Biopterin

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Biopteritl (S-( R*,S*)-2-amino-6-{ 1,2-dihydoxypropy] )-4( 111 )-ptcridmonc, 6.7-dihydropicridine, molecular weight 237) is a moderately water-soluble heterocyclic compound. The biologically active form is tetrahydtrobiopterin (BH4).

Abbreviations

BHt 6,7-dihydropteridine 8Hj 5,6,7,8-tetrahydrobiopterin FTP 6-pyruvoyltetra hydro pterin

Nutritional summary

Function: Biopterin is needed for the metabolism of phenylalanine, tyrosine, and tryptophan, and for the synthesis of hormones, neurotransmitters, and skin pigments (catecholamines, melanin, serotonin, melanotonin), and cell signaling {nitric oxide). Roles in promoting angiogcncsis, neuronal survival, cellular immunity, and for protection against free radicals also are likely.

Requirements: The body can produce adequate amounts in the absence of dietary intake; synthesis requires GTP, niacin and magnesium.

Food sources; White many animal foods contain various bioactive forms of biopterin. the amounts have not been well investigated.

Deficiency; Genetic defects of biopterin synthesis or actuation cause severe phenylketonuria with neurological damage and weak muscle tonus. Deficiency has also been suggested to contribute to Alzheimer's disease. Parkinson's disease, autism, and depression. Trimethoprim inhibits reactivation of oxidized biopterin: whether this causes deficiency symptoms is not known.

Excessive intake: The risk from using supplemental biopterin at any level is not well documented.

Endogenous sources

Biopterin is synthesized endogenously in most tissues, starling with a molecular rearrangement of GTP t Bonafe et a!.. 2001). The reactions use NADPH. NADI I. and magnesium as eofactors.

NHi" N

XjC>

OH OH

GTP cycto-hyd tolas e I

NHf Dihydroneo pterin triphosphate

6-pyruvoyl tetraliydropterin synthase [Mg 'J

NADPH

N- NAOP

6-Pyruvoyl- nh^V tetrahydropterin I q nhp

NADPH ,

NW^/Sopaplonn flactuclase n

NW^/Sopaplonn flactuclase n

NH2" 2'-0xo-letrahydfopterin

Aldehyde Reductases.

Aldehyde \( RoduclaseN^^ NADP

Carbonyl Poductasfi o

NACPH

Sepunienr» nHj-^^m Reductase

NADPM .

NADP

y Ret

tetrahydroptertn

Sepiapterin Reductase

y Ret

T et ra h ydrobi Opte ri n

Dlhydroptendlne

Dlhydroptendlne

N H 7.6-Difiydro-bioptefin

N H 7.6-Difiydro-bioptefin

Figure 10.47 Tetrahydrobiopterin synthesis

GTP cyclohydrolase 1 (EC3.5.4.16) generates a neopterin intermediate which is converted by the NADPM- and magnesium-requiring 6-pyruvoy I tetrahy droptcrin synthase (EC4.6.1.10) into 6-pyruvoy 1 tetrahy droptcn n (PTP). Both keto groups of the side chain then have to he reduced to arrive at the linal product 5.6.7,8-tclrahydro-biopterin <BH4). Sepiapten n reductase (EC 1.I.I.1S3) can accomplish this in three distinct steps w ith 2'-oxo-tetrahydropterin and I '-oxo-tetrahydropterin as intermediates. I his pathway accounts for about half of the BH4 synthesis in vivo. The remainder is generated through alternative pathways that rely on aldehyde reductase (EC1.1.1.21) and carbonyl reductase (EC1.1.1.184), some in conjunction with sepiapterm reductase.

The NADPH-requiring enzyme ptenn-4a-carbinolatiiine dehydratase (EC4.2.1.96) appears to facilitate B1 fi synthesis by accelerating the formation of quinoid dihydro-biopterin and preventing the formation of inactive 7-pterins, 1 lovvever, the mechanism of this reaction is still unclear.

Dietary sources

Forms present in food include tetrahydrobiopterin, dihydrobiopterin, and neopterin. The quantities available from specific foods or typical intake levels are not yet well characterized.

Digestion and absorption

Some ingested tctrahydrobiopterin is absorbed as demonstrated by the rapid lowering of phenylalanine levels in a patient with detective biopterin synthesis (Snydcrman el at., 19X7). The mechanisms of uptake and export are uncertain.

Transport and cellular uptake

The plasma concentrations of total biopterin and Bl I, in plasma were found to be highest al nine in the morning, and lowest shortly past midnight (Hashimoto et a!.. 1993). BH4 from blood is rapidly taken up into liver and kidneys, and transferred across the placenta to the fetus, whereas transfer into brain and other tissues appears to be very limited (Hoshiga et al., 1993). The extent of transport in blood circulation and mechanism of uptake into cells has not been well characterized yet.

