Skip to main content
SpringerLink
Log in

The polyamine-derived amino acid hypusine: its post-translational formation in eIF-5A and its role in cell proliferation

  • Minireview Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Summary

The unusual amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is a unique component of one cellular protein, eukaryotic translation initiation factor 5A (eIF-5A, old terminology, eIF-4D). It is formed posttranslationally and exclusively in this protein in two consecutive enzymatic reactions, (i) modification of a single lysine residue of the eIF-5A precursor protein by the transfer of the 4-aminobutyl moiety of the polyamine spermidine to itsε-amino group to form the intermediate, deoxyhypusine [Nε-(4-aminobutyl)lysine] and (ii) subsequent hydroxylation of this intermediate to form hypusine. The amino acid sequences surrounding the hypusine residue are strictly conserved in all eukaryotic species examined, suggesting the fundamental importance of this amino acid throughout evolution. Hypusine is required for the activity of eIF-5Ain vitro. There is strong evidence that hypusine and eIF-5A are vital for eukaryotic cell proliferation. Inactivation of both of the eIF-5A genes is lethal in yeast and the hypusine modification appears to be a requirement for yeast survival (Schnier et al., 1991 [Mol Cell Biol 11: 3105–3114]; Wöhl et al., 1993 [Mol Gen Genet 241: 305–311]). Furthermore, inhibitors of either of the hypusine biosynthetic enzymes, deoxyhypusine synthase or deoxyhypusine hydroxylase, exert strong anti-proliferative effects in mammalian cells, including many human cancer cell lines. These inhibitors hold potential as a new class of anticancer agents, targeting one specific eukaryotic cellular reaction, hypusine biosynthesis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbruzzese A, Park MH, Folk JE (1986) Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J Biol Chem 261: 3085–3089

    Google Scholar 

  • Abbruzzese A, Hanauske-Abel HM, Park MH, Henke S, Folk JE (1991) The active site of deoxyhypusyl hydroxylase: use of catechol peptides and their component chelator and peptide moieties as molecular probes. Biochim Biophys Acta 1077: 159–166

    Google Scholar 

  • Bevec D, Klier H, Holter W, Tschachler E, Valent P, Lottspeich F, Baumruker T, Hauber J (1994) Induced gene expression of the hypusine-containing protein eukaryotic initiation factor 5A in activated human T lymphocytes. Proc Natl Acad Sci USA 91: 10829–10833

    Google Scholar 

  • Byers TL, Ganem B, Pegg AE (1992) Cytostasis induced in L1210 murine leukemia cells by the S-adenosyl-L-methionine decarboxylase inhibitor, Biochem J 287: 717–724

    Google Scholar 

  • Chen, K-Y, Dou Q-P (1988) NAD+ stimulated the spermidine-dependent hypusine formation on the 18-kDa protein in cytosolic lysates derived from NB-15 mouse neuroblastoma cells. FEBS Letters 229: 325–328

    Google Scholar 

  • Cooper HL, Park MH, Folk JE (1982) Post-translational formation of hypusine in a single major protein occurs generally in growing cells and is associated with activation of lymphocyte growth. Cell 29: 791–797

    Google Scholar 

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

    Google Scholar 

  • Duncan RF, Hershey JWB (1986) Changes in eIF-4D hypusine modification or abundance are not correlated with translational repression in HeLa cells. J Biol Chem 261: 12903–12906

    Google Scholar 

  • Hanauske-Abel HM, Park MH, Hanauske A-R, Popowicz AM, Lalande M, Folk JE (1994) Inhibition of the G1/S of the cell cycle by inhibitors of deoxyhypusine hydroxylation. Biochim Biophys Acta 1221: 115–124

    Google Scholar 

  • Hölttä E, Pohjanpelto P, Jänne J (1979) Dissociation of the early antiproliferative action of methylglyoxal bis(guanylhydrazone) from polyamine depletion. A comparison of the effects of DL-alpha-difluoromethyl ornithinine and methylglyoxal bis(guanylhydrazone) on the growth of human fibroblasts. FEBS Lett 97: 9–14

    Google Scholar 

  • Imaoka N, Nakaijima T (1973) Hypusine, N6-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid, in tissue proteins of mammals. Biochim Biophys Acta 320: 97–103

    Google Scholar 

  • Jakus J, Wolff EC, Park MH, Folk JE (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

    Google Scholar 

  • Joe YA, Park MH (1994) Structural features of the eIF-5A precursor required for posttranslational synthesis of deoxyhypusine. J Biol Chem 269: 25916–25921

