Wednesday, September 25, 2013

RBC Metabolism Notes (Part 4) : Maturation of RBC and role of Folic acid

MATURATION OF RBC - ROLE OF FOLIC ACID & VITAMIN B12 IN DNA SYNTHESIS

 

FOLIC ACID

  • Folic acid (or folate) plays a key role in one-carbon metabolism, and is essential for the biosynthesis of the purines and the pyrimidine, thymine. 
     
  • Folic acid deficiency is probably the most common vitamin deficiency in the U.S., particularly among pregnant women and alcoholics.

Structure of Folic Acid

  • Folic acid is composed of a pterin ring attached to p-aminobenzoic acid (PABA) and conjugated with one or more glutamic acid residues.
  • Humans cannot synthesize PABA or attach the first glutamic acid (Fig 28.9). 
     
  • The biologically active form of folic acid is tetrahydrochloric acid (THF), which is produced by the two-step reduction of folate by dihydrofolate reductase.
  • Dihydrofolate reductase is competitively inhibited by methotrexate, a folic acid analogue that has been used to effect the remission of acute leukemia in children.
  • Sulfanilamide and its derivatives are structural analogs of PABA (Fig 28.9). These drugs competitively inhibit the synthesis of folic acid, and thereby decrease the synthesis of critical nucleotides needed for the replication of DNA and RNA (Fig 29.7). Sulfa drugs do not affect human DNA and RNA synthesis because mammalian cells cannot synthesis folic acid.


    PURINE SYNTHESIS

     

     

     Biochemical functions:
     
     
  • Folate is essential for the de novo synthesis of purine, deoxythymidylate monophosphate (dTMP) and methionine, serving as an intermediate carrier of 1-carbon fragments used in the biosynthesis of these compounds. Its active form is tetrahydrofolate (H4folate, THF). 
     
  • THF acquires the 1-carbon fragment principally from serine, which is converted to glycine in the course of the reaction. 
     
  • For purine synthesis, the 1-carbon fragment is first oxidized to the level of formic acid, then transferred to substrate. 
     
  • For methionine synthesis, a cobalamine-requiring reaction, the 1-carbon fragment is first reduced to the level of a methyl group, then transferred to homocysteine.

  • In these reactions the cofactor is released as THF, which can immediately participate in another 1-carbon transfer cycle. 
     
  • During the production of dTMP from dUMP, however, the 1-carbon fragment is reduced from formaldehyde to a methyl group in the course of the transfer reaction. The hydrogen atoms used for this reduction come from the cofactor, which is therefore released, not as THF, but as dihydrofolate (H2folate, DHF). 
     
  • To participate further in the 1-carbon transfer cycle, the DHF has to be re-reduced to THF, reaction catalyzed by dihydrofolate reductase.

Clinical Indications
  • Folic acid deficiency is characterized by growth failure and megaloblastic anemia. The anemia is a result of diminised DNA synthesis in erythropoeitic stem cells, a process that requires THF derivatives.

  • The anemia of cobalamin deficiency is really due to tissue folate deficiency. This deficiency results from an impairment in the cobalamin-dependent transfer of the methyl group from N5-methylTHF to homocysteine, leading to a delay in the attachment of a polyglutamate chain to the folate molecule (a process known as conjugation) and the leakage of the unconjugated folate out of the cell.

  • Folate therefore corrects the anemia of cobalamin deficiency. The neurologic defects of cobalamin deficiency, however, are thought to result from inadequate methionine synthesis, leading to a deficiency of the methylating agent S-adenosylmethionine and an abnormality in the production of methylated phospholipids such as phosphatidylcholine.

  • Folate does not correct the neurologic defects seen in cobalamin deficiency.
 Folate Deficiency
  • The primary use of the vitamin is in deficiency states that arise from the inadequate levels of folate. 
     
  • These can be caused by increased demand (for example, pregnancy and lactation) or by poor absorption due to pathology of small intestine, alcoholism or treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate). 
     
  • A primary result of folic acid deficiency is megaloblastic anemia, caused by diminished synthesis of purines and thymidine leading to an inability of cells to make DNA and to divide. 
     
    [Note: It is important to evaluate the cause of the megaloblastic anemia prior to instituting therapy, because vitamin B12 deficiency indirectly causes symptoms of this disorder.]
  • Pregnant and lactating women may require folic acid supplementation. 
  • In the case of inadequate absorption due to alcoholism, a commercial preparation of folic acid may be administered either orally or by intramuscular injection.
We will discuss about Vitamin B12 in next.



(source: Wintrobe's Textbook of Hematology; Tietz's Textbook of Clinical Chemistry)
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