One-Carbon Metabolism Pathway Lecture Notes

Introduction

• Focus on the role of folic acid and tetrahydrofolate (THF) in the one-carbon metabolism pathway.
• Discuss the purpose of this pathway.

Folate (Vitamin B9)

• Derived from dietary sources: green leafy vegetables, fortified foods (breads, grains).
• Synthetic form: Folic acid in fortified foods.
• Precursor for tetrahydrofolate (THF).

Tetrahydrofolate (THF)

• Similar in structure to folate.
• Acts as a carbon donor and cofactor for enzymes.
• Involved in nucleic acid and amino acid synthesis.

Formation of THF

1. Dihydrofolate Reductase (DHFR)
   • Converts folate to dihydrofolate (DHF) and then to THF.
   • Requires NADPH (oxidized to NAD+).
   • NADPH comes from the pentose phosphate pathway.
   • Target for anti-cancer drugs like methotrexate (inhibits DHFR).

Role of Enzymes in THF Pathway

1. Serine Hydroxymethyltransferase (SHMT)

   • Converts THF to N5N10-methylene THF.
   • Utilizes serine; produces glycine.
   • Requires pyridoxal phosphate (vitamin B6 derivative).

2. Thymidylate Synthase

   • Converts N5N10-methylene THF back to DHF.
   • Converts D-UMP to D-TMP (important for DNA synthesis).
   • Inhibited by 5-fluorouracil (anti-cancer drug).

3. Methylene Tetrahydrofolate Reductase (MTHFR)

   • Converts N5N10-methylene THF to 5-methyl THF.
   • Uses NADPH; inhibited by dihydrofolate and SAM.

4. Methionine Synthase

   • Converts homocysteine to methionine using 5-methyl THF.
   • Requires vitamin B12.

Activated Methyl Cycle

• Methionine is converted to S-adenosylmethionine (SAM).
• SAM inhibits MTHFR.
• SAM involved in various biosynthetic processes (e.g., catecholamine, melatonin).

Alternative Pathways and Products

1. Methylene Tetrahydrofolate Dehydrogenase & Cyclohydrolase
   • Convert N5N10-methylene THF to N10-formyl THF.
   • Utilized for purine synthesis.

Summary of Pathway Directions

• N5N10-methylene THF as the central hub of the pathway.
• Can lead to four outcomes based on cellular needs:
  1. Recycled back to THF by SHMT.
  2. Converted to DTMP via thymidylate synthase.
  3. Processed to 5-methyl THF for activated methyl cycle.
  4. Converted to N10-formyl THF for purine synthesis.

Folate Cycle

• Pathway from folate to THF and back to folate.

Conclusion

• Overview of one-carbon metabolism, folate cycle, and its relationship to the activated methyl cycle.
• Encourage further learning and exploration of related videos.