Metabolic Pathway of Methionine and Cysteine
Conversion of Methionine to S-Adenosyl Methionine
- Methionine is a nutritionally essential amino acid, therefore, the dietary source is generally proteins.
- S-adenosyl methionine synthase catalyzes the conversion of methionine to S-adenosyl methionine
- Require ATP, the ATP is hydrolyzed to AMP and PPi, therefore two energy equivalent of ATP is consumed in the reaction
Metabolic Pathway for the methionine metabolism
Formation of S-Adenosyl homocysteine from S-Adenosyl methionine
- S-adenosyl methionine serves as an active methyl group donor in various metabolic pathways including amino acid metabolism, hormones/neurotransmitter synthesis, etc.
- Once the methyl group is transferred to the methyl acceptor, the S-Adenosyl methionine is formed
- Generally transferred by specific methyltransferase
Hydrolysis of S-Adenosyl homocysteine to form homocysteine
-The hydrolysis of S-Adenosyl homocysteine forms homocysteine
- Homocysteine can enter into two pathways, first the recycling of homocysteine to methionine in presence of an enzyme homocysteine methyltransferase.
- Homocysteine methyltransferase (methionine synthase) require Vit B12 as a cofactor
- Catalyzes the transfer of methyl group from N5-methyltetrahydrofolate to form methionine
Conversion of Homocysteine to Cystathionine
-The reaction is catalyzed by an enzyme cystathionine beta-synthase
- Cystathionine beta-synthase is pyridoxal phosphate requiring enzyme
- In the reaction, the condensation of homocysteine with serine results in the formation of cystathionine
- Deficiency of this enzyme leads to the accumulation of homocysteine in plasma and homocystinuria
Conversion of Cystathionine to Cysteine
- The reaction is catalyzed by an enzyme gamma-cystathionase
- Cleavage of cystathionine to cysteine and alpha-ketobutyrate
- alpha-ketobutyrate is oxidatively decarboxylated to form propionyl CoA
- Cysteine enters its metabolic fates
Homocystinuria and Homocysteinemia: Inborn errors of Methionine Metabolism
-Homocystinuria is an inherited disorder primarily caused by a deficiency of enzymes of methionine metabolism
- The enzyme defect or enzyme cofactors deficiency leads to the accumulation and excretion of homocystine in the urine.
- Increased blood homocysteine is also known as homocysteinemia is associated with various cardiovascular diseases and stroke but the mechanism is not unknown.
Prevalence
- The most common form of homocystinuria affects at least 1 in 200,000 to 335,000 people worldwide
Inheritance Pattern
Enzyme defective homocystinuria are inherited in an Autosomal recessive manner
Biochemical Basis
Homocystinuria Type I
- Type I is a classical homocystinuria
- Inherited in is an autosomal recessive manner
- Caused by the mutation of cystathionine beta-synthase (CBS) gene ( long arm of chromosome 21 (21q22.3)
- the mutation of the CBS gene may result in reduced activity of cystathionine beta-synthase
Homocystinuria Type II & Type III
- Methylcobalamin is required for the reconversion of homocysteine to methionine
- the defect in the formation of methylcobalamin or methylation pathway results in type II & III homocystinuria.
- Type II & Type III homocystinuria possess mild clinical severity
- Characterized by megaloblastic anemia, homocystinuria, and low levels of methionine with mild clinical severity.
Pathological Manifestation
Homocystinuria caused by cystathionine beta-synthase has multiple organ involvement including
Homocystinuria caused by cystathionine beta-synthase has multiple organ involvement including
the eye (ectopia lentis or severe myopia),
- skeletal system (excessive height, long limbs, scoliosis, etc)
- vascular system (thromboembolism),
- CNS (delayed development, and intellectual disability).
Diagnosis
Screening/Diagnostic Test
Screening/Diagnostic Test
- Nitroprusside test for homocystine in urine
- Amino Acid Chromatography in urine- Increased plasma total homocysteine > 50 to 100 micromol/L ( healthy controls <15 micromol/L)
- Increased plasma methionine > 50 to 200 micromol/L ( healthy controls 10-40 micromol/L)
Confirmatory Diagnosis
- Sequence analysis of the CBS gene, followed by targeted deletion/duplication analysis
Treatment
-Dietary Management
- Supplementation of cyanocobalamin, folic acid, and pyridoxine may alleviate the symptoms.
-No approved treatment, but the pegylated cystathionine-beta-synthase enzyme replacement therapy is under clinical development.
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