Metabolism of sulphur amino acids. (2025)

Sulfur-containing amino acids — primarily methionine and cysteine — are essential components of metabolism. While methionine is an essential amino acid obtained from the diet, cysteine is considered semi-essential, as it can be synthesized from methionine through the transsulfuration pathway. These amino acids play important roles in methyl group transfer, antioxidant defense, and the synthesis of several biologically active compounds.

Methionine metabolism[edit | edit source]

Activation of methionine and synthesis of S-adenosylmethionine (SAM)[edit | edit source]

Methionine is activated by methionine adenosyltransferase (MAT) to form S-adenosylmethionine (SAM), a universal methyl group donor. This reaction requires ATP:

Methionine + ATP → SAM + PPi​ + Pi​

SAM serves as a donor of methyl groups in numerous transmethylation reactions, such as the methylation of DNA, RNA, proteins, and lipids.

Source: Murray RK et al. Harper’s Illustrated Biochemistry. 31st ed. 2018.

Formation of homocysteine[edit | edit source]

After donating its methyl group, SAM is converted to S-adenosylhomocysteine (SAH), which is subsequently hydrolyzed to homocysteine and adenosine:

SAH → Homocysteine + Adenosine

Homocysteine is a central intermediate with two possible fates: remethylation to methionine or transsulfuration to cysteine.

Source: Devlin TM. Textbook of Biochemistry with Clinical Correlations. 7th ed. 2010.

Remethylation of homocysteine[edit | edit source]

Methionine synthase (folate-dependent pathway)[edit | edit source]

In most tissues, methionine synthase catalyzes the transfer of a methyl group from N⁵-methyltetrahydrofolate (N⁵-methyl-THF) to homocysteine, regenerating methionine. This reaction requires vitamin B₁₂ (methylcobalamin) as a cofactor:

Homocysteine + N⁵-methyl-THF → Methionine + THF

Betaine-homocysteine methyltransferase (BHMT)[edit | edit source]

In the liver and kidney, an alternative remethylation pathway utilizes betaine (trimethylglycine):

Homocysteine + Betaine → Methionine + Dimethylglycine

Source: Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. 2021.

Transsulfuration pathway: synthesis of cysteine[edit | edit source]

In tissues such as the liver, homocysteine undergoes transsulfuration to form cysteine in two vitamin B₆-dependent steps:

1. Cystathionine β-synthase (CBS) catalyzes the condensation of homocysteine with serine to form cystathionine: Homocysteine+Serine→Cystathionine
2. Cystathionine γ-lyase (CGL) then cleaves cystathionine to yield cysteine, α-ketobutyrate, and ammonia: Cystathionine → Cysteine + α-Ketobutyrate + NH3​

This is the main route of endogenous cysteine synthesis in humans.

Source: Marks DB et al. Marks’ Basic Medical Biochemistry: A Clinical Approach. 5th ed. 2017.

Metabolism of cysteine[edit | edit source]

Cysteine is utilized for various essential biological functions:

Protein synthesis[edit | edit source]

Cysteine is incorporated into proteins, where it contributes to disulfide bond formation, influencing protein folding and stability.

Glutathione synthesis[edit | edit source]

Cysteine combines with glutamate and glycine to form glutathione (GSH), a tripeptide antioxidant important in redox balance and detoxification.

Glutamate + Cysteine + Glycine → Glutathione

Synthesis of taurine[edit | edit source]

Cysteine is metabolized to taurine via the intermediate cysteinesulfinic acid. Taurine is essential for:

• Conjugation of bile acids (e.g. taurocholic acid)
• Osmoregulation
• Modulation of neurotransmission

Sulfate production and detoxification[edit | edit source]

Cysteine degradation produces sulfite and then sulfate, which is used in sulfation reactions (e.g., conjugation of xenobiotics and hormones) and synthesis of glycosaminoglycans.

Source: Zempleni J, Suttie JW, Gregory JF III, Stover PJ. Present Knowledge in Nutrition. 10th ed. 2012.

Regulation[edit | edit source]

• S-adenosylmethionine (SAM) plays a key regulatory role:
  • Inhibits methylenetetrahydrofolate reductase (MTHFR), reducing remethylation
  • Activates CBS, enhancing the transsulfuration pathway
• Vitamins B₆, B₁₂, and folate are essential cofactors in these reactions
• Cellular need for glutathione influences cysteine utilization

Source: Murray RK et al. Harper’s Illustrated Biochemistry. 31st ed. 2018.

Clinical significance[edit | edit source]

Homocystinuria[edit | edit source]

A rare autosomal recessive disorder, most commonly due to CBS deficiency. Leads to accumulation of homocysteine and methionine.

Symptoms include:

• Lens dislocation (ectopia lentis)
• Marfanoid body habitus
• Osteoporosis
• Intellectual disability
• Thromboembolism

Diagnosis: Elevated plasma homocysteine and methionine

Treatment: Vitamin B₆ supplementation (in responsive forms), low-methionine diet, betaine

Source: Scriver CR et al. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. 2001.

Hyperhomocysteinemia[edit | edit source]

A milder increase in plasma homocysteine levels, associated with cardiovascular disease risk.

Causes:

• Deficiency of B vitamins (B₆, B₁₂, folate)
• Genetic mutations in CBS or MTHFR
• Renal insufficiency

Treatment: Dietary supplementation with folate, B₆, and B₁₂

Cystinuria[edit | edit source]

A disorder of renal tubular reabsorption of cystine and dibasic amino acids (lysine, arginine, ornithine), leading to cystine stone formation in the urinary tract.

Source: Valle D et al. The Online Metabolic and Molecular Bases of Inherited Disease. OMIM.

Summary[edit | edit source]

Sulfur-containing amino acids are central to methylation reactions, antioxidant defense, and detoxification. Methionine serves as a precursor for SAM and cysteine, while cysteine supports glutathione synthesis, taurine production, and sulfation. Proper metabolism depends on adequate intake of B vitamins and is tightly regulated by intracellular SAM concentrations. Genetic or nutritional imbalances can result in significant metabolic and clinical consequences.