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Figur* 8.4T Pathway* of L-lryptophan briakdown pattern. Alternatively, the PLP-dependent enzyme tryptophan aminotransferase (EC2.6.1.27) can deaminate Trp; the fate of the resulting indole 3-pyruvate is uncertain, hut it may also undergo ring opening and rejoin the main catabolic pathway, Arylfor-mamidase (EC3.5.1.9) generates kynurenine by hydroly/ing N-formy I kynurenine. Most kynurenine is then oxidized by the davoenzyme kynurenine 3-monooxygenase (EC1.14.13.9). Two quantitatively minor alternative reactions also occur. One is the irreversible transamination, dependent on pyridoxaI-5-phosphate (PLP). to kvnurenie acid (4-(2-aminophenyl)-2,4-dioxobutanoate). Kynurenine-glvoxylate aminotransferase (EC2.6.1 .63). aromatic-amino-acid-glyoxylate aminotransferase (EC2.6.1,60), or kynurenine-oxoglutarate aminotransferase (KAT; EC2.6.I.7) can catalyze this reaction. Two genetically distinct forms of the latter enzyme, KATl and KATIi. occur in many tissues including liver, kidney, and brain. Kynurenic acid is a potent inhibitor of all three known ionotropic excitatory amino acid receptors, including the NMDA-receptor. Another minor reaction is the premature cleavage by PLP-dependent kynureninase (EC3.7.1,3), which releases anthralinate and L-alanine. Both kynurenic acid and anthralinate are dead-end products, which can be excreted after glucuronidation. The preferred reaction of kynureninase, however, is the hydrolysis of 3-hydroxy-kynurenine io 3-hydroxyanthralinate and L-alanine. The alternalivelv possible transamination of 3-hydroxy-kynurenine by kynurenine-oxoglutarate aminotransferase (EC2.6.1.7) to xanthurenic acid is insignificant as long as kynureninase activity is normal.

Oxidative cleavage ot 3-hydroxy-anthraliiiatc by the iron-enzyme 3-hydroxy-anthranilate 3.4-d¡oxygenase (EC1.13.11.6) generates 2-amino-3-earbo.xymuconate semialdehyde. This is the branch-point for nicotinate synthesis, since a small percentage of it spontaneously rearranges to the NAD precursor quinolinic acid. The bulk of 2-amino-3-earboxymuconate semialdehyde is dccarhoxvlated by aminocarboxymuconate-semialdehyde decarboxylase fEC4.1.1.45). Some of the product. 2-amino-muconate semialdehyde {2-aiiiiuo-3-(3-oxoprop-2-cnyl)-but-2-enedioate). may rearrange non-enzymieally to picolinatc. Most is oxidized, however, to 2-aminomuconate bv ami nomuconalc-sem ¡aldehyde dehydrogenase (EC1.2.1.32) and then reduced again to 2-oxoadipaie by an as yet unknown enzyme.

In exchange for alpha-ketoglutarate the oxodicarboxylate carrier (Fiermonte t-t a!,, 201)1) transports 2-oxoadipate, which is also an intermediate of lysine catabolism. across the inner mitochondrial membrane. Continued catabolism to acetyl-CoA takes place at the mitochondrial matrix. An enzyme complex whose identity is not entirely clear catalyzes the oxidative phosphorylation and conjugation to CoA. The oxoglu-taraic dehydrogenase (ECI.2.4.2) complex is able to facilitate the reaction (Bunik and Pavlova, 1947). but the existence of a closely related 2-oxoadipate dehydrogenase has not been ruled out. The alpha-ketoglutarate dehydrogenase complex contains thiamin pyrophosphate ibound to the El subuuits). and lipoic acid (bound to the E2 subunits); a third type of subunit. dihydrolipoamide dehydrogenase (E3. EC1.8.1.4). then uses its covalently bound FAD to reduce NAD. The resulting glutaryl-CoA is oxidized and deearboxylated by glutaryl-CoA dehydrogenase (ECU.00.7). which contains covalently bound FAD. Crotonyl-CoA completes beta-oxidation to two moles of acetyl-CoA. The three successive steps ate catalyzed by mitochondrial enoyl-CoA hydrolase (LC4.2.1,17), mitochondrial short-chain 3-hydroxyacyl-CoA

dehydrogenase (ECI.t.1.35), and mitochondrial acciyl-CoA C-acyltransferase (3-ketoacyl-CoA thiolase: EC2.3.U6).

