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Catalytic Site Atlas

CSA LITERATURE entry for 1qcn

E.C. namefumarylacetoacetase
SpeciesMus musculus (Mouse)
E.C. Number (IntEnz) 3.7.1.2
CSA Homologues of 1qcn1hyo,1qco,1qqj,2hzy,
CSA Entries With UniProtID P35505
CSA Entries With EC Number 3.7.1.2
PDBe Entry 1qcn
PDBSum Entry 1qcn
MACiE Entry M0180

Literature Report

IntroductionFumarylacetoacetate hydrolase catalyses hydrolytic cleavage of a carbon-carbon bond in fumarylacetoacetate to give fumarate and acetoacetate - this step occurs as the final step in Phe and Tyr degradation. FAH functions as a metalloenzyme.
Herditary tyrosinemia type I is a fatal disease caused by loss of FAH activity. This enzyme also catalyses reactions required by soil bacteria to degrade aromatic hydrocarbons, and so understanding of this enzyme may have possible applications in bioengineering efforts to bioremediate toxic hydrocarbon wastes.
MechansimThe catalytic mechanism of fumarylacetoacetate hydrolase begins with binding of the fumarylacetoacetate substrate, which is activated by the Ca ion. A nucleophilic water molecule is activated by the His 133 and Glu 199, which is itself primed by the calcium ion, and it attacks the substrate facilitated by proton abstraction by His 133, which is being activated in turn by Glu 364. The formation of a tetrahedral alkoxide transition state is stabilised by the oxyanion hole formed by Gln 240, Lys 253 and Arg 237 as well as the Ca ion. Collapse of the transition state occurs with proton donation by Lys 253, with formation of the acetoacetate leaving group stabilised by the Ca ion.
Reaction

Catalytic Sites for 1qcn

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA199199macie:sideChainActivates water for nucleophilic attack
HisA133133macie:sideChainActivates water by proton abstraction.
GluA364364macie:sideChainActivates His 133 as part of the His-Glu dyad.
ArgA237237macie:sideChainForms part of the oxyanion hole.
LysA253253macie:sideChainForms part of the oxyanion hole, and donates a proton as a general acid catalyst in the collapse of the tetrahedral transition state.
GlnA240240macie:sideChainForms part of the oxyanion hole.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA199199macie:sideChainActivates water for nucleophilic attack
HisA133133macie:sideChainActivates water by proton abstraction.
GluA364364macie:sideChainActivates His 133 as part of the His-Glu dyad.
ArgA237237macie:sideChainForms part of the oxyanion hole.
LysA253253macie:sideChainForms part of the oxyanion hole, and donates a proton as a general acid catalyst in the collapse of the tetrahedral transition state.
GlnA240240macie:sideChainForms part of the oxyanion hole.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
ArgB737237macie:sideChainError
LysB753253macie:sideChainError
GlnB740240macie:sideChainError
HisB633133macie:sideChainError
GluB864364macie:sideChainError

Literature References

Notes:
Timm DE
Crystal structure and mechanism of a carbon-carbon bond hydrolase.
Structure 1999 7 1023-1033
PubMed: 10508789
Bateman RL
Mechanistic inferences from the crystal structure of fumarylacetoacetate hydrolase with a bound phosphorus-based inhibitor.
J Biol Chem 2001 276 15284-15291
PubMed: 11154690
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