    Google Scholar 

  • Joe YA, Wolff EC, Park MH (1995) Cloning and expresssion of human deoxyhypusine synthase cDNA: structure-function studies with the recombinant enzyme and mutant proteins. J Biol Chem 270: 22386–22392

    Google Scholar 

  • Kang HA, Hershey JWB (1994) Effect of initiation factor eIF-5A depletion on protein synthesis and proliferation of Saccharomyces cerevisiae. J Biol Chem 269: 3934–3940

    Google Scholar 

  • Kang KR, Wolff EC, Park MH, Folk JE, Chung SI (1995) Identification of YHR068w in Saccharomyces cerevisiae chromosome VIII as a gene for deoxyhypusine synthase: expression and characterization of the enzyme. J Biol Chem 270: 18408–18412

    Google Scholar 

  • Kemper WM, Berry KW, Merrick WC (1976) Purification and properties of rabbit reticulocyte protein synthesis initiation factors M2Bα and M2Bβ. J Biol Chem 251: 5551–5557

    Google Scholar 

  • Klier H, Csonga R, Steinkasser A, Wöhl T, Lottspeich F, Eder J (1995) Purification and characterization of human deoxyhypusine synthase from HeLa cells. FEBS Lett 364: 207–210

    Google Scholar 

  • Lee YB, Park MH, Folk JE (1995) Diamine and triamine analogs and derivatives as inhibitors of deoxyhypusine synthase: synthesis and biological activity. J Med Chem 38: 3053–3061

    Google Scholar 

  • Lee YB, Joe YA, Park MH (1996) Inhibitors of hypusine biosynthesis: potential anticancer agents. J Biomedical Res (in press)

  • Murphey RJ, Gerner EW (1987) Hypusine formation in protein by a two-step process in cell lysates. J Biol Chem 262: 15033–15036

    Google Scholar 

  • Nakajima T, Matsubayashi T, Kakimoto Y, Sano I (1971) Distribution of hypusine, N6-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid, in mammalian organs. Biochim Biophys Acta 252: 92–97

    Google Scholar 

  • NC-IUB [Nomenclature Committee, IUB], Safer B (1989) Nomenclature of initiation, elongation and termination factors for translation in eukaryotes. Recommendations 1988. Eur J Biochem 186: 1–3

    Google Scholar 

  • Park MH (1987) Regulation of biosynthesis of hypusine in Chinese hamster ovary cells. Evidence for eIF-4D precursor polypeptides. J Biol Chem 262: 12730–12734

    Google Scholar 

  • Park MH (1989) The essential role of hypusine in eukaryotic translation initiation factor 4D (eIF-4D). Purification of eIF-4D and its precursors and comparison of their activities. J Biol Chem 264: 18531–18535

    Google Scholar 

  • Park MH, Folk JE (1986) Biosynthetic labeling of hypusine in mammalian cells. Carbonhydrogen bond fissions revealed by dual labeling. J Biol Chem 261: 14108–14111

    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

    Google Scholar 

  • Park MH, Cooper HL, Folk JE (1982) The biosynthesis of protein-bound hypusine [Nε-(4-anmino-2-hydroxybutyl)-lysine]. lysine as the amino acid precursor and the intermediate role of deoxyhypusine [Nε-(4-aminobutyl)lysine]. J Biol Chem 257: 7217–7222

    Google Scholar 

  • Park MH, Chung SI, Cooper HL, Folk JE (1984a) The mammalian hypusine-containing protein, eukaryotic initiation factor 4D. Stuctural homology of this protein from several species. J Biol Chem 259: 4563–4565

    Google Scholar 

  • Park MH, Liberato DJ, Yergey AL, Folk JE (1984b) The biosynthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. Alignment of the butylamine segment and source of the secondary amino nitrogen. J Biol Chem 259: 12123–12127

    Google Scholar 

  • Park MH, Wolff EC, Smit-McBride Z, Hershey JWB, Folk JE (1991) Comparison of the activities of variant forms of eIF-4D. The requirement for hypusine or deoxyhypusine. J Biol Chem 266: 7988–7994

    Google Scholar 

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

    Google Scholar 

  • Park MH, Wolff EC, Folk JE (1993b) Is hypusine essential for eukaryotic cell proliferation? Trends Biochem Sci 18: 475–479

    Google Scholar 

  • Park MH, Wolff EC, Lee YB, Folk JE (1994) Antiproliferative effects of inhibitors of deoxyhypusine synthase: inhibition of growth of CHO cells by guanyl diaminess. J Biol Chem 269: 27827–27832

