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Review
. 2007 Aug;33(2):341-50.
doi: 10.1007/s00726-007-0525-0. Epub 2007 May 4.

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

E C Wolff  1 , K R Kang, Y S Kim, M H Park
Affiliations
Review

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

E C Wolff et al. Amino Acids. 2007 Aug.

Abstract

A naturally occurring unusual amino acid, hypusine [N (epsilon)-(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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Figures

Fig. 1
Fig. 1
Model structure of eIF5A (A) and the hypusine synthesis pathway (B). eIF5A is comprised of two domains with β-sheet structures (based on Facchiano et al., 2001). Domain I (N-terminal domain) and II (C-terminal domain) are connected by a hinge (around Pro82 for the human protein). Hypusine synthesis occurs at one specific lysine residue (Lys50 for human protein) located on an exposed loop of the N-terminal domain. Side chain structures of lysine, deoxyhypusine and hypusine are shown. Deoxyhypusine synthase (DHS) reaction is reversible, whereas the deoxyhypusine hydroxylase (DOHH) reaction is not
Fig. 2
Fig. 2
Amino acid sequence conservation of eIF5A, DHS and DOHH in eukaryotes. In each case (eIF5A-1, DHS and DOHH), the human sequence is shown. The degree of conservation is indicated by color coding: red, 100% identity; dark orange to yellow, conservative replacements (e.g. F, Y; D, E; K, R, L, V, I, M; T, S; A, G, C, S) with >80 to >50% sequence identity; white, no significant sequence identity. The diagram is based on eukaryotic sequences (40 for eIF5A, 36 for DHS and 14 for DOHH) chosen from a range of eukaryotic phyla and species. Critical amino acids for binding of substrates are shown by symbols under the residues
Fig. 3
Fig. 3
Proposed mode of spermidine binding at the active site of human deoxyhypusine synthase. The amino acid residues of the spermidine binding site of human DHS are shown. Upon NAD-dependent dehydrogenation of spermidine between the secondary nitrogen and carbon 5, the butylimine moiety is transferred to the ε-amino group of Lys329 to form a covalent enzyme intermediate. Subsequently, the butylimine moiety is transferred from the enzyme intermediate to the substrate protein. Spermidine is predicted to be anchored at its terminal amino groups by the acidic amino acids, Glu323, Asp316, and Asp243. Hydrophobic amino acid Trp327 is presumed to interact with the methylene chain of spermidine. The diagram was constructed based on the crystal structures of human DHS and is consistent with the results of mechanism and site-directed mutagenesis studies. Modified from Lee et al. (2001)
Fig. 4
Fig. 4
Structural requirements for eIF5A polypeptides as substrates for DHS and DOHH. Truncated polypeptides of eIF5A(Lys) and eI-F5A(Dhp) were used as substrates for DHS (Joe and Park, 1994) and DOHH (Kang et al., 2007), respectively. The relative effectiveness of truncated peptides as substrates, in comparison to the intact protein (1–154), is indicated as + + ++, + + +, ++, +, or −, where − denotes little or no substrate activity. nd Not determined
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References

    1. Abbruzzese A, Park MH, Folk JE. Deoxyhypusine hydroxylase from rat testis: partial purification and characterization. J Biol Chem. 1986;261:3085–3089. - PubMed
    1. Bartig D, Schumann H, Klink F. The unique posttranslational modification leading to deoxyhypusine or hypusine is a general feature of the archebacterial kingdom. System Appl Microbiol. 1990;13:112–116.
    1. Brochier C, Lopez-Garcia P, Moreira D. Horizontal gene transfer and archaeal origin of deoxyhypusine synthase homologous genes in bacteria. Gene. 2004;330:169–176. - PubMed
    1. Byers TL, Ganem B, Pegg AE. 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. 1992;287:717–724. - PMC - PubMed
    1. Byers TL, Lakanen JR, Coward JK, Pegg AE. The role of hypusine depletion in cytostasis induced by S-adenosyl-L-methionine decarboxylase inhibition: new evidence provided by L-methylspermidine and 1,12-dimethylspermine. Biochem J. 1994;303:363–368. - PMC - PubMed

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