Function

Thymidylate synthesis: Thymidylate synthetase (EC2.1.1.45) methylatcs dUMP to dTMP using 5,10-methylene-THF as one-carbon donor.

Purine synthesis: Both the third step of purine synthesis, catalyzed by glycinamide ribonucleotide (GAR) transformyläse (EC2.1.2,2), and the penultimate step, catalyzed by the bifunctional purine biosynthesis protein (phosphor!bosyI aminoimidazole car-boxamide formy I transferase: EC2.1.2.3), utilize 10-formyl-THF as one-carbon donor. Ammo acid metabolism: Homocysteine is remethylaled to methionine by 5-methylte-trahydrofolatc-homocysteine S-methv I transferase (EC2.1.1.13). a cytoplasmic enzyme with covalently bound methylcobalamin. Homocysteine remethylation converts the cosubstratc 5-methyl-THF back into TU F and makes this form available again for other reactions. The methionine metabolite S-adcnosyl-mclhionine is the major methyl-group donor for DNA methylation and for the synthesis of numerous essential compounds including catecholamines, carnitine, choline, melatonin, and creatine.

Glycine hydroxymelhyltransferase (FC2.1.2.1). cytosolic and mitochondrial, methylates glycine to serine, or catalyzes the reverse reaction.

The linal step of the conversion of L-histidinc to L-glutamale is catalyzed by the PLP-dependent enzyme glutamatc formiminotransferase (EC2.I.2.5). The metabolite generated in this reaction and excreted with urine in response to a histidine load formim-inoglutamate (FIGLU). has been used in the past as a marker of folate deficiency. Formate utilization. The metabolism of choline generates formaldehyde in the last two oxidative steps. Formaldehyde can react non-enzymically with THF and ATP to generate 10-formyl-Tl IF or it is converted into formate in an N AD-requirtng reaction catalyzed by glutathione-dependent formaldehyde dehydrogenase (EC1.2.1.1; identical with alcohol dehydrogenase class 111 chi chain, contains zinc). An important source of formate is the non-oxidative release from I O-formyl-TH F by formyltetrahy-drofolate dehydrogenase (ECU. 1.6). The main activity of this dehydrogenase is the oxidativ e release of the formyl group from 10-formyl-THF in a NADI'H-generating reaction. Formyltetrahydrofolate dehydrogenase contains pcntaglutamyl-THF as a tightly bound non-catalytic cofactor. The amounts of formate generated from

Formaldehyde glutathione H?0

Formaldehyde dehydrogenase (zinc)

glutathione

H;0 glutathione

S-lormytglutathione

Formyt-THF dehydrogenase (pentaglutamyt-THF)

S-formylglutathione ' hydrolase

Formate

S-lormytglutathione

Formyt-THF dehydrogenase (pentaglutamyt-THF)

S-formylglutathione ' hydrolase

Formate

JO-Formyl-THF

10-Formyl-DHF

JO-Formyl-THF

Formyt-THF dehydrogenase (pentaglutamyl-THF)

NADP

V NADPH

10-Formyl-DHF

Figure 10.32 Formate detoxification require4 THF both as a cosubstrate and as a tightly bound enzyme cofactor methanol metabolism ace usually small, but can be significant with high dietary or industrial exposure (Bouchard et al.. 2001). Formate moves into cytosol where formate-tetrabydrofolatc ligase (EC'6.3.4.3, an activity of the trifunctional protein CI-THF synthase. MTHFD1) can link it to I MF in an ATE-dependent reaction.

An alternative formate- removi ng enzyme is formate-dihydrofolate ligase (EC6.3.4.17). T his magnesium-dependent cytosotic en/yme links formate to dthydro-folate in an ATP-dependent reaction. 10-f'ormyl dihydrofolate can then be used by phosphonhosylaminoimidazolecarboxamide formyttransferase(AlCAR transformyiase: F.C2.1,2.3) to generate 5-formamido» I -(5-phospho-D-ribosyl liuudazole-l-carboxamidc (formyl-AlCAR), the precursor for purine synthesis. Some 1O-fonmyl-dihydro folate may oxidize non-enzymically to the dead-end product 10-formyl-folate (Baggott et a!.. 2001), Orcadian rhythm Cryptoehrome I and eryptoehrome 2 arc proteins in mitochondria which appear to act as photoreceptors that help maintain circadian period length and rhythmiclty; they use FAD and folate as cofactors (Sancar. 2000). Fetal development: Inadequate folate supplies during the first weeks of pregnancy increase the risk of neural tube defects (NTD), cleft palate (Martinelli et id.. 2001), congenital heart disease (Kapusta el al.. 10l)9). and other organ malformations. The exact causal mechanisms arc still not well understood. Less acme forms of several gene products involved in folate metabolism are known or suspected to increase NTD risk, including methylene T1IF reductase (EC!.5.1.20. Rosenberg et al.. 2002), pteroylpoly-gamma-glutamate carboxypeptidase (EC3.4.17.21; Devlin et id.. 2000), methylcnctetrahydrofolate-dehydrogenase (MTUI D. Ct-THF synthase. Ho) et al.. 1998). and RFC! (De Marco et a!., 2(H) 1). The risk of placental abruption and pregnancy failure may also be related in part to inadequate folate availability (Lskes. 2001). Folate synthesis in microorganisms: Sulfa drugs inhibit conjugation of para-amino benzoic acid (PABA) to pterin in bacteria. Since humans cannot synthesize folate through this reaction, they are not affected bv its inhibition-

References

Baggott JE. Robinson CB, Johnston KE. Bioactivitv of [6R|-5-formyltetmhydrofolate, an unusual isomer, in humans and Etitemcoccus hirue, and cytochrome c oxidation of lO-formytetrahydrofolate to 1 (Mormyldihydrofolate. Bioehem J 2001.354:115-22 Bhandari SD. Gregory JI 3d. Folic acid, 5-mcthyl-tetrahydrofolate and 5-formyl-tetrahy-drofolate exhibit equivalent intestinal absorption, metabolism and in vivo kinetics in rats.,/ N'utr 1992:122:1847-54 Bouchard M. Brunei RC, Droz PO, Carrier Ci. A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans Toxu ol Sci 2001:64:169-84 Caudill MA. Gregory JF. Hutsoti AD. Bailey 1 B. Folate calabolism in pregnant and nonpregnant women wnh controlled folate intakes../ Nutr 1998:128:204 8 Deleu D. Louon A, Sivagnanam S. Sundaram K. Okerekc P. Ci rave 11 IX Al-Salmy HS, Al Bahrani I, Nam D. Knox-MacAulay 11. Hanssens Y. Long-term effects of nitrous oxide anaesthesia on laboratory and clinical parameters in elderly Omant paticnis: a randomized double-blind study. ./Clin Pharmacol Therap 2000:25:271 7

De Marco P. Calevo MG, Moroni A, Arata L. Merello E, ( ama A. Finnell RH, Andreussi 1., Capra V. Polymorphisms in genes involved in folate metabolism as risk factors for NTDs, Eur ■/ Ped Surg 200 I.I LS14-S17 Devlin AM. Ling EH, Peerson JM. Fernando S. Clarke R. Smith AD Halsted CH. Glutamalc carboxy peptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocystememia. Hum Mai Gen 2000:9:2837 44 Dudeja PK, Kode A. Alnoudu M. Tyagi S. Torania S. Subramanian VS. Said HM. Mechanism of folate transport across the human colonic basolateral membrane. Am ./ Phvsiol Gastroimest Liver Physiol 2001:281 .<¡54-60 Lskes TK. Clotting disorders and placental abruption: homocysteine a new risk factor.

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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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