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Pathway Description
Tryptophan Metabolism
Caenorhabditis elegans
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2018-08-10
Last Updated: 2019-08-30
This pathway depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.
References
Tryptophan Metabolism References
Genome sequence of the nematode C. elegans: a platform for investigating biology. Science. 1998 Dec 11;282(5396):2012-8. doi: 10.1126/science.282.5396.2012.
Pubmed: 9851916
van der Goot AT, Zhu W, Vazquez-Manrique RP, Seinstra RI, Dettmer K, Michels H, Farina F, Krijnen J, Melki R, Buijsman RC, Ruiz Silva M, Thijssen KL, Kema IP, Neri C, Oefner PJ, Nollen EA: Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14912-7. doi: 10.1073/pnas.1203083109. Epub 2012 Aug 27.
Pubmed: 22927396
Michels H, Seinstra RI, Uitdehaag JC, Koopman M, van Faassen M, Martineau CN, Kema IP, Buijsman R, Nollen EA: Identification of an evolutionary conserved structural loop that is required for the enzymatic and biological function of tryptophan 2,3-dioxygenase. Sci Rep. 2016 Dec 20;6:39199. doi: 10.1038/srep39199.
Pubmed: 27995966
Bhat SG, Babu P: Mutagen sensitivity of kynureninase mutants of the nematode Caenorhabditis elegans. Mol Gen Genet. 1980;180(3):635-8. doi: 10.1007/bf00268072.
Pubmed: 6936603
Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M: A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature. 1999 May 13;399(6732):162-6. doi: 10.1038/20208.
Pubmed: 10335847
Fukuoka S, Ishiguro K, Yanagihara K, Tanabe A, Egashira Y, Sanada H, Shibata K: Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and "quinolinate hypothesis". J Biol Chem. 2002 Sep 20;277(38):35162-7. doi: 10.1074/jbc.M200819200. Epub 2002 Jul 24.
Pubmed: 12140278
Loer CM, Davidson B, Mckerrow J: A phenylalanine hydroxylase gene from the nematode C. elegans is expressed in the hypodermis. J Neurogenet. 1999 Nov;13(3):157-80.
Pubmed: 10928216
Calvo AC, Pey AL, Ying M, Loer CM, Martinez A: Anabolic function of phenylalanine hydroxylase in Caenorhabditis elegans. FASEB J. 2008 Aug;22(8):3046-58. doi: 10.1096/fj.08-108522. Epub 2008 May 6.
Pubmed: 18460651
Alkema MJ, Hunter-Ensor M, Ringstad N, Horvitz HR: Tyramine Functions independently of octopamine in the Caenorhabditis elegans nervous system. Neuron. 2005 Apr 21;46(2):247-60. doi: 10.1016/j.neuron.2005.02.024.
Pubmed: 15848803
Burkewitz K, Morantte I, Weir HJM, Yeo R, Zhang Y, Huynh FK, Ilkayeva OR, Hirschey MD, Grant AR, Mair WB: Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal. Cell. 2015 Feb 26;160(5):842-855. doi: 10.1016/j.cell.2015.02.004.
Pubmed: 25723162
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0000063
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