Cystathionine β-synthase: Difference between revisions
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There are more than 100 reported mutations in CBS gene from patients with homocystinuria most of which are missense. Among most frequent mutations is I278T (c.833T>C) in C-terminal domain found in about 25 % of all homocystinuric alleles, and G307S (c.919G>A) located in active site. | There are more than 100 reported mutations in CBS gene from patients with homocystinuria most of which are missense. Among most frequent mutations is I278T (c.833T>C) in C-terminal domain found in about 25 % of all homocystinuric alleles, and G307S (c.919G>A) located in active site. | ||
''Mutations in active site'' | '''Mutations in active site''' | ||
The active site is accessible only via a narrow channel. Four of the six known point mutations in the active site involve glycine residues: G148R, G305R, G307S and G259S. The residue G259 separates the active site from the heme-binding pocket. The residue G307 lines the entry to the active site cleft and the orientation of G307 do not allow accommodating of the side chain of a serine residue which causes incorporation of the side chain and conformation change in the loop. As the second substrate homocysteine probably binds here the mutation could inhibit binding of homocysteine. | The active site is accessible only via a narrow channel. Four of the six known point mutations in the active site involve glycine residues: G148R, G305R, G307S and G259S. The residue G259 separates the active site from the heme-binding pocket. The residue G307 lines the entry to the active site cleft and the orientation of G307 do not allow accommodating of the side chain of a serine residue which causes incorporation of the side chain and conformation change in the loop. As the second substrate homocysteine probably binds here the mutation could inhibit binding of homocysteine. | ||
''Mutations in the heme-binding site'' | '''Mutations in the heme-binding site''' | ||
Mutations in this part of the enzyme reduces the ability to bind heme and affects proper folding of CBS. | Mutations in this part of the enzyme reduces the ability to bind heme and affects proper folding of CBS. | ||
''Mutations in the dimer interface'' | '''Mutations in the dimer interface''' | ||
Numerous CBS mutations (e.g. A114V and G116R) are located at interface of the two monomers and destabilise monomer-monomer interactions and their communication. | Numerous CBS mutations (e.g. A114V and G116R) are located at interface of the two monomers and destabilise monomer-monomer interactions and their communication. | ||
''Other mutations'' | '''Other mutations''' | ||
Residues in regulatory domain (414-551) bind the allosteric activator S-adenosyl-L-methionine and are responsible for the tetramerization. Mutation R336/H belong to this group of mutations – the side chain of this arginine is packed against the protein surface and the guanidium groups forms a salt bridge to the carboxyl group of D388, residue that does not contribute to any interaction between the two monomers. | Residues in regulatory domain (414-551) bind the allosteric activator S-adenosyl-L-methionine and are responsible for the tetramerization. Mutation R336/H belong to this group of mutations – the side chain of this arginine is packed against the protein surface and the guanidium groups forms a salt bridge to the carboxyl group of D388, residue that does not contribute to any interaction between the two monomers. | ||
The most common mutation, I278T, is located in β-sheet of the C-terminal domain. | The most common mutation, I278T, is located in β-sheet of the C-terminal domain. | ||