51. Metabolism of S-Containing Amino Acids: Cysteine and Methionine.Synthesis of SAM. Enzyme Defects.

Metabolism of Sulfur-Containing Amino Acids: Methionine and Cysteine, SAM, and Associated Enzyme Defects

Methionine as an Essential Amino Acid

• Methionine must be obtained from dietary protein.
• It contains sulfur in the form of a thioether group.
• Methionine’s major metabolic function is to serve as a methyl group donor through its activated form S-adenosylmethionine (SAM).

Activation of Methionine to S-Adenosylmethionine (SAM)

• Methionine reacts with ATP to form SAM.
• This reaction is catalyzed by methionine adenosyltransferase.
• SAM contains a highly reactive methyl group that can be donated to nucleic acids, proteins, lipids, neurotransmitters.
• SAM is the universal methyl donor in biochemical reactions (e.g., DNA methylation, epinephrine synthesis, phospholipid methylation).

Demethylation of SAM to S-Adenosylhomocysteine (SAH)

• After donating its methyl group, SAM becomes SAH.
• SAH is hydrolyzed to homocysteine and adenosine.

Homocysteine Metabolism – Two Possible Fates

• Homocysteine is a metabolic branch point that can:

1. a) Be remethylated to Methionine
2. b) Enter the Transsulfuration Pathway to Form Cysteine

Remethylation of Homocysteine to Methionine

• Enzyme: Methionine synthase.
• Requires Vitamin B12 and Folic Acid (THF) as cofactors.
• Defects in Vitamin B12 or Folate will cause homocysteine accumulation.

Transsulfuration Pathway: Conversion of Homocysteine to Cysteine

• Homocysteine + Serine → Cystathionine, catalyzed by Cystathionine β-Synthase (CBS).
• Requires Vitamin B6 (pyridoxal phosphate) as a coenzyme.
• Cystathionine is then converted to Cysteine.
• Cysteine becomes a nonessential amino acid because it can be synthesized from methionine.

Importance of Cysteine

• Used for protein synthesis.
• Serves as a precursor for glutathione (major antioxidant).
• Component of taurine, used in bile acid conjugation.

Clinical Significance: Homocysteine Levels

• Elevated homocysteine (hyperhomocysteinemia) is associated with:
• Endothelial damage
• Atherosclerosis
• Thrombosis
• Increased risk of stroke and myocardial infarction
• Enzyme Defects and Disorders

a) Cystathionine β-Synthase (CBS) Deficiency

• Leads to Classical Homocystinuria.
• Homocysteine accumulates and spills into urine.
• Clinical manifestations:
• Mental retardation
• Osteoporosis
• Lens dislocation (downward displacement unlike Marfan’s upward)
• Increased blood clot risk
• Treatment:
• High-dose Vitamin B6
• Folate, B12 supplementation
• Low methionine diet
• Betaine (helps remethylate homocysteine)

b) Methionine Synthase or Vitamin B12 Deficiency

• Causes elevated homocysteine, but no cysteine deficiency.
• May result in megaloblastic anemia.

c) Folate Deficiency

• Impairs remethylation → high homocysteine
• Leads to neural tube defects in fetus if during pregnancy.
• Regulation of Methionine and SAM Levels
• High SAM levels inhibit methylenetetrahydrofolate reductase (MTHFR), regulating methyl group transfers.
• Prevents excessive remethylation when methionine is abundant.
• Methionine and SAM in Neurotransmitter and Hormone Synthesis
• SAM is required for synthesis of:
• Epinephrine from norepinephrine
• Phosphatidylcholine from phosphatidylethanolamine (important for membranes)
• Melatonin synthesis in the pineal gland.