Metabolism of one-carbon residues- sources and utilization of one-carbon residues, cofactors.

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Introduction

The transfer of one-carbon units (–CH₃, –CH₂–, =CH–, –CHO, –COOH) is essential in many biosynthetic and regulatory reactions. These one-carbon residues are used in the synthesis of nucleotides, amino acids, and other vital molecules. The metabolism of one-carbon units is tightly regulated and depends on several coenzymes, primarily derived from folate and vitamin B12.

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1. Definition and Importance of One-Carbon Metabolism

One-carbon metabolism involves the transfer of single-carbon groups between molecules, contributing to:

• DNA and RNA synthesis (purines and thymidylate)
• Methylation reactions (epigenetic regulation)
• Amino acid interconversions (e.g., serine ↔ glycine)
• Detoxification and metabolism of homocysteine

This metabolic network is crucial for rapidly dividing cells and for maintaining cellular homeostasis.

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2. Sources of One-Carbon Units

The body obtains one-carbon units primarily from the catabolism of certain amino acids, especially:

• Serine – the main donor; transfers a methylene group (–CH₂–)
• Glycine – can provide one-carbon units via glycine cleavage system
• Histidine – yields formimino groups (–CH=NH), which are converted to formyl groups
• Tryptophan – contributes to the pool during its degradation
• Formate – an additional source, especially in mitochondrial reactions

These carbon units are not transferred freely but are carried by specific cofactors, most importantly tetrahydrofolate (THF).

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3. Cofactors in One-Carbon Metabolism

Tetrahydrofolate (THF)

• THF is the active form of folic acid (vitamin B9)
• It acts as a carrier of one-carbon units in different oxidation states:
  • Methyl (–CH₃)
  • Methylene (–CH₂–)
  • Methenyl (=CH–)
  • Formyl (–CHO)
  • Formimino (–CH=NH)

These groups are attached to the N⁵ or N¹⁰ nitrogen atoms of the THF molecule (or both).

THF-derived coenzymes include:

• N⁵,N¹⁰-methylene-THF
• N¹⁰-formyl-THF
• N⁵-methyl-THF

THF is regenerated through reversible reactions, except for N⁵-methyl-THF, which is a metabolic “trap” that can only be recycled via vitamin B12-dependent reactions.

Vitamin B12 (Cobalamin)

• Vitamin B12 is essential for the conversion of:
  • Homocysteine to methionine, using N⁵-methyl-THF as the methyl donor
  • This reaction is catalyzed by methionine synthase, which requires both B12 and THF
• Lack of B12 leads to methyl-THF trap and secondary functional folate deficiency

S-adenosylmethionine (SAM)

• SAM is derived from methionine and ATP
• It is the universal methyl donor in the cell for methylation of:
  • DNA, RNA
  • Proteins (e.g., histones)
  • Phospholipids
  • Neurotransmitters (e.g., norepinephrine → epinephrine)

After donating the methyl group, SAM becomes S-adenosylhomocysteine (SAH), which is hydrolyzed to homocysteineand adenosine.

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4. Utilization of One-Carbon Units

One-carbon units carried by THF and SAM are used in multiple biochemical pathways:

Nucleotide Synthesis

• Purine synthesis requires:
  • N¹⁰-formyl-THF for carbon atoms at positions C2 and C8 of the purine ring
• Thymidylate (TMP) synthesis:
  • dUMP → dTMP requires N⁵,N¹⁰-methylene-THF as methyl donor via thymidylate synthase
  • This reaction also produces dihydrofolate (DHF), which must be reduced back to THF by dihydrofolate reductase (DHFR)

Amino Acid Metabolism

• Serine ↔ Glycine interconversion involves N⁵,N¹⁰-methylene-THF
• Homocysteine → Methionine requires N⁵-methyl-THF and vitamin B12
• Histidine degradation produces formiminoglutamate (FIGLU), converted to formiminyl-THF

Methylation Reactions

• SAM donates methyl groups in:
  • DNA and histone methylation (epigenetic regulation)
  • Synthesis of neurotransmitters
  • Conversion of norepinephrine to epinephrine
  • Phosphatidylethanolamine → phosphatidylcholine (in membranes)

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5. Clinical Relevance

• Folate deficiency leads to:
  • Impaired DNA synthesis
  • Megaloblastic anemia
  • Neural tube defects in pregnancy
• Vitamin B12 deficiency results in:
  • Megaloblastic anemia
  • Neurological symptoms due to methylmalonic acid accumulation
  • Folate trap due to accumulation of N⁵-methyl-THF
• Elevated homocysteine (hyperhomocysteinemia) is associated with:
  • Cardiovascular disease risk
  • Occurs in deficiencies of B6, B12, folate, or defects in methionine synthase

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Conclusion

One-carbon metabolism is a highly interconnected network essential for DNA synthesis, methylation, and amino acid metabolism. It relies heavily on cofactors like tetrahydrofolate, vitamin B12, and S-adenosylmethionine (SAM). Disruption of this metabolism has profound biochemical and clinical consequences, especially in rapidly dividing cells and during development.

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References

1. Löffler, G., Petrides, P.E. Biochemie und Pathobiochemie, 9th ed. Springer.
2. Murray, R.K., Bender, D.A., Botham, K.M., et al. Harper’s Illustrated Biochemistry, 31st ed. McGraw-Hill.
3. Berg, J.M., Tymoczko, J.L., Stryer, L. Biochemistry, 8th ed. W.H. Freeman.
4. Voet, D., Voet, J.G. Biochemistry, 5th ed. Wiley.