Skip to main content
SpringerLink
Log in

Role of the Polyamine Spermidine as a Precursor for Hypusine Modification in eIF5A

  • Chapter
  • First Online:
Polyamines

Abstract

Although polyamines exert various effects on nucleic acids and macromolecular synthesis as polycations, spermidine is covalently incorporated into a single protein, eukaryotic initiation factor 5A (eIF5A), through a unique posttranslational modification. In this reaction, the aminobutyl moiety of spermidine is conjugated to a specific lysine residue of eIF5A to form an unusual amino acid, hypusine [N ε-(4-amino-2-hydroxybutyl)-lysine]. It occurs by two enzymatic steps catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). Hypusine synthesis occurs exclusively in eIF5A and is essential for eukaryotic cell proliferation. Although only a small percentage of the total spermidine in cells is used for hypusine formation, cells cannot survive/grow when hypusinated eIF5A falls below a critical level. Inactivation of the eIF5A gene or DHS gene is lethal in yeast and in mouse, further indicating the vital role of hypusinated eIF5A. eIF5A has been proposed to promote translation of a subset of cellular mRNAs. Indeed, recent evidence suggests that eIF5A facilitates translation at the elongation step, particularly at multiple strings of proline residues. A model of eIF5A docked in the ribosome reveals the hypusine directed toward the peptidyl transferase center. Thus, the hypusine modification defines a link between polyamines and cell growth, through promotion of translation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Notes

  1. 1.

    Approved anti-fungal drug.

  2. 2.

    Approved anti-thalassemia drug.

Abbreviations

DHS :

Deoxyhypusine synthase

DOHH :

Deoxyhypusine hydroxylase

EF-P:

Bacterial elongation factor P

eIF5A :

Eukaryotic initiation factor 5A

GC7:

N1-guanyl-1,7-diaminoheptane

SSAT1:

Spermidine /spermine acetyltransferase 1

References

  • Byers TL, Ganem B, Pegg AE (1992) Cytostasis induced in L1210 murine leukaemia cells by the S-adenosyl-l-methionine decarboxylase inhibitor 5′-([(Z)-4-amino-2-butenyl]methylamino)-5′-deoxyadenosine may be due to hypusine depletion. Biochem J 287:717–724

    CAS  PubMed Central  PubMed  Google Scholar 

  • Byers TL, Lakanen JR, Coward JK et al (1994) The role of hypusine depletion in cytostasis induced by S-adenosyl-l-methionine decarboxylase inhibition: new evidence provided by 1-methylspermidine and 1,12-dimethylspermine. Biochem J 303:363–368

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cano VS, Jeon GA, Johansson HE et al (2008) Mutational analyses of human eIF5A–1: identification of amino acid residues critical for eIF5A activity and hypusine modification. FEBS J 275:44–58

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Caraglia M, Park MH, Wolff EC et al (2013) eIF5A isoforms and cancer: two brothers for two functions? Amino Acids 44:103–109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chattopadhyay MK, Park MH, Tabor H (2008) Hypusine modification for growth is the major function of spermidine in Saccharomyces cerevisiae polyamine auxotrophs grown in limiting spermidine. Proc Natl Acad Sci USA 105:6554–6559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen ZP, Chen KY (1997a) Dramatic attenuation of hypusine formation on eukaryotic initiation factor 5A during senescence of IMR-90 human diploid fibroblasts. J Cell Physiol 170:248–254

    Article  CAS  PubMed  Google Scholar 

  • Chen ZP, Chen KY (1997b) Marked elevation of hypusine formation activity on eukaryotic initiation factor 5A in v-HA-RAS transformed mouse NIH3T3 cells. Cancer Lett 115:235–241

    Article  CAS  PubMed  Google Scholar 

  • Chen KY, Liu AY (1997) Biochemistry and function of hypusine formation on eukaryotic initiation factor 5A. Biol Signals 6:105–109

    Article  CAS  PubMed  Google Scholar 

  • Clement PM, Hanauske-Abel HM, Wolff EC et al (2002) The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Cancer 100:491–498

