TAILIEUCHUNG - Chapter 100. Megaloblastic Anemias (Part 4)

Biochemical Basis of Megaloblastic Anemia The common feature of all megaloblastic anemias is a defect in DNA synthesis that affects rapidly dividing cells in the bone marrow. All conditions that give rise to megaloblastic changes share in common a disparity in the rate of synthesis or availability of the four immediate precursors of DNA: the deoxyribonucleoside triphosphates (dNTPs): dA(adenine)TP and dG(guanine)TP (purines), dT(thymine)TP and dC(cytosine)TP (pyrimidines). In deficiencies of either folate or cobalamin, there is failure to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), the precursor of dTTP (Fig. 100-1). . | Chapter 100. Megaloblastic Anemias Part 4 Biochemical Basis of Megaloblastic Anemia The common feature of all megaloblastic anemias is a defect in DNA synthesis that affects rapidly dividing cells in the bone marrow. All conditions that give rise to megaloblastic changes share in common a disparity in the rate of synthesis or availability of the four immediate precursors of DNA the deoxyribonucleoside triphosphates dNTPs dA adenine TP and dG guanine TP purines dT thymine TP and dC cytosine TP pyrimidines . In deficiencies of either folate or cobalamin there is failure to convert deoxyuridine monophosphate dUMP to deoxythymidine monophosphate dTMP the precursor of dTTP Fig. 100-1 . This is because folate is needed as the coenzyme 5 10-methylene-THF polyglutamate for conversion of dUMP to dTMP the availability of 5 10-methylene-THF is reduced in either cobalamin or folate deficiency. An alternative theory for megaloblastic anemia in cobalamin or folate deficiency is misincorporation of uracil into DNA because of a build-up of deoxyuridine triphosphate dUTP at the DNA replication fork as a consequence of the block in conversion of dUMP to dTMP. Cobalamin-Folate Relations Folate is required for many reactions in mammalian tissues. Only two reactions in the body are known to require cobalamin. Methylmalonyl CoA isomerization which requires adocobalamin and the methylation of homocysteine to methionine requires both methylcobalamin and both 5-MTHF Fig. 100-1 . This reaction is the first step in the pathway by which 5-MTHF which enters bone marrow and other cells from plasma is converted into all the intracellular folate coenzymes. The coenzymes are all polyglutamated the larger size aiding retention in the cell but the enzyme folate polyglutamate synthase can use only THF not MTHF as substrate. In cobalamin deficiency MTHF accumulates in plasma while intracellular folate concentrations fall due to failure of formation of THF the substrate on which folate polyglutamates .

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