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Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification

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Summary.

A naturally occurring unusual amino acid, hypusine [N ɛ-(4-amino-2-hydroxybutyl)-lysine] is a component of a single cellular protein, eukaryotic translation initiation factor 5A (eIF5A). It is a modified lysine with structural contribution from the polyamine spermidine. Hypusine is formed in a novel posttranslational modification that involves two enzymes, deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). eIF5A and deoxyhypusine/hypusine modification are essential for growth of eukaryotic cells. The hypusine synthetic pathway has evolved in eukaryotes and eIF5A, DHS and DOHH are highly conserved, suggesting maintenance of a fundamental cellular function of eIF5A through evolution. The unique feature of the hypusine modification is the strict specificity of the enzymes toward its substrate protein, eIF5A. Moreover, DHS exhibits a narrow specificity toward spermidine. In view of the extraordinary specificity and the requirement for hypusine-containing eIF5A for mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes present new potential targets for intervention in aberrant cell proliferation.

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Abbreviations

aIF5A:

archaeal initiation factor 5A

DHS:

deoxyhypusine synthase

DOHH:

deoxyhypusine hydroxylase

EF-P:

elongation factor P

eIF5A:

eukaryotic translation initiation factor 5A

eIF5A-1:

primary isoform of eIF5A

eIF5A-2:

secondary isoform of eIF5A

eIF5A(Dhp):

eIF5A intermediate containing deoxyhypusine

eIF5A(Hpu):

eIF5A active form containing hypusine

eIF5A(Lys):

eIF5A precursor

GC7:

N 1-guanyl-1,7-diaminoheptane

HEAT-repeat:

alpha-helical structural motif characteristic of Huntingtin, elongation factor 3E, a subunit of protein phosphatase 2A, and the target of rapamycin

NAD:

nicotinamide adenine dinucleotide

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Wolff, E., Kang, K., Kim, Y. et al. Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification. Amino Acids 33, 341–350 (2007). https://doi.org/10.1007/s00726-007-0525-0

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