Tetrahydrofolates

AMP, ADP, and ATP = adenosine mono-, di-, and triphosphate IMP = inosine 5 -monophosphate AICAR = 5 -phosphoribosyl-5-amino-4-imida2olecarboxamide DAP = diaminopimelic acid PRPP = phosphoribosyl pyrophosphate a — KGA = a-ketoglutaric acid Orn = ornithine Cit = citnilline represents the one carbon unit lost to tetrahydrofolate as serine is converted to glycine. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

The conversion of a-ketoisovalerate (32) to ketopantoate (21) is cataly2ed by ketopantonate hydroxymethyltransferase and a cofactor tetrahydrofolate (65). Further reduction of ketopantoate (21) to (R)-pantoate (22) is cataly2ed by ketopantoic acid reductase (66). 

Metabolism and Mobilization. On entry of vitamin B 2 into the cell, considerable metaboHsm of the vitamin takes place. Co(III)cobalamin is reduced to Co(I)cobalamin, which is either methylated to form methylcobalamin or converted to adenosylcobalamin (coenzyme B>22)- The methylation requires methyl tetrahydrofolate. 

Fig. 1. The choline and methionine cycles showing the origin and disposition of labile methyl groups. FAH = tetrahydrofolic acid CH3BJ2 = methylated...

The chiralities at C-6 of natural 5,6,7,8-tetrahydrofolic acid and related folates, e.g. 5,10-methylene-, 5-methyl- and 5-formyl-5,6,7,8-tetrahydrofolic acid, from various biological systems are the same and possess the absolute configuration (S) at C-6 as deduced from an X-ray study of the ion (51) (79JA6114). 

Catalytic reduction of folic acid to 5,6,7,8-tetrahydrofolic acid (225) proceeds fast in trifluoroacetic acid (66HCA875), but a modified method using chemical reductants leads with sodium dithionite to 7,8-dihydrofolic acid (224). Further treatment with sodium borohydride gives (225) which has been converted into 5-formyl-(6i ,S)-5,6,7,8-tetrahydro-L-folic acid (leucovorin) (226) by reaction with methyl formate (equation 70) (80HCA2554). 

Mn-+ K+ Ni " Arginase Pyruvate kinase (also requires Mg ) U rease Tetrahydrofolate (THF) Other one-carbon groups Thymidylate synthase... 

The first two of these are mediated by 5 -deoxyadenosylcobalamin, whereas methyl transfers are effected by methylcobalamin. The mechanism of ribonucleotide reductase is discussed in Chapter 27. Methyl group transfers that employ tetrahydrofolate as a coenzyme are described later in this chapter. 

Folic acid derivatives (folates) are acceptors and donors of one-carbon units for all oxidation levels of carbon except that of CO2 (where biotin is the relevant carrier). The active coenzyme form of folic acid is tetrahydrofolate (THF). THF is formed via two successive reductions of folate by dihydrofolate reductase (Figure 18.35). One-carbon units in three different oxidation states may be bound to tetrahydrofolate at the and/or nitrogens (Table 18.6). These one-carbon units... 

Oxidation States of Carbon in 1-Carbon Units Carried by Tetrahydrofolate ... 

Oxidation Number Oxidation Level One-Carbon Form Tetrahydrofolate Form... 

We are familiar with several examples of chemical activation as a strategy for group transfer reactions. Acetyl-CoA is an activated form of acetate, biotin and tetrahydrofolate activate one-carbon groups for transfer, and ATP is an activated form of phosphate. Luis Leloir, a biochemist in Argentina, showed in the 1950s that glycogen synthesis depended upon sugar nucleotides, which may be... 

A subclass of lyases, involved in amino acid metabolism, utilizes pyridoxal 5-phosphate (PLP, 3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinecarbaldehyde) as a cofactor for imine/ enamine-type activation. These enzymes are not only an alternative to standard fermentation technology, but also offer a potential entry to nonnatural amino acids. Serine hydroxymethyl-tansferase (SHMT EC 2.1.2.1.) combines glycine as the donor with (tetrahydrofolate activated) formaldehyde to L-serine in an economic yield40, but will also accept a range of other aldehydes to provide /i-hydroxy-a-amino acids with a high degree of both absolute and relative stereochemical control in favor of the L-erythro isomers41. 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

Dihydrofolate reductase is required for the sythesis of tetrahydrofolate, a co-factor required for the transfer of single carbon groups. Inhibition of dihydrofolate... 

Tetrahydrofolic acid (H PteGlu) accqrts and transfers activated one-carbon units in the form of 5-methyl-,... 

N5-Methyltetrahydrofolate homocysteine methyl-transferase (= methionine synthase). This reaction is essential to restore tetrahydrofolate from N5-methyltetrahydrofolate (Fig. 2). 

However, an almost classical attempt to generate an a, -unsaturated e-capro-lactam 87 involved a Knoevenagel condensation of 86 as the ring forming step. The material was employed in a synthesis of conformationally restricted analogs of some anti cancer agents (tetrahydrofolate analog) (Scheme 17) [24]. 

Glycine. The glycine synthase complex of Ever mitochondria sphts glycine to COj and NH4+ and forms A, A -methylene tetrahydrofolate (Figure 30-5). 

Figure 30-4. Catabolism of i-histidine to a-ketoglu-tarate. (H4 folate, tetrahydrofolate.) Histidase is the probable site of the metabolic defect in histidinemia.

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

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