Metabolism

BHj-utilizing reactions generate several products including 4a-hydroxytetrahydro-bioptcrin (4a-carbinolamine). quinonoid dihydrobiopterin. and 4a-cyclic-tetrahydro-biopterin. These reaction products are inactive as cofactors until convened again to HI l,t. The reactivation of dihydrobiopterin is accomplished by a NADi P)H-dependcnt enzyme, dihydropteridine reductase (EC1.6.99.7). Tltis enzyme is inhibited by the antibiotic trimethoprim. 4a-Hydroxytctrahydrobiopterin and 4a-eye lie-tetrahy drohiopterin can be

4a-hydraxytet ra-hydrobiopterin

4a-hydraxytet ra-hydrobiopterin

4a-Carbln-

otamine dehydratase

4a-Carbln-

otamine dehydratase nh2-

Dihydrobiopterin

Oihydro ptondine reductase

nh2-

Tetrahydrobiopterm

Figure 10.48 Tftrahydrobioptrr-tn reactivation

reactivated to Ml t by pterin-4a-carbinol amine dehydratase (HC4.2.1.96) in conjunction with dihydroptcridine rcductasc.

ii is of note that pterin-4a-carbinolaminc dehydratase (ft'4,2,! .96) participates in gene regulation as a cofactor for hepatocyte nuclear factor 1 homeobox transcription factors. It has been suggested that it might play a role in the development of colon carcinoma and melanoma.

There is evidence that the peroxisomal enzyme xanthine dehydrogenase (EC 1,1.3,22) participates in the conversion of pterin to isoxanthoptcrin (Blau et at.. 1996). This enzyme contains molvbdenitm cofactor, iron-sulfur clusters, and FAD.

Storage

Neither the body content ofbiopterin or its precursors, nor specific storage mechanisms arc known.

Excretion

The oxidized form of biopterin is excreted much more rapidly than BM4 (lloshiga et at., 1993). Unnary metabolites derived from biopterin synthesis and metabolism include D-threo-bioptenn and L-threo-biopterin (Fukushima and Shiota. ! 472). neopterin. isoxanthopterin, 7-biopterin (primapterin). and N2-(3-aminopropyl (biopterin (oncopterin).

Low activity of pierin--la-carbinolamine dehydratase (EC4.2.1.96) increases the excretion as 7-biopterin (primapterin).

A methotrexate-derived compound coelutcs on HPLC with oncoptenn. and might be misinterpreted as a marker for cancer-specific alteration of biopterin metabolism (Ilibiyae/«/., 1997).

Regulation

Biopterin status is predominantly controlled by modulation of GTP cyclo hydrolase I expression and activity. Gam ma-inter feron and oilier cytokines increases biopterin production by inducing GTP cyclohydrolase I (Thony et at., 20(10). Glucocorticoids prevent cytokine-mediated induction of GTP cyclohydrolase I (Simmons et al., 1996). apparently via a cAMP-mediated signaling cascade (Ohtsuki el a!.. 2002).

Food deprivation of animals increases biopterin production and concentration in blood (Roller etui., 1990).

Function

Tyrosine synthesis: Phenylalanine can be the precursor of tyrosine through the action of the ferroenzvme phenylalanine hydroxylase (EC 1.14.16.1). This hydroxylation of phenylalanine is driven by the oxidation of BFI4 to 4a-hydroxytetrahydrobiopterin (4a-carbinolamine).

Catecholamine and pigment synthesis: Synthesis of the catecholamines, dopamine, noradrenaline, and adrenaline is initiated by tyrosine 3-monooxygcnase (EC1. 14.16.2).

Serotonin and melanotomn synthesis: Tryptophan hydroxylase (EC1.14.16.4) utilizes B114 for the synthesis of serotonin and melatonin from I -try ptophan or tryptamin. Nitric oxide synthesis: All isoforms (NOSI. NOS2, NOS3) of nitric oxide synthase (EC1.14.13.39i require one mole BH4 and one mole heme per dtmer as cofactors iRafferty et at., 1999). Diminished BH4 synthesis and the resulting decrease in nitric oxide production has been suggested to contribute importantly to impaired angiogen-esis (Marinos et at., 2001). and epithelial dysfunction and insufficient vasodilation (Gruhn el at.. 2001).

Cell growth and survival: Activation of neuronal Ca " channels (Koshimura el at., 1999) has been found to enhance neuronal survival. Whether biopterin actually affects the risk of Alzheimer's disease. Parkinson's disease, autism or depression through this or another mechanism remains to be seen (Thony et at., 2000). Dopaminergic neurons are specifically protected against free-radical damage during periods of glutathione depletion by a tetrahydrobiopterin-dependent mechanism (Nakamura et a!., 2000). Regulation of O-alkylatedglycerolipids: Glyceryl-ether monooxygenase (ECl.14.16,5) is a microsomal enzyme that hydroxy!ates O-alkyl moieties in glycerolipids; the resulting hydroxyalkvl spontaneously breaks down into glycerol and a fatty aldehyde. Folic acid can serve as electron donor instead of tetrahydroptendine. Immune defense Increased neopterin levels are observed in patients with acute graft rejections. Viral infections, auto-immune diseases and several malignancies tAsano eta!., 1997).