    Article  CAS  PubMed  Google Scholar 

  • Cooper HL, Park MH, Folk JE et al (1983) Identification of the hypusine-containing protein hy+ as translation initiation factor eIF-4D. Proc Natl Acad Sci USA 80:1854–1857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doerfel LK, Wohlgemuth I, Kothe C et al (2013) EF-P is essential for rapid synthesis of proteins containing consecutive proline residues. Science 339:85–88

    Article  CAS  PubMed  Google Scholar 

  • Gerner EW, Mamont PS, Bernhardt A et al (1986) Post-translational modification of the protein-synthesis initiation factor eIF-4D by spermidine in rat hepatoma cells. Biochem J 239:379–386

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gregio AP, Cano VP, Avaca JS et al (2009) eIF5A has a function in the elongation step of translation in yeast. Biochem Biophys Res Commun 380:785–790

    Article  CAS  PubMed  Google Scholar 

  • Gutierrez E, Shin BS, Woolstenhulme CJ et al (2013) eIF5A promotes translation of polyproline motifs. Mol Cell 51:35–45

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hanauske-Abel HM, Park MH, Hanauske AR et al (1994) Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation. Biochim Biophys Acta 1221:115–124

    Article  CAS  PubMed  Google Scholar 

  • Hyvonen MT, Keinanen TA, Cerrada-Gimenez M et al (2007) Role of hypusinated eukaryotic translation initiation factor 5A in polyamine depletion-induced cytostasis. J Biol Chem 282:34700–34706

    Article  PubMed  Google Scholar 

  • Ishfaq M, Maeta K, Maeda S et al (2012) Acetylation regulates subcellular localization of eukaryotic translation initiation factor 5A (eIF5A). FEBS Lett 586:3236–3241

    Article  CAS  PubMed  Google Scholar 

  • Jakus J, Wolff EC, Park MH et al (1993) Features of the spermidine-binding site of deoxyhypusine synthase as derived from inhibition studies. Effective inhibition by bis- and mono-guanylated diamines and polyamines. J Biol Chem 268:13151–13159

    CAS  PubMed  Google Scholar 

  • Jasiulionis MG, Luchessi AD, Moreira AG et al (2007) Inhibition of eukaryotic translation initiation factor 5A (eIF5A) hypusination impairs melanoma growth. Cell Biochem Funct 25:109–114

    Article  CAS  PubMed  Google Scholar 

  • Kemper WM, Berry KW, Merrick WC (1976) Purification and properties of rabbit reticulocyte protein synthesis initiation factors M2Balpha and M2Bbeta. J Biol Chem 251:5551–5557

    CAS  PubMed  Google Scholar 

  • Kim SC, Sprung R, Chen Y et al (2006a) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23:607–618

    Article  CAS  PubMed  Google Scholar 

  • Kim YS, Kang KR, Wolff EC et al (2006b) Deoxyhypusine hydroxylase is a Fe(II)-dependent, HEAT-repeat enzyme. Identification of amino acid residues critical for Fe(II) binding and catalysis [corrected]. J Biol Chem 281:13217–13225

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klier H, Csonga R, Joao HC et al (1995) Isolation and structural characterization of different isoforms of the hypusine-containing protein eIF-5A from HeLa cells. Biochemistry 34:14693–14702

    Article  CAS  PubMed  Google Scholar 

  • Lee SB, Park JH, Kaevel J et al (2009) The effect of hypusine modification on the intracellular localization of eIF5A. Biochem Biophys Res Commun 383:497–502

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee SB, Park JH, Folk JE et al (2011) Inactivation of eukaryotic initiation factor 5A (eIF5A) by specific acetylation of its hypusine residue by spermidine/spermine acetyltransferase 1 (SSAT1). Biochem J 433:205–213

    Article  CAS  PubMed  Google Scholar 

  • Mandal S, Mandal A, Johansson HE et al (2013) Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc Natl Acad Sci USA 110:2169–2174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakajima T, Matsubayashi T, Kakimoto Y et al (1971) Distribution of hypusine, N 6-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid, in mammalian organs. Biochim Biophys Acta 252:92–97

    Article  CAS  PubMed  Google Scholar 

  • Nishimura K, Murozumi K, Shirahata A et al (2005) Independent roles of eIF5A and polyamines in cell proliferation. Biochem J 385:779–785