Most 5-1 IT and some tryptanune are normally metabolized by monophenol monooxy-genase (MAO; EC1.14.18.11 and one or more of the aldehyde dehydrogenases (AlDH ECI.2.1.3 NAD-requiring. EC1.2.1,4/NADP-rcquiring. EC1.2.1.5/NAD or NADP-requirmg); 5-HT is converted into 5-hydroxyindole-3-acetate, and tryptamine into indole-3-acetate. Both 5-HT and tryptamine can also be shunted into the main Trp cala-bolic pathway by tryptophan 2.3-dioxygenase (EC 1.13.11.11. see above).

Some 5-HT can also be converted into the dead-end product 5-hydroxytryptophol (5-1ITOL) by alcohol dehydrogenase (EC). 1.1.1). Ethanot acutely increases the proportion converted into 5-1ITOL, A single dose of ethanot (I liter of beer in a 70 kg man I ingested with several bananas was enough to cause headaches, diarrhea, and fatigue in healthy subjects (I lelander and Some. 2000).

Storage

Body protein contains about 14mg Trp g (Smith. 1980): hemoglobin is a moderately Trp-rich protein (3.8%).

Excretion

Due to very effective renal reabsorption «(Tillered Trp very little is lost with urine. Uptake from the proximal tubular lumen uses mainly the sodium-dependent system B" I Avissar el u/.. 20011, and is augmented by the action of the sodium-independent transporter complexes bu-'-rBAT and BATl-rBAT (Verrey el al., 1999). Impaired reabsorption in I lartnup disease, possibly due to defective system B". causes excessive renal losses.

Minor Trp metabolites in urine include 5-hydroxyindoleacetic acid, from serotonin breakdown, and 2-(alpha-mannopyran«syl)-l-trypt«phan. from a pathway involving mannosylation of Trp (Gutsche el al.. 1999).

Regulation

High tissue concentration ofTrp stabilizes tryptophan 2.3-dioxygenase (EC 1.13.11.11) and thereby promotes Trp breakdown.

A carbohydrate-rich, protein-poor diet aids in the retention ofTrp in brain (Kaye el at. 2000).

Enhanced tryptophan catabolism through selective upregulation of indoleamine-pyrrole 2.3-dioxygenase (EC 1,13.11.42) expression in irophoblasts and macrophages appears to suppress T cell activ ity and contribute in a critical way to the immune tolerance of genetically different fetal tissues during pregnancy (Munn el at.. 1998).

Function

Protein synthesis: Trp is a constituent of practically all proteins and peptides synthesized in the body. Tryptophan-tRNA ligase(EC'6.1.1.2) loads Trp onto a specific l-RNA in an ATP 'magnesium-dependent react ion.

Proteins

L-Tryptophan t Kynurenic acid i

Xanthurenic ^ i acid A

6-imino-5-oxo- \ L_Alamne cyclohexa-1,3- y diene carboxylate , x

NAD(P) 2 Acetyl-Co A

Figure B.42 Usei of L-Iryjnoph.in

Energy production Eventually, most I rp is completely oxidi/cd prov iding about 5.8 kcal/g. The proportion that is conv erted to dead-end products such as kynurenic acid or used for the synthesis of products with lower energy yield is insignificant NAD synthesis: A small proportion of catabolized Trp (as well as tryptaminc, 5-hydroxytryptophan, serotonin, and melatonin) gives rise to nicotinamide-Containing compounds. Impaired absorption in Hartnup syndrome is associated with pellagra-like skin changes that are typical for niacin deficiency. The branch-point is at the conversion of 2-amino-3-carboxvmneonate semialdehyde. While most of this intermediate is en/vmically decarboxylated. a small proportion undergoes spontaneous dehydration to quinolinic acid (pyridine-2.3-dicarhoxylate). Nicotinate-nucleolide pyrophospho-rylase (EC2.4.2.19) decarboxylates quinolinatc and attaches a ribose phosphate moiety. Nicotinate-nucleotide adenylyltransferase (EC'2.7.7.18) can then add adenosine phosphate. Amination by either of two NAD synthases (EC6.3.5.1 and ECii.3.1.5) then completes NAD synthesis. It is usually assumed that about one-sixtieth of the metabolized Trp goes to NAD synthesis (Horwitt el a!., 1981).

Serotonin synthesis: The two-step synthesis of serotonin from Trp takes place in pinealocyles (pineal gland), raphe neurons of the brain, beta-cells of the islets of Langerhans. enterochromaffine cells of pancreas and small intestine, mast cells and mononuclear leukocytes and requires biopterin and \ itamin 116.

