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Functional significance of eIF5A and its hypusine modification in eukaryotes

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Abstract

The unusual basic amino acid, hypusine [Nε-(4-amino-2-hydroxybutyl)-lysine], is a modified lysine with the addition of the 4-aminobutyl moiety from the polyamine spermidine. This naturally occurring amino acid is a product of a unique posttranslational modification that occurs in only one cellular protein, eukaryotic translation initiation factor 5A (eIF5A, eIF-5A). Hypusine is synthesized exclusively in this protein by two sequential enzymatic steps involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The deoxyhypusine/hypusine synthetic pathway has evolved in archaea and eukaryotes, and eIF5A, DHS and DOHH are highly conserved suggesting a vital cellular function of eIF5A. Gene disruption and mutation studies in yeast and higher eukaryotes have provided valuable information on the essential nature of eIF5A and the deoxyhypusine/hypusine modification in cell growth and in protein synthesis. In view of the extraordinary specificity and functional significance of hypusine-containing eIF5A in mammalian cell proliferation, eIF5A and the hypusine biosynthetic enzymes are novel potential targets for intervention in aberrant cell proliferation.

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Abbreviations

aIF5A:

Archaeal initiation factor 5A

EF-P:

Elongation factor P

eIF5A:

Eukaryotic translation initiation factor 5A

eIF5A-1:

Primary isoform of eIF5A

eIF5A-2:

Secondary isoform of eIF5A

eIF5A(Lys):

eIF5A precursor

eIF5A(Dhp):

eIF5A intermediate containing deoxyhypusine

eIF5A(Hpu):

eIF5A active form containing hypusine

UBR5A:

Ubiquitin arginine-fusion yeast eukaryotic initiation factor 5A

DHS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

GC7:

N1-guanyl-1,7-diaminoheptane

A site:

Aminoacyl-tRNA site

P site:

Peptidyl-tRNA site

E site:

Exiting tRNA site

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Acknowledgments

The research was supported in part by the Intramural Research Program of National Institute of Dental and Craniofacial Research (NIDCR), NIH, FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) and KANAE Foundation for the Promotion of Medical Science. We thank Dr. Edith C. Wolff (NIDCR, NIH) for critical reading of the manuscript and helpful suggestions.

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Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bldg 30, Room 211, Bethesda, MD, 20892-4340, USA

    M. H. Park & K. Nishimura

  2. Department of Biological Sciences, School of Pharmaceutical Sciences, Sao Paulo State University, Araraquara, Brazil

    C. F. Zanelli & S. R. Valentini

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  1. M. H. Park
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  2. K. Nishimura
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  3. C. F. Zanelli
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  4. S. R. Valentini
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Correspondence to M. H. Park.

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Park, M.H., Nishimura, K., Zanelli, C.F. et al. Functional significance of eIF5A and its hypusine modification in eukaryotes. Amino Acids 38, 491–500 (2010). https://doi.org/10.1007/s00726-009-0408-7

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  • DOI: https://doi.org/10.1007/s00726-009-0408-7

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