Tetrahydrofolate coenzymes

The enzymes involved in catecholamine biosynthesis have been studied intensively and are the targets of many drugs. The key enzyme is tyrosine hydroxylase, which requires a tetrahydrofolate coenzyme, O, and Fe +, and is quite specific. As usual for the first enzymes in a biosynthetic pathway, tyrosine hydroxylase is rate limiting, and... 

Cobalmin Deficiency. Pernicious anemia is the disease associated with vitamin Bi2 deficiency. It is usually caused by the inability to produce intrinsic factor. Indeed, many times the vitamin must be administered by injection. The blood picture, a megaloblastic anemia, is indistinguishable from that caused by folic acid deficiency. Indeed folic acid supplements can mask the blood picture. This is illustrated in Fig. 8.53. Removal of ad-enosyl cobalamin eliminates the regeneration of tetrahydrofolate during the methylation of homocysteine to methionine. Folic acid supplements provide a fresh source of tetrahydrofolate coenzymes. DNA synthesis can continue and new erythrocytes form. Excess folic acid also may compete for the available vitamin, further exacerbating vitamin deficiency. 

Synthesis of thymidylic acid (TMP). Fluorodeoxyuridylate inhibits conversion of dUMP to TMP, and methotrexate inhibits regeneration of the tetrahydrofolate coenzyme. 

FH4 is carried out by the crucial enzyme thimidylate synthetase (Fig. 4-13). It should be noted that this is a reductive methylation where the tetrahydrofolate coenzyme serves both as a one-carbon donor and reductant. The resultant FH2 must be reduced back to FH4 by folate reductase, thus offering further opportunity for DNA synthesis inhibition at this point. Thymidylate synthetase is the sole de novo path to thymidylate there are no alternate routes. The interest of this point as a target for anticancer agents is obvious. 

Methotrexate inhibits the enzyme folate reductase at two steps (Fig. 4-12). Even though the inhibition is technically a competitive one, the enzyme binds MTX much more strongly than the natural substrate, FH2 (Table 4-5). In practical terms there is no dissociation of the enzyme-drug complex. For thymidylate synthetase to continue to produce thymidylic acid (and therefore DNA), perpetual reduction of FH2 is essential for cellular survival. The efficiency of MTX inhibition of folate reductase thus indirectly becomes the mechanism by which this drug is so cytotoxic in the S phase. In addition, there is evidence that MTX may, by binding to the tetrahydrofolate coenzyme, also inhibit the thymidylate synthetase... 

Serine - Serine has many important biological roles, including the biosynthesis of phosphopholipids and cysteine. Serine also contributes activated one-carbon units to the pool of tetrahydrofolate coenzymes. Serine can be made in a variety of ways, including the way shown here and Figure 21.24. Serine is catabolized by conversion to glycine or by action of serine-threonine dehydratase (Figure 21.25). 

Because methionine synthase is the only mammalian enzyme known to act on 5-methyltetrahydrofolate, the decreased intracellular activity of this enzyme causes 5-methyltetrahydrofolate to accumulate, at the expense of depleted pools of the other tetrahydrofolate coenzymes. Thus, even though total folate levels may seem ample, there is a functional folate deficiency, with insufficient levels of the formyl and methylene derivatives needed for synthesis of nucleic acid precursors. 

See also Glutamate as a Precursor of Other Amino Acids, Tetrahydrofolate Coenzymes... 

See also De Novo Biosynthesis of Purine Nucleotides, Tetrahydrofolate Coenzymes, DHF, THF,... 

The tetrahydrofolate coenzyme and 5-fluoro-dUIVIP that is covalently bonded to cysteine 146 of the enzyme are shown in yellow, The fluorine (turquoise), tyrosine 94, and the catalytic water molecule are also visible. The side chains that hold the coenzyme in the proper position at the active site are pink. 

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