Metabolic regulation: Tyrosinase activity is regulated by (6R)-L-erythro-5.6,7, 8-tetrahydrobiopterin through specific allostenc inhibition (Schallreuter et til.. 1999). Hydrogen peroxide inhibits recycling of 6(R)-L-erythro-5,6.7.X-tetrahydrobiopterin by 4a-OH-tetrahydrobiopterin dehydratase and thereby might play an important role in the regulation of BH4-dependent enzymes (Schallreuter et oi. 20011. Patches of skin affected by \ itiligo are known to have abnormally high hydrogen peroxide concentrations which accordingly would slow the recycling of 6(R)-L-crythro-5,6.7.8-tetrahydrobiopterin to Bll4. Loss of skin pigmentation in vitiligo thus appears to occur because the oxidized metabolite competitively inhibits epidermal phenylalanine hydroxylase and thus blocks the production of melanin (Schallreuter et til., 2001).

References

AsanoT. Nakajima E Odajima k. Tsuji A, Hayafcawa M. Nakamura H. [Urinary neopterin levels in patients with genitourinary tract malignancies.) Nippon Hinyokika Gakkai Zasshi-JapJUmi 1997:88:53 S Ulau N. de Klerk JB, Thony B, Heizmann CW. Kierat I , Smeitink JA. Duran M Tetrahydrobiopterin loading test in xanthine dehydrogenase and molybdenum cofactor deficiencies. Biochem Motet Med 1996;58:199-203 Bonafe L,Thony B, Pcnzien JM. Czarneeki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel t et rahyd mb i opt en n-dependent monoamine-neurotransmitter deficiency without hyperphcnylalanineinia. lmJ Hum Genet 2001:69:269 77 fukushuna T. Shiota T. Pterins in human urine.J Biol Chem 1972:247:4549 56 Gruhn N. Aldersln ile J. Boesgaard S, Tctrahydrobioptcrin improves endothelium-dependent vasodilation in nitroglycerin-tolcrant rats. Eur J Pharmacol 2001:416:245 9 Hashimoto R. Mizutani M. Qhta T, Naka/awa K. |On the fluctuation of plasma blopterin levels for 24 h in normal controls] |ln Japanese). Yakubutsu, Seishin, Kudo [Japanese Journal of Psychopharmacology] 1993:13:59 63 Hibiya M, Teradaira R, Shimpo K. Matsui T, Sugimoto T. Nagaisu T. Interference of a methotrexate derivative with urinary oncopterin [N2-(3-aminopropyl)biopteiin] measurement by high-performance liquid chromatography with tluorimetric detection. JChmmaragr B. BiomedSci Appt 1947:691:223 7 Hoshiga M. Hatakeyama K. Watanahe M, Shimada M. Kagamiyama II Autoradiographic distribution of [ l4C]tetrahydrobiopterin and its developmental change in mice. J Pharmacol Exp Ther 1993:267:971 X Kollcr M. Goldberg M. Schramm G. Merkenschlager M, The influence of nutritional factors on biopterin excretion in laboratory animals. ZEmahrungsw I990;29:169 77

Koshimura K. Tanaka J, Murakami Y. Kato Y. Enhancement of neuronal survival by

6R-tetrahydrobiopterin. Neumscience 1999:88:56) 9 Marines RS. /hang W, Wu G. Kelly KA. Meimngcr CJ.Tetrahydrobiopterin levels regulate endothelial eell proliferation. Am J Physiol Heart Citr Physiol 200 1 ¿81 ;H482 9 Nakamura K, Wright DA, Wiatr T, Kowtessur D, Milstien S. Lei XCi, Kang UJ. Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetnthydro-biopterin. JNeurochem 2000:74:2305 -514 Ohtsuki M, Shiraishi H, KatoT, Kunxla R, Tazawa M, Sumi-IehinoscC,Tada S. UdagawaY, Itoh M. Hishtda H, lehinose H. Nagatsu T. Hagino Y. Nomura T. cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. Life Sei 2002:70:1-12 Ralferty SP. Buying tun.[(', Kulansky R. Sun PD. Matcch HL. Stoichiometric arginine binding in the oxygenase domain of inducible nitric oxide synthase requires a single molecule of tetrahydrobiopterin per dimer. Bioehem Biophy Res Comm 1999;257:344-7 Schallrculcr KU, Moore J. Tobin DJ, Gibbons NJ. Marshall I IS. Jenner T, Beazley WD. Wood JM. Alpha-MSH can control the essential eofactor 6-tetrahydrobiopterin in melanogencsis. Ann New York Acatl Sei 1999;885:329-41 Schallrcuter KU, Moore J. Wood JM. Bea/ley WD, Peters EM. Maries LK. Behrens-Wtlliams St', Dummer R. Blau N.Thony B. Epidermal 11(2)0(2) accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: identification of a general mechanism in regulation of all 6BII4-dependent processes? J Invest Dermatol 2001;116:167-74

Simmons WW. Ungureanu-Longrois D, Smith GK. Smith TW, Kelly RA. Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and L-arginine transport. J BioI Client 1996:271:23928 37 Snyderman SL. Sansaricq C. Pulmones M l. Successful long term therapy of biopterin deficiency, J Inker Metab Pis 1987:10:260 6 Thony B. Aueibaeh G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Bioehem J 2000:347:1 16

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Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

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