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Catalytic Site Atlas

CSA LITERATURE entry for 1roz

E.C. namedeoxyhypusine synthase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 2.5.1.46
CSA Homologues of 1roz1dhs,1rlz,1rqd,
CSA Entries With UniProtID P49366
CSA Entries With EC Number 2.5.1.46
PDBe Entry 1roz
PDBSum Entry 1roz
MACiE Entry 1roz

Literature Report

IntroductionDeoxyhypusine is a highly rare posttranslational modification that occurs in eukaryotes where the it is vital for the formation of the initiation factor eIF5A. The enzyme carrying the reaction out is deoxyhypusine synthase which is able to transfer a butylamine moiety from spermidine to a lysine in eIF5A, using NAD as a cofactor. Since active eIF5A is required for tumour cell proliferation, design of inhibitors for this enzyme could prove useful in the treatment of certain cancers. The high specificity of the enzyme is also of interest, because the only incidence of this modification in eukaryotic proteins appears to be in this particular case.
MechansimThe enzymatic reaction proceeds in four steps. First, hydride transfer from spermidine to NAD with concomitant deprotonation by His 288 leads to the dehydration of spermidine to dehydrospermidine. The dehydrospermidine is thus activated to act as an electrophile; nucleophilic attack from lys 239 transfers the butylimine moiety to the enzyme forming an imine-enzyme intermediate, releasing diaminopropane. The lysine residue from eIF5A to be modified then attacks as a nucleophile, resulting in the formation of eIF5A imine intermediate and regenerating the catalytic lysine residue. Finally, the imine is converted to the butylamine moiety to form deoxyhypusine and NAD. Hydride transfer to and from NAD is assisted by Glu 157 which activates C4 of the NAD through electrostatic interactions.
Reaction

Catalytic Sites for 1roz

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA329329macie:sideChainActs as a nucleophile to accept the butylimine moiety from dehydrospermidine, forming an enzyme-imine intermediate. This then acts as an electrophile for transfer of the butylimine moiety to eIF5A with the lysine residue in eIF5A to be modified acting as a nucleophile.
GluA137137macie:sideChainActivates the NAD towards accepting a hydride ion in the first stage of the reaction through repulsion between the rozC4's pi electrons and the negative charge. Subsequently activates the eIF5A towards accepting a hydride ion through repulsion between the CN double bond and the negative charge.
HisA288288macie:sideChainAccepts proton from spermidine to facilitate hydride transfer. Subsequently releases proton back to the modified lysine in eIF5A to allow hydride transfer from NADH to occur.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysB329329macie:sideChainActs as a nucleophile to accept the butylimine moiety from dehydrospermidine, forming an enzyme-imine intermediate. This then acts as an electrophile for transfer of the butylimine moiety to eIF5A with the lysine residue in eIF5A to be modified acting as a nucleophile.
GluB137137macie:sideChainActivates the NAD towards accepting a hydride ion in the first stage of the reaction through repulsion between the rozC4's pi electrons and the negative charge. Subsequently activates the eIF5A towards accepting a hydride ion through repulsion between the CN double bond and the negative charge.
HisB288288macie:sideChainAccepts proton from spermidine to facilitate hydride transfer. Subsequently releases proton back to the modified lysine in eIF5A to allow hydride transfer from NADH to occur.

Literature References

Notes:
Wolff EC
Deoxyhypusine synthase generates and uses bound NADH in a transient hydride transfer mechanism.
J Biol Chem 2000 275 9170-9177
PubMed: 10734052
Umland TC
A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme.NAD.inhibitor ternary complex.
J Biol Chem 2004 279 28697-28705
PubMed: 15100216
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