Cobalaminfolate relationship

Folate is required for many other reactions in mammalian tissues, including two in purine synthesis (Table 5.2), but impairment of these is far less important clinically.

Only two reactions in the body are known to require cobal-amin (Figure 5.2). Methylmalonyl CoA isomerization, which requires deoxyadenosyl(ado)-cobalamin, is discussed later. The methylation of homocysteine to methionine requires both 5-methyltetrahydrofolate (THF) as methyl donor and methyl-cobalamin as coenzyme (Figure 5.3). This reaction, which is almost completely irreversible, is the first step in the pathway by which methyl-THF, which enters bone marrow and other cells from plasma, is converted into all the intracellular folate co-enzymes (Figure 5.3). The coenzymes are all polyglutamated (the larger size aiding retention in the cell), but the enzyme folate polyglutamate synthase cannot use methyl-THF as substrate. Tetrahydrofolate is needed as substrate for synthesis of folate polyglutamates. In cobalamin deficiency, methyl-THF

Table 5.2 Biochemical reactions of folate coenzymes of folate coenzymes.

Reaction

Coenzyme form of folate involved

Single carbon unit transferred

Importance

Formate activation Purine synthesis

Formation of glycinamide ribonucleotide

Formylation of amino-imidazole-carboxamide-ribotide (AICAR)

Pyrimidine synthesis Methylation of deoxyurine monophosphate (dUMP) to thymidine monophosphate (dTMP)

Amino acid interconversion Serine-glycine interconversion Homocysteine to methionine

Forminoglutamic acid to glutamic acid in histidine catabolism

THF -CHO

5,10-Methenyl-THF -CHO

10-Formyl-THF -CHO

5,10-Methenyl-THF -CH3

5-Methyl-THF THF

Generation of 10-formyl-THF

Formation of purines needed for DNA, RNA synthesis, but reactions probably not rate limiting

Rate limiting in DNA synthesis Oxidizes THF to DHF

Some breakdown of folate at the C-9-N-10 bond

Entry of single carbon units into active pool Demethylation of 5-methyl THF to THF; also requires cobalamin, flavine adenine dinucleotide, ATP and adenosylmethionine Basis of the Figlu test (now obsolete)

DHF, dihydrofolate; THF, tetrahydrofolate.

Intracellular Metabolism

Figure 5.2 Intracellular cobalamin metabolism. Cbl1+, Cbl2+, Cbl3+ refer to the oxidation state of the central cobalt atom of cobalamin. A-G refer to the sites ofblocks that have been identified by complementation analysis in infants with metabolic defects. AdoCbl, adenosylcobalamin; MeCbl, methylcobalamin; TC, transcobalamin. The mitochondrial lysosomal and cytoplasmic compartments are indicated (reproduced with permission from Paediatric Haematology, eds JS Lilleyman, IM Hann and VS Blanchette, 2nd edn, 1999, Churchill Livingstone).

Figure 5.2 Intracellular cobalamin metabolism. Cbl1+, Cbl2+, Cbl3+ refer to the oxidation state of the central cobalt atom of cobalamin. A-G refer to the sites ofblocks that have been identified by complementation analysis in infants with metabolic defects. AdoCbl, adenosylcobalamin; MeCbl, methylcobalamin; TC, transcobalamin. The mitochondrial lysosomal and cytoplasmic compartments are indicated (reproduced with permission from Paediatric Haematology, eds JS Lilleyman, IM Hann and VS Blanchette, 2nd edn, 1999, Churchill Livingstone).

Transcobalamin

Folic acid--------------------------------------------------------------------------------> Folic acid

Figure 5.3 The role of folates in DNA synthesis and in formation on S-adenosylmethionine (SAM), which is involved in numerous methylation reactions. Enzymes are shown in yellow boxes (figure prepared in conjunction with Professor John Scott).

Folic acid--------------------------------------------------------------------------------> Folic acid

Figure 5.3 The role of folates in DNA synthesis and in formation on S-adenosylmethionine (SAM), which is involved in numerous methylation reactions. Enzymes are shown in yellow boxes (figure prepared in conjunction with Professor John Scott).

accumulates in the plasma, while intracellular folate concentrations fall due to failure of formation of intracellular folate poly-glutamates because of 'THF starvation' or 'methylfolate trapping'.

This theory explains the abnormalities of folate metabolism, which occur in cobalamin deficiency (high serum folate, low cell folate, positive purine precursor AICAR excretion; Table 5.2) and also why the anaemia that occurs in cobalamin deficiency will respond to folic acid in large doses. The explanation of why the serum cobalamin falls in folate deficiency may also be related to impairment of the homocysteine-methionine reaction, with reduced formation of methylcobalamin, the main form of cobalamin in plasma, but other mechanisms may be responsible.

Many symptomless patients are detected through the finding of a raised mean corpuscular volume (MCV) on a routine blood count. The main clinical features in more severe cases are those of anaemia. Anorexia is usually marked and there may be weight loss, diarrhoea or constipation. Other particular features include glossitis, angular cheilosis, a mild fever in the more severely anaemic patients, jaundice (unconjugated) and reversible melanin skin hyperpigmentation, which may occur with either deficiency. Thrombocytopenia sometimes leads to bruising (and this may be aggravated by vitamin C deficiency in malnourished patients. The (anaemia and) low leucocyte count may predispose to infections, particularly of the respiratory or urinary tracts. Cobalamin deficiency has also been associated with impaired bactericidal function of phagocytes.

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