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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1n2t
Original Entry
Title:
Lyase
Compound:
L-cysteine-cystine lyase c-des
Mutant:
Yes
UniProt/Swiss-Prot:
Q9ZHG9-Q9ZHG9
EC Class:
4.4.-.-
Other CSA Entries:
Overview of all sites for 1n2t
Homologues of 1n2t
Entries for UniProt/Swiss-Prot: Q9ZHG9
Entries for EC: 4.4.-.-
Other Databases:
PDB entry: 1n2t
PDBsum entry: 1n2t
UniProt/Swiss-Prot: Q9ZHG9
IntEnz entry: 4.4.-.-
Literature Report:
Introduction:
Cyst(e)ine C-S lyase (C-DES), isolated from Synechocystis sp. PCC 6714, is a pyridoxal 5'-phosphate (PLP)-dependent enzyme. It catalyses the conversion of cystine to cysteine persulfide, pyruvate and ammonia. The enzyme can also use cysteine, but to a lesser extent. C-DES is an important enzyme in sulfur mobilisation and Fe-S cluster assembly.

Mechanism:
PLP is covalently bound to the enzyme through Lys223; this is the internal aldimine. One of the amino groups of cystine is deprotonated by His114 and this causes transaldimination via a gem-diamine to form an external aldimine. Lys223 abstracts the C-alpha proton of the substrate and PLP acts as an electron sink. This is followed by beta-lysis, forming cysteine persulfide and an aminoacrylate intermediate. There is another transaldimination reaction involving Lys223 and the released product is hydrolysed to pyruvate and ammonia.

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
3001 0Sidechain
ElectrophileSubstrate
ElectrophileResidue
In the active enzyme PLP is covalently bound to Lys223 through an imine linkage. The residue is then replaced by the substrate. The cofactor acts as an electron-sink when C-alpha of the substrate is deprotonated and as an electron source to cause the elimination of cysteine persulfide. The product is then displaced by Lys223.
Evidence from paper Evidence concerns Evidence type
PubMed ID 17020883 Current protein
PubMed ID 12386155 Current protein Ligand is essential for catalysis
PubMed ID 12386155 Current protein
PubMed ID 10715213 Related protein: UniProt Q9X218 Structural similarity to homologue of known mechanism
PubMed ID 10760256 Current protein Residue is covalently bound to intermediate, based on structural data
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 114 114Sidechain
ElectrostaticCofactor
Acid/baseSubstrate
His114 deprotonates the amine group of the substrate so that it can act as a nucleophile for attack on the enzyme-bound PLP. The imidazole ring interacts with the pyridine ring of PLP, stabilising the electronic distributions that form in the ring during the reaction.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10715213 Related protein: UniProt Q9X218 Structural similarity to homologue of known mechanism
PubMed ID 17020883 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ASPA 197 197Sidechain
ElectrostaticCofactor
Asp197 forms a salt bridge with the nitrogen of the pyridine ring of PLP. This stabilises the electronic distributions that form in the ring during the reaction.
Evidence from paper Evidence concerns Evidence type
PubMed ID 17020883 Current protein Conservation of residue
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ALAA 199 199Sidechain
ElectrostaticCofactor
Ala199 interacts with the pyridine ring of PLP, stabilising the electronic distributions that form in the ring during the reaction.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLNA 200 200Sidechain
ElectrostaticCofactor
Gln200 hydrogen bonds to the C3 hydroxyl group of PLP. This stabilises the electronic distributions that form in the ring during the reaction.
Evidence from paper Evidence concerns Evidence type
PubMed ID 17020883 Current protein Conservation of residue
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ALAA 223 223Sidechain
Acid/baseSubstrate
ModifiedSubstrate
NucleophileCofactor
Lys223 forms an internal aldimine complex with PLP. It is the leaving group during transaldimination. It deprotonates C-alpha of this intermediate and then protonates the cysteine persulfide leaving group. It then forms another internal aldimine complex with PLP so that the product can be released.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10760256 Current protein Residue is covalently bound to intermediate, based on structural data
PubMed ID 10715213 Related protein: UniProt Q9X218 Structural similarity to homologue of known mechanism
PubMed ID 12386155 Current protein
PubMed ID 17020883 Current protein Conservation of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ARGA 360 360Sidechain
ElectrostaticSubstrate
Steric strainSubstrate
Upon formation of the external aldimine, Arg360 and the carboxylate of the substrate rearrange relative to each other and form electrostatic interactions. This induces strain in the substrate and is necessary for C-S cleavage.
Evidence from paper Evidence concerns Evidence type
PubMed ID 12386155 Current protein
PubMed ID 17020883 Current protein Conservation of residue
PubMed ID 12386155 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10760256 Current protein Residue is positioned appropriately (ligand position known)
Notes:


References:
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