First, tryptophan 5-monooxygenase (EC1.14.16.4) hydroxylates Trp in a tetrahydropteridinc-depcndcnt reaction. The enzyme in neurons of the cerebral cortex is activated by protein kinase-dependent protein 14-3-3. The PLP-depcndem aromatic-L-amino-acid decarboxylase (I ( 4.1.1.28) then completes the synthesis of serotonin, t ryptophan 5-monooxygenase can also act directly on tryptamine (which may be ingested with cheeses or other fermented or spoiled foods) to synthesize serotonin. Serotonin is an important neurotransmitter in brain (serotonergic system) and a hormone-like substance in other tissues. Several synaptic receptors initiate neuron depolarization upon binding serotonin. Modulation of serotonin reuptake is an important drug target for the treatment of mood disorders as well as appetite control.

Various observations have suggested links between Trp intake and serotonin-mediated actions in brain, at least in particularly susceptibly individuals. Thus, men with aggressive histories may be more prone to aggressive behavior during Trp depletion (Ujork c/ al.. 20(H)), During Trp depletion women with bulimia nervosa were more likely to experience depression, mood lability, sadness, and desire to binge than other women (Kayc etul.. 2000).

Melatonin synthesis: Serotonin serves as the precursor for melatonin (N-aeetyl-5-methoxytryptamine) synthesis in brain, retina, and pineal gland in two reactions thai are dependent on adequate supplies of methionine, folate, and vitamin B12. Serotonin uptake into pinealocytes proceeds via the Na' - and CI -dependent transporter SLC6A4, whose activity appears to increase at night (I ima and Schmeer, 1994). Serotonin is then acetylated by aralkylamine N-acelylmmsferase (EC2.3.1 ,87) and methylated by acetyl serotonin O-methyltranslerase (EC2.I,1.4)

Melatonin participates in the regulation of circadian (I lebert et til.. 1999) and seasonal rhythms (Pevet 2000). influences growth hormone and thyroid hormone status (Meeking el til., 1999). increases pigmenrion (Iyengar, 2(M)0). promotes immune function (Guerrero et til.. 2000), and may contribute to free radical scavenging (Karbownik eral.. 2(H)(1).

Photoprotection; Human lens epithelial cells produce 3-hydroxy kynurenine glycoside. This pigment absorbs short-wave light and thereby appears to help protecting the eye from UV-induced photodamage (Wood and Truscott. 1993).

References

Anonymous. Use of ethyl esters of tryptophan to bypass the absorption defect in Hartnup disease. Nutr Rev I990;48:22 4 Avissar NE, Ryan CK. Ganapathy V, Sax HC. Na' -dependent neutral amino acid transporter ATBo isa rabbit epithelial cell brush border protein. J Physiol Cell Physiol 200l;28t:C963 71

Barih H, Berg PA, Klein R. Is there any relationship between eosinophil^ myalgia syndrome (F.MS) and fibromyalgia syndrome (FMS|? An analysis of clinical and immunological data. Adv Exp Med Biol 1999:467:487-96 Birlouez-Aragon I, Moreaux V. Nicolas M. Ducan/e CJ. Effect of iron and lactose supplementation of milk on the Maillard reaction and tryptophan content. Food Additives Contaminants 1997:14:381-8 Bjork JM, Dougherty DM. Moeller FG. Swann AC. Differential behavioral effects of plasma tryptophan depletion and loading in aggressive and nonaggressivc men. Neumpsyi hopharmacology 2000:22:357-69 Bunik VI, Pa\'lovaOG. Inacuvation of alpha-ketoglutarate dehydrogenase during its enzymatic reaction. Biocheni ¡Moscow) 1907;62:973-82 Dworsehak I-.. Nonenzyme browning and its effect on protein nutrition. Crit Rev FoodSci Nutr 1980; 13: MO

Fiermonte G. Dolce V. Palmieri L. Ventura M, Runsvvick MJ, Pal mien F, Walker JE. Identification of the human mitochondrial oxodicarboxylate carrier. ./ Bio! Chan 2001;276:8225-30

Guerrero ,IM. Pozo D, Garcia-Maurino S, CarrilloA,OsunaC. Molinero P. CalvoJR. Nuclear receptors are involved in the enhanced IL-6 production by melatonin in U937 cells. Biol Signals Receptors 2000:9:19? 202 Gutsche B. Diem s. Herderich M. Electrospray ionization-tandem mass spectrometry for the analysis of tryptophan derivatives in food. Adv Exp Med Biol 1999;467:757-67 Hcbert M. Martin SK. Eastman CI. Nocturnal melatonin secretion is not suppressed by light exposure behind the knee in humans. Neurosci Lett 1999;274:127-30 Melander A. Some M. Dietary serotonin and alcohol combined may provoke adverse physiological symptoms due to 5-hydroxytryptophol. Life Sci 2000;67;799 X06 Horwitt MK. Harper AE. Henderson LM. Niacin-tryptophan relationships for evaluating niacin equivalents. Am J Clin Nutr 1981:34:423-7 Iyengar B. Melatonin and melanocyte functions. Bud Signals Receptors 2(H)0;9;260 Karbownik M. fan DX, Reiter R.I. Melatonin reduces the oxidation of nuclear DNA and membrane lipids induced by the carcinogen dclia-aminolevulinic acid, hit J Cancer 2000:88:7-11