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nishimura K, Lee SB, Park JH et al (2012) Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development. Amino Acids 42:703–710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park MH (2006) The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A). J Biochem 139:161–169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park MH, Cooper HL, Folk JE (1981) Identification of hypusine, an unusual amino acid, in a protein from human lymphocytes and of spermidine as its biosynthetic precursor. Proc Natl Acad Sci USA 78:2869–2873

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park MH, Wolff EC, Folk JE (1993) Hypusine: its post-translational formation in eukaryotic initiation factor 5A and its potential role in cellular regulation. Biofactors 4:95–104

    CAS  PubMed  Google Scholar 

  • Park MH, Wolff EC, Lee YB et al (1994) Antiproliferative effects of inhibitors of deoxyhypusine synthase. Inhibition of growth of Chinese hamster ovary cells by guanyl diamines. J Biol Chem 269:27827–27832

    CAS  PubMed  Google Scholar 

  • Park MH, Joe YA, Kang KR (1998) Deoxyhypusine synthase activity is essential for cell viability in the yeast Saccharomyces cerevisiae. J Biol Chem 273:1677–1683

    Article  CAS  PubMed  Google Scholar 

  • Park JH, Aravind L, Wolff EC et al (2006) Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci USA 103:51–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park MH, Mandal S, Mandal A et al (2014) eIF5A and cancer. In: Parsyan A (ed) Translation and cancer: applications in medicine. Springer, New York, pp 223–232

    Google Scholar 

  • Patel PH, Costa-Mattioli M, Schulze KL et al (2009) The Drosophila deoxyhypusine hydroxylase homologue nero and its target eIF5A are required for cell growth and the regulation of autophagy. J Cell Biol 185:1181–1194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Saini P, Eyler DE, Green R et al (2009) Hypusine-containing protein eIF5A promotes translation elongation. Nature (Lond) 459:118–121

    Article  CAS  Google Scholar 

  • Sasaki K, Abid MR, Miyazaki M (1996) Deoxyhypusine synthase gene is essential for cell viability in the yeast Saccharomyces cerevisiae. FEBS Lett 384:151–154

    Article  CAS  PubMed  Google Scholar 

  • Schnier J, Schwelberger HG, Smit-McBride Z et al (1991) Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol 11:3105–3114

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shi XP, Yin KC, Ahern J et al (1996) Effects of N 1-guanyl-1,7-diaminoheptane, an inhibitor of deoxyhypusine synthase, on the growth of tumorigenic cell lines in culture. Biochim Biophys Acta 1310:119–126

    Article  PubMed  Google Scholar 

  • Shiba T, Mizote H, Kaneko T et al (1971) Hypusine, a new amino acid occurring in bovine brain. Isolation and structural determination. Biochim Biophys Acta 244:523–531

    Article  CAS  PubMed  Google Scholar 

  • Ude S, Lassak J, Starosta AL et al (2013) Translation elongation factor EF-P alleviates ribosome stalling at polyproline stretches. Science 339:82–85

    Article  CAS  PubMed  Google Scholar 

  • Wang FW, Guan XY, Xie D (2013) Roles of eukaryotic initiation factor 5A2 in human cancer. Int J Biol Sci 9:1013–1020

    Article  PubMed Central  PubMed  Google Scholar 

  • Wolff EC, Kang KR, Kim YS et al (2007) Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification. Amino Acids 33:341–350

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhou H, Shen T, Luo Y et al (2010) The antitumor activity of the fungicide ciclopirox. Int J Cancer 127:2467–2477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Intramural Research Program of the NIH/NIDCR.

Author information

Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA

    Edith C. Wolff & Myung Hee Park

Authors
  1. Edith C. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myung Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myung Hee Park .

Editor information

Editors and Affiliations

  1. Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai-city, Miyagi, Japan

    Tomonobu Kusano

  2. Graduate School of Science and Technology, Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto, Japan

    Hideyuki Suzuki

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Japan

About this chapter

Cite this chapter

Wolff, E.C., Park, M.H. (2015). Role of the Polyamine Spermidine as a Precursor for Hypusine Modification in eIF5A. In: Kusano, T., Suzuki, H. (eds) Polyamines. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55212-3_10

Download citation

Publish with us

Policies and ethics

Search

Navigation