high and low cognitive reactivity to depression. , 2009, Clinical nutrition.

[31]  O. Hayaishi,et al.  Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. , 1967, The Journal of biological chemistry.

[32]  D. McMillan,et al.  Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response. , 1998, The Journal of nutrition.

[33]  D. Fuchs,et al.  Weight loss in patients with hematological neoplasias is associated with immune system stimulation , 2004, The clinical investigator.

[34]  G. Schutz,et al.  Purification and properties of rat liver tryptophan oxygenase. , 1972, Journal of Biological Chemistry.

[35]  P. Garlick The nature of human hazards associated with excessive intake of amino acids. , 2004, The Journal of nutrition.

[36]  R. Stocker,et al.  Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[37]  W. Pardridge Tryptophan transport through the blood-brain barrier: in vivo measurement of free and albumin-bound amino acid. , 1979, Life sciences.

[38]  R. Dantzer,et al.  Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. , 2009, Journal of Neuroscience.

[39]  U. Hadding,et al.  Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. , 1998, The Journal of infectious diseases.

[40]  S. Fromm,et al.  The Effect of Acute Tryptophan Depletion on the Neural Correlates of Emotional Processing in Healthy Volunteers , 2008, Neuropsychopharmacology.

[41]  C. I. Pogson,et al.  The metabolism of L-tryptophan by isolated rat liver cells. Effect of albumin binding and amino acid competition on oxidatin of tryptophan by tryptophan 2,3-dioxygenase. , 1980, The Biochemical journal.

[42]  J. McQueen,et al.  The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo , 1982, Psychological Medicine.

[43]  R. Ulijn,et al.  Bionanotechnology: from Self-assembly to Cell Biology Three-dimensional Cell Culture of Chondrocytes on Modified Di-phenylalanine Scaffolds , 2022 .

[44]  E. Borden,et al.  Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. , 1991, Advances in experimental medicine and biology.

[45]  G. Barr,et al.  Manipulations of dietary tryptophan: Effects on mouse killing and brain serotonin in the rat , 1979, Brain Research.

[46]  D. Mahan,et al.  Essential and nonessential amino acid composition of pigs from birth to 145 kilograms of body weight, and comparison to other studies. , 1998, Journal of animal science.

[47]  O. Takikawa,et al.  Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme. , 1985, The Biochemical journal.

[48]  R. Yolken,et al.  Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia , 2004, Neurobiology of Disease.

[49]  W. Knox,et al.  The hormonal control of tryptophan peroxidase in the rat. , 1955, The Journal of biological chemistry.

[50]  E. Bosmans,et al.  Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. , 2002, Life sciences.

[51]  Y. Mine,et al.  l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. , 2010, The Journal of nutritional biochemistry.

[52]  M. Linnoila,et al.  Low Central Nervous System Serotonergic Activity Is Traitlike and Correlates with Impulsive Behavior , 1997, Annals of the New York Academy of Sciences.

[53]  W. Pardridge Brain metabolism: a perspective from the blood-brain barrier. , 1983, Physiological reviews.

[54]  Alexander Neumeister,et al.  Interactive Effects of Sex and 5-HTTLPR on Mood and Impulsivity During Tryptophan Depletion in Healthy People , 2007, Biological Psychiatry.

[55]  B. Kerr,et al.  Effects of supplemental L-tryptophan on serotonin, cortisol, intestinal integrity, and behavior in weanling piglets. , 2006, Journal of animal science.

[56]  G. Prendergast,et al.  The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity1 , 2009, The Journal of Immunology.

[57]  D. Fuchs,et al.  Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences. , 2000, Current drug metabolism.

[58]  J. Leklem Quantitative aspects of tryptophan metabolism in humans and other species: a review. , 1971, The American journal of clinical nutrition.

[59]  B. Séve,et al.  The effects of energy source and tryptophan on the rate of protein synthesis and on hormones of the entero-insular axis in the piglet , 1994, British Journal of Nutrition.

[60]  P. Garlick,et al.  Diurnal pattern of protein and energy metabolism in man. , 1981, The American journal of clinical nutrition.

[61]  C. MacKenzie,et al.  Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immuno-regulation: tryptophan depletion versus production of toxic kynurenines. , 2007, Current drug metabolism.

[62]  R. Dantzer,et al.  Bacille Calmette-Guérin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice. , 2005, The Journal of infectious diseases.

[63]  O. Hayaishi,et al.  Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. , 1986, The Journal of biological chemistry.

[64]  U. Hadding,et al.  Interferon-γ-Induced Activation of Indoleamine 2,3-Dioxygenase in Cord Blood Monocyte-Derived Macrophages Inhibits the Growth of Group B Streptococci , 1998 .

[65]  W. Riedel,et al.  Monoamine depletion in psychiatric and healthy populations: review , 2003, Molecular Psychiatry.

[66]  B. Baban,et al.  Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. , 2007, The Journal of clinical investigation.

[67]  F. Hirata,et al.  Indoleamine 2,3-dioxygenase. Purification and some properties. , 1978, The Journal of biological chemistry.

[68]  A. Mehler,et al.  The adaptive increase of the tryptophan peroxidase-oxidase system of liver. , 1951, Science.

