Metabolism of Cysteine & Methionine and Related Inborn Errors (Homocystinuria & Homocysteinemia): Biochemistry

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
Figure 1: 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.

- 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 
the eye (ectopia lentis or severe myopia), 
- skeletal system (excessive height, long limbs, scoliosis, etc)
- vascular system (thromboembolism), 
- CNS (delayed development, and intellectual disability). 

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

-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.