Kave WlI. Gendall KA. Fernsirom Mil. Femstrom JD. McConaha CW, Weltzin TF. Effects of acute tryptophan depletion on mood in bulimia nervosa. Biol Psychtat 2000:47:151 7 Kim DK. Kanai Y, C'hairoungdua A. Matsuo II. C'ha SH. Endou II. Expression cloning of a Na"-independent aromatic amino acid transporter with structural similarity to 11 monocarboxylaic transporters. J Biol Chem 2001 ;27(i: 17 221-8 Klarskm K. Johnson KL, Benson I M. Oleic h OJ. Nay lor S. Eosinophil ia myalgia syndrome case-assoeiaied contaminants in commercially available 5-hydroxytryptophan. .4tA Exp Med Biol 1999:467:461-8 I albrcc R. Rigo//i K. Paganetti M. Vlossi W, Guainazzi 1'. Calderari G Aspects of melatonin manufacturing and requirements for a reliable active component. Biol Signals Receptors 1999:8:143-6 Lima L. Sehmeer C, Characterization of serotonin transporter in goldfish retina by the binding of [3FT)paroxetine and the uptake of [3H]scrotonin: modulation by light, JNeuruchem 1994:62:528 35

Luthman J. The kvnurcninc pathway of tryptophan degradation as a target for neuroprotective therapies. Amino Acid« 2000:19:27.1-4 Mccking DR. Wallace Jl). ( unco RC. Forsting M. Russell-Jones Dt Exercise-induced Gl I secretion is enhanced hy the oral ingestion of melatonin in healthy adult male subjects. Fur J Endocrinol 1499:141:22-6 Mizoguchi K, Cha Sil. Chairoungdua A. Kim DK. ShigetaY, Matsuo If. Fukushhna J. AwaY. Akakura k. GqyaT. Ito H, Endou M. Kanai Y. Human cystinuria-related innsporter: localization and functional characterization. Kidney Im 2001:59:1 82! 33 Müller B. Paeholski C, Simat T. Steinhan H. Synthesis and formation of an EMS correlated contaminant in biotechnologically manufactured L-tryptophan. Adv Exp Med Biol 1999:467:481 6

Munn Dil. Zhou M. Attwood JT. Bondarev 1, Conway SJ, Marshall B. Brown C, Mel I or AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998:281:1191 3 Naylor S, Williamson BL, Johnson KL, Gleich (iJ. Structural characterization of case-associated contaminants peak C and FF in L-tryptophan implicated in eosinophilia-myalgia syndrome. Adv Exp Med Biol 1999;467;453 60 Pevet I'. Melatonin and biological rhythms. Biol Signals Receptors 2000:9:203-12 Rajan DP, Kekuda R. Huang W. Devoe LD. Leibach III, Prasad I'D, Ganapathy V, Cloning and functional characterization of a Naf+ ^independent. broad-specific neutral amino acid transporter from mammalian intestine. Biochim Biophys Acta 2000: 1463:6-14

Ritchic JW, Taylor I'M. Role of the System I permease LA IT m amino acid and iodothy-

roninc transport in placenta. Bi/uhem J 2001:356:719 25 Rossier Ci. MeierC, Bauch C, Summa V, Sordat B. Verrcv F. kühn I C, LAT2,a new haso-lateral 4F2hc'CD9X-associatcd amino acid transporter of kidney and intestine../ Biol Client 1999;274:3494H 5-1 Smith RH. Comparative amino acid requirements. Proc NutrSoc 1980:39:71 8 Verrcy F, Jack DL., Paulsen IT, Saier MH jr, Pfeiffer R. New glycoprotein-associated amino acid transporters. J Membrane Biol 1999;I72:181 42 Wood AM. Truscott RJ. UV filters in human lenses: tryptophan catabolism. Exp Eye Res 1993:56:317-25

Young VR. Borgonha S. Nitrogen and amino acid requirements: the Massachusetts Institute of lechnology amino acid requirement pattern. J Nutr 2000:130:1841S—49S Zicgenhagcn R. Boczck P. Vicll B. Formation of the comutagenic bcta-carboline norharman in a simple tryptophan-containing model system at low temperature (4IVC 80 Ci. Adv Exp Med Biol 1999:467:693 6

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