folate

Question 1

Mention the sources and RDA of folic acid

Answer 1

Sources:
1. Rich sources of folate are yeast, green leafy vegetables
2. Moderate sources are cereals, pulses, oil seeds, and egg
3. Milk is a poor source for folic acid

RDA:
Adult → 200mg/day
Pregnancy women → 400mg/day
Lactating women → 300mg/day

Question 2

Recall the composition of folic acid

Answer 2

Folate is a Vitamin B9 w/ 3 components:

1. Pteridine gorup
2. Para-amino benzoic acid (PABA)
   - (1) and (2) make pteroid acid
3. Attached to glutamic acid to form pteroyl glutamic acid or folic acid

• Soluble in water
• Rapidly destroyed when exposed to light

Question 3

Outline the synthesis and activation of folic acid

Answer 3

The active form of folic acid is know as tetrahydrolate (THF)

Synthesis:
1. Folic acid reduced to 7,8 dihydrofoilic acid
2. Reduced again to 5,6,7,8-THFA

• Both reactions are catalyzed by NADPH depedent folate reductase (dihydrofolate reductase)
• Reduction process adds 4 Hydrogen atoms to 5,6,7,8 position on the pteridine ring

Question 4

List the coenzyme forms and functions of Folic Acid

Answer 4

Folic acid itself is not biologically active. It needs to be reduced into the active coenzyme forms:

1. THF
2. N5-methyl THF → Methionine synthesis from homocysteine
3. N5,N10 methylene THF → Thymidine monophosphate synthesis and serine synthesis from glycine
4. N10 formyl THF → Purine nucleotide synthesis
5. N5 formimino THF

• The way to think about the naming → methyl is addition of methyl group to position 5/10N.
  → formyl is addition of caroxylic group to “ “
  → formimino → addition of CH=NH (methenyl)

Question 5

Explain the clinical application of inhibitors of folic acid synthesis and its activation (Sulfonamides)

Answer 5

Anti folates in Bacterial infection ⇒ Sulphonamides
→ Synthetic analog of PABA and hence a competitive inhibitor (against PABA) of the dihydropteroate synthase.
→ Theferore, THFA is failed to convert to purines, which are essential for synthesis of nuclei acid (DNA) of bacterial cells.
→ Since no DNA molecules, the bacteria cannot divide

Question 6

Explain the clinical application of inhibitors of folic acid synthesis and its activation ( Methotrexate)

Answer 6

Anti folates in Cancer ⇒ Methotrexate
→ Inhibits the enzyme dihydrofolate reductase (DHFR)
→ Inhibition of DHFR leads to partial depletion of the THF cofactors (N5,N10 methylene THF and N10 formyl THF) that is required for the synthesis of thymidylate and purines
→ Inhibits production of thymidylate synthase which is required for conversion of dUMP → dTMP. Therefore, less DNA replication and → less cancer cell division.

Question 7

Explain the clinical application of inhibitors of folic acid synthesis and its activation ( trimethoprim, pyrimethamine)

Answer 7

Anti folates in Malaria
→ Targets of the Dihydropteroate synthase ⇒ Sulfa Drugs
→ Targets of dyhydrofolate reductase ⇒ Pyrimethamine, cycloguanil, and trimethoprim.
→ Ultimately, inhibits the folate metabolism of the parasite, both in synthesis and use of cofactors.
- It is common to use combinations of the two inhibitors which act against different targets (Synergistic effect) and also preventing drug resistance.

Question 8

Mention the biochemical basis of the symptoms of folic acid deficiency

Answer 8

1. Megaloblastic / Macrocytic anemia without neuropathy
   - Presence of abnormally large developing RBC in bone marrow due to inhibition of DNA synthesis during erythropoiesis (Mitotically the inhibition of DNA synthesis will impair the progression of the cell cycle from G2 to M)
   - Haemopoietic precursor cells nuclei appear abnormally, large, and immature resulting from nucelear maturation that lags behind cytoplasmic maturation.
   - Reticulocytosis is seen
   - Leukopenia and thrombocytopenia
   - NO neurological symptoms
2. Elevation of homocysteine
   - High homocysteine causes oxidative stress, damages endothelium and enhances thrombogenicity there by increasing the risk of myocardial infarction and stroke
3. Spina Bifida
   - Cause developmental defects through disturbances of DNA biosynthesis and/or methylation.
   - Most common anencephaly.

Deficiency symptoms:
1. Pallor
2. Weakness
3. Shortness of breath
4. Confusion

Question 9

Describe the rections involved with the activated form of Folic acid, THFA

Answer 9

1. Transmethylation reactions
   → Methyl group in N5-methyl THFA is used for synthesis of active methionine.
   → Methyl group donor is SAM, are required for synthesis of choline, epinephrine, creatine

2.THF receives one carbon fragments from donors such as serine, glycine and histidine and transfers them to intermediates in the synthesis of a.a, purine nucleotides, and thymidine monophosphate (TMB), a pyrmidine nucleotide incorporated into DNA.