[69]  Y. Nagamura,et al.  Tryptophan 2,3-dioxygenase activity in rat skin. , 1989, Archives of Biochemistry and Biophysics.

[70]  A. Young,et al.  Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: A pooled analysis of nine studies , 2007, Neuroscience & Biobehavioral Reviews.

[71]  C. McDougle,et al.  Tryptophan Depletion During Continuous CSF Sampling in Healthy Human Subjects , 1998, Neuropsychopharmacology.

[72]  D. Nutt,et al.  Tryptophan metabolism in the central nervous system: medical implications , 2006, Expert Reviews in Molecular Medicine.

[73]  B. Séve,et al.  Interactive effects of dietary levels of tryptophan and protein on voluntary feed intake and growth performance in pigs, in relation to plasma free amino acids and hypothalamic serotonin. , 1992, Journal of animal science.

[74]  B. Séve,et al.  Marginal efficiency of free or protected crystalline L-tryptophan for tryptophan and protein accretion in early-weaned pigs. , 1997, Journal of Animal Science.

[75]  T. Ettle,et al.  Specific dietary selection for tryptophan by the piglet. , 2004, Journal of animal science.

[76]  B. Séve,et al.  Growth performance and brain neurotransmitters in pigs as affected by tryptophan, protein, and sex. , 1996, Journal of animal science.

[77]  B. Baban,et al.  Cutting Edge: CpG Oligonucleotides Induce Splenic CD19+ Dendritic Cells to Acquire Potent Indoleamine 2,3-Dioxygenase-Dependent T Cell Regulatory Functions via IFN Type 1 Signaling1 , 2005, The Journal of Immunology.

[78]  C. MacKenzie,et al.  Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-gamma-induced tryptophan degradation. , 2008, FEMS immunology and medical microbiology.

[79]  Defa Li,et al.  Tryptophan enhances ghrelin expression and secretion associated with increased food intake and weight gain in weanling pigs. , 2007, Domestic animal endocrinology.

[80]  L. Vécsei,et al.  Kynurenic acid inhibits intestinal hypermotility and xanthine oxidase activity during experimental colon obstruction in dogs , 2007, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[81]  O. Hayaishi Utilization of superoxide anion by indoleamine oxygenase-catalyzed tryptophan and indoleamine oxidation. , 1996, Advances in experimental medicine and biology.

[82]  I. Sargent,et al.  Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. , 2004, Journal of reproductive immunology.

[83]  H. Westenberg,et al.  The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. , 2000, The American journal of clinical nutrition.

[84]  B. Stoll,et al.  The high metabolic cost of a functional gut. , 2002, Gastroenterology.

[85]  H. Tilg,et al.  Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. , 2004, Clinical Immunology.

[86]  U. Grohmann,et al.  T cell apoptosis by tryptophan catabolism , 2002, Cell Death and Differentiation.

[87]  S. Koopmans,et al.  Surplus dietary tryptophan reduces plasma cortisol and noradrenaline concentrations and enhances recovery after social stress in pigs , 2005, Physiology & Behavior.

[88]  E. Ragazzi,et al.  Enzyme activities involved in tryptophan metabolism along the kynurenine pathway in rabbits. , 2001, Biochimica et biophysica acta.

[89]  G. Ortiz,et al.  Antioxidant activity of tryptophan in rats under experimental endotoxic shock. , 2010, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[90]  H. Wolf The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. , 1974, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[91]  R. Ball,et al.  Enteral Tryptophan Requirement Determined by Oxidation of Gastrically or Intravenously Infused Phenylalanine Is Not Different from the Parenteral Requirement in Neonatal Piglets , 2004, Pediatric Research.

[92]  T. Stone,et al.  Tryptophan Loading Induces Oxidative Stress , 2004, Free radical research.

[93]  W. Pardridge Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids , 1998, Neurochemical Research.

[94]  I. Ragno,et al.  [Studies on tryptophan-nicotinic acid metabolism in hepatic cirrhosis in man. Preliminary note]. , 1961, Bollettino della Societa italiana di biologia sperimentale.

[95]  D. Munn,et al.  Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism , 1999, The Journal of experimental medicine.

[96]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[97]  L. Reis,et al.  Expression of Indoleamine 2,3-Dioxygenase, Tryptophan Degradation, and Kynurenine Formation during In Vivo Infection with Toxoplasma gondii: Induction by Endogenous Gamma Interferon and Requirement of Interferon Regulatory Factor 1 , 2002, Infection and Immunity.

[98]  G. Sarwar,et al.  Liquid concentrates are lower in bioavailable tryptophan than powdered infant formulas, and tryptophan supplementation of formulas increases brain tryptophan and serotonin in rats. , 1999, The Journal of nutrition.

[99]  D. Fuchs,et al.  Longitudinal study of tryptophan degradation during and after pregnancy. , 2003, Life sciences.

[100]  J. Korf,et al.  Tryptophan as a Link between Psychopathology and Somatic States , 2003, Psychosomatic medicine.

[101]  J. Mench,et al.  The effect of dietary tryptophan on aggressive behavior in developing and mature broiler breeder males. , 1990, Poultry science.

[102]  D. Fuchs,et al.  Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection , 2007, Journal of Virology.