    Google Scholar 

  • Paz MA, Torrelio BM, Gallop PM (1984) Hydralazine inhibition of the posttranslational hydroxylation of deoxyhypusine, a polyamine-derived amino acid. Biochem Pharmacol 33: 779–785

    Google Scholar 

  • Pegg AE (1988) Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res 48: 759–774

    Google Scholar 

  • Ruhl M, Himmelspach M, Bahr GM, Hammerschmid F, Jaksche H, Wolff B, Aschauer H, Farrington GK, Probst H, Bevec D, Hauber J (1993) Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation. J Cell Biol 123: 1309–1320

    Google Scholar 

  • Sano A, Kotani K, Kakimoto Y (1986) Isolation and identification of 2-(γ-aminobutyryl) hypusine. J Neurochem 46: 1046–1049

    Google Scholar 

  • Schnier J, Schwelberger H, Smit-McBride Z, Kang HA, Hershey JWB (1991) Translation initiation factor 5A and its hypusine modification are essential for cell viability in yeast. Mol Cell Biol 11: 3105–3114

    Google Scholar 

  • Schreier MH, Erni B, Staehelin T (1977) Initiation of mammalian protein synthesis. Purification and characterization of seven initiation factors. J Mol Biol 116: 727–753

    Google Scholar 

  • Schümann H, Klink F (1989) Archaebacterial protein contains hypusine, a unique amino acid characteristic for eukaryotic translation initiation factor 4D. System Appl Microbiol 11: 103–107

    Google Scholar 

  • Shiba T, Mizote H, Kaneko T, Nakajima T, Kakimoto Y, Sano I (1971) Hypusine, a new amino acid occuring in bovine brain. Isolation and structural determination. Biochim Biophys Acta 244: 523–531

    Google Scholar 

  • Shiba T, Akiyama H, Umeda I, Okada S, Wakamiya T (1982) Synthesis and stereochemistry of hypusine, a new amino acid. Bull Chem Soc Jpn 55: 899–903

    Google Scholar 

  • Smit-McBride Z, Dever TE, Hershey JWB, Merrick WC (1989) Sequence determination and cDNA cloning of eukaryotic initiation factor 4D, the hypusine-containing protein. J Biol Chem 264: 1578–1583

    Google Scholar 

  • Smit-McBride Z, Schnier J, Kaufman RJ, Hershey JWB (1989) Protein synthesis initiation factor eIF-4D. Functional comparison of native and unhypusinated forms of the protein. J Biol Chem 264: 18527–18530

    Google Scholar 

  • Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53: 749–790

    Google Scholar 

  • Tao Y, Chen KY (1995) Purification of deoxyhypusine synthase from Neurospora crassa to homogeneity by substrate elution affinity chromatography. J Biol Chem 270: 383–386

    Google Scholar 

  • Ueno S, Kotani K, Sano A, Kakimoto Y (1991) Isolation and identification of 2-(β-alanyl)hypusine from bovine brain. Biochim Biophys Acta 1073: 233–235

    Google Scholar 

  • Wöhl T, Klier H, Ammer H, Lottspeich F, Magdolen V (1993) The HYP2 gene of Saccharomyces cerevisiae is essential for aerobic growth: characterization of different isoforms of the hypusine-containing protein Hyp2p and analysis of gene disruption mutants. Mol Gen Genet 241: 305–311

    Google Scholar 

  • Wolff EC, Park MH, Folk JE (1990) Cleavage of spermidine as the first step in deoxyhypusine synthesis. The role of NAD+. J Biol Chem 265: 4793–4799

    Google Scholar 

  • Wolff EC, Lee YB, Chung SI, Folk JE, Park MH (1995) Deoxyhypusine synthase from rat testis: purification and characterization. J Biol Chem 270: 8660–8666

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Cellular Development and Oncology, National Institute of Dental Research, National Institutes of Health, Bldg. 30, Rm 211, NIDR, NIH, 20892-4330, Bethesda, Maryland, USA

    Myung Hee Park, Young Ae Joe, Kee Ryeon Kang, Young Bok Lee & Edith C. Wolff

Authors
  1. Myung Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Ae Joe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kee Ryeon Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young Bok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edith C. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, M.H., Joe, Y.A., Kang, K.R. et al. The polyamine-derived amino acid hypusine: its post-translational formation in eIF-5A and its role in cell proliferation. Amino Acids 10, 109–121 (1996). https://doi.org/10.1007/BF00806584

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00806584

Keywords

Search

Navigation