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Catalytic Site Atlas

CSA LITERATURE entry for 1mt5

E.C. namefatty acid amide hydrolase
SpeciesRattus norvegicus (Rat)
E.C. Number (IntEnz) 3.5.1.99
CSA Homologues of 1mt5
CSA Entries With UniProtID P97612
CSA Entries With EC Number 3.5.1.99
PDBe Entry 1mt5
PDBSum Entry 1mt5
MACiE Entry 1mt5

Literature Report

IntroductionMammalian fatty acid amide hydrolase (FAAH) degrades fatty acid primary amides and ethanolamides such as anandamide and oleamide. Anandamide binds and activates cannabinoid and vanilloid receptors exerting an analgesic and cannabinoid effects while oleamide has been found to be sleep inducing.
Rat FAAH is an integral membrane protein. The wild type protein hydrolyses esters and amides at the same rate but the Lys142Ala mutant hydrolyses esters more rapidly than amides.

MechansimFAAH has a catalytic triad consisting of Ser217, Ser241 and Lys142. Initially Lys142 deprotonates Ser217. Ser241 acts as a nucleophile, attacking the carbonyl carbon of the substrate. The tetrahedral intermediate is formed in a concerted process with the deprotonation of Ser241 by the alkoxide of Ser217. The negative charge on the tetrahedral intermediate is stabilised by strong hydrogen bonds with the backbone NH groups of Ile238, Gly239, Gly240 and Ser241 which form an oxyanion hole.
The acylation of the enzyme is the rate limiting step. Deacylation occurs with a water molecule from the solvent acting as the nucleophile. There are four water molecules near the active site. Water-bridgined proton transfer is thought to be necessary for the hydrolysis of the acyl intermediate.

Reaction

Catalytic Sites for 1mt5

Annotated By Reference To The Literature - Site 17 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerA218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleA238238macie:mainChainAmideForms part of the oxyanion hole.
SerA241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerA241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyA240240macie:mainChainAmideForms part of the oxyanion hole.
GlyA239239macie:mainChainAmideForms part of the oxyanion hole.
SerA217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 18 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysB142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerB218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleB238238macie:mainChainAmideForms part of the oxyanion hole.
SerB241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerB241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyB240240macie:mainChainAmideForms part of the oxyanion hole.
GlyB239239macie:mainChainAmideForms part of the oxyanion hole.
SerB217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 19 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysC142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerC218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleC238238macie:mainChainAmideForms part of the oxyanion hole.
SerC241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerC241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyC240240macie:mainChainAmideForms part of the oxyanion hole.
GlyC239239macie:mainChainAmideForms part of the oxyanion hole.
SerC217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 20 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysD142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerD218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleD238238macie:mainChainAmideForms part of the oxyanion hole.
SerD241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerD241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyD240240macie:mainChainAmideForms part of the oxyanion hole.
GlyD239239macie:mainChainAmideForms part of the oxyanion hole.
SerD217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 21 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysE142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerE218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleE238238macie:mainChainAmideForms part of the oxyanion hole.
SerE241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerE241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyE240240macie:mainChainAmideForms part of the oxyanion hole.
GlyE239239macie:mainChainAmideForms part of the oxyanion hole.
SerE217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 22 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysF142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerF218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleF238238macie:mainChainAmideForms part of the oxyanion hole.
SerF241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerF241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyF240240macie:mainChainAmideForms part of the oxyanion hole.
GlyF239239macie:mainChainAmideForms part of the oxyanion hole.
SerF217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 23 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysG142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerG218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleG238238macie:mainChainAmideForms part of the oxyanion hole.
SerG241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerG241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyG240240macie:mainChainAmideForms part of the oxyanion hole.
GlyG239239macie:mainChainAmideForms part of the oxyanion hole.
SerG217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 24 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysH142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerH218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleH238238macie:mainChainAmideForms part of the oxyanion hole.
SerH241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerH241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyH240240macie:mainChainAmideForms part of the oxyanion hole.
GlyH239239macie:mainChainAmideForms part of the oxyanion hole.
SerH217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 25 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysI142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerI218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleI238238macie:mainChainAmideForms part of the oxyanion hole.
SerI241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerI241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyI240240macie:mainChainAmideForms part of the oxyanion hole.
GlyI239239macie:mainChainAmideForms part of the oxyanion hole.
SerI217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 26 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysJ142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerJ218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleJ238238macie:mainChainAmideForms part of the oxyanion hole.
SerJ241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerJ241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyJ240240macie:mainChainAmideForms part of the oxyanion hole.
GlyJ239239macie:mainChainAmideForms part of the oxyanion hole.
SerJ217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 27 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysK142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerK218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleK238238macie:mainChainAmideForms part of the oxyanion hole.
SerK241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerK241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyK240240macie:mainChainAmideForms part of the oxyanion hole.
GlyK239239macie:mainChainAmideForms part of the oxyanion hole.
SerK217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 28 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysL142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerL218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleL238238macie:mainChainAmideForms part of the oxyanion hole.
SerL241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerL241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyL240240macie:mainChainAmideForms part of the oxyanion hole.
GlyL239239macie:mainChainAmideForms part of the oxyanion hole.
SerL217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 29 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysM142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerM218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleM238238macie:mainChainAmideForms part of the oxyanion hole.
SerM241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerM241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyM240240macie:mainChainAmideForms part of the oxyanion hole.
GlyM239239macie:mainChainAmideForms part of the oxyanion hole.
SerM217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 30 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysN142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerN218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleN238238macie:mainChainAmideForms part of the oxyanion hole.
SerN241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerN241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyN240240macie:mainChainAmideForms part of the oxyanion hole.
GlyN239239macie:mainChainAmideForms part of the oxyanion hole.
SerN217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 31 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysO142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerO218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleO238238macie:mainChainAmideForms part of the oxyanion hole.
SerO241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerO241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyO240240macie:mainChainAmideForms part of the oxyanion hole.
GlyO239239macie:mainChainAmideForms part of the oxyanion hole.
SerO217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Annotated By Reference To The Literature - Site 32 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysP142142macie:sideChainLys142 initially acts as a base, deprotonating Ser217 and later as an a acid, protonating Ser217.
SerP218218macie:sideChainThe exact function of Ser218 is uncertain but it may be hydrogen bonding to Ser217 and stabilising the negative charge on it.
S218A mutants have a decreased kcat with no significant change in Km.
IleP238238macie:mainChainAmideForms part of the oxyanion hole.
SerP241241macie:sideChainSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
SerP241241macie:mainChainAmideSer241 is the nucleophile that attacks the carbonyl carbon of the substrate. The backbone NH group of Ser241 contributes to the oxyanion hole.
GlyP240240macie:mainChainAmideForms part of the oxyanion hole.
GlyP239239macie:mainChainAmideForms part of the oxyanion hole.
SerP217217macie:sideChainSer217 is deprotonated by Lys142 and then acts as a general base for the deprotonation of Ser241 which is the nucleophile. Then, it acts a general acid by protonating the leaving group of the substrate. Finally, the alkoxide is restored to an OH group by obtaining a proton from Lys142.

Literature References

Notes:A detailed mechanism for the catalysis is proposed by Tubert-Brohman et al (PMID:17177441) on the basis of mixed quantum and molecular mechanics calculations and previous studies. This pdb (1mt5) contains the structure of FAAH complexed with methoxyarachidonyl phosphate (MAP).
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