Deoxyhypusine synthase

MOLL, S., ANKE, S., KAHMANN, U., HANSCH, R., HARTMANN, T., OBER, D., Cell-specific expression of homospermidine synthase, the entry enzyme of the pyrrolizidine alkaloid pathway in Senecio vemalis, in comparison with its ancestor, deoxyhypusine synthase. Plant Physiol, 2002,130,47-57. 

OBER, D., HARTMANN, T., Homospermidine synthase, the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, evolved from deoxyhypusine synthase. Proc. Natl. Acad. Sci. U. S. A., 1999,96, 14777-14782. 

PARK, M.H., JOE, Y.A., KANG, K.R., Deoxyhypusine synthase activity is essential for cell viability in the yeast Saccharomyces cerevisiae. J. Biol. Chem., 1998,273, 1677-1683. 

OBER, D., HARTMANN, T., Deoxyhypusine synthase from tobacco cDNA isolation, characterization, and bacterial expression of an enzyme with extended substrate specificity. J. Biol. Chem., 1999,274, 32040-32047. 

OBER, D., GIBAS, L., WITTE, L., HARTMANN, T., Universal occurrence of homospermidine in plants and its supposed origin as by-product of deoxyhypusine synthase. Phytochemistry, 2003, 62, 339-344. 

Figure 5.27 The role of homospermidine synthase (HSS) in pyrrolizidine alkaloid biosynthesis and deoxyhypusine synthase (DHS) in the activation of the eukaryotic initiation factor 5A (eIF5A).

The relationship between deoxyhypusine synthase and homospermidine synthase becomes also evident by a comparison of their reactions. Deoxyhypusine synthase transfers the aminobutyl moiety of spermidine to the e-amino group of a single specific lysine residue in the elF-5A (Fig. 18). Homospermidine synthase catalyzes exactly the same reaction but uses putrescine instead of the elF-5A as acceptor for the aminobutyl moiety (Fig. 18). AH other mechanistic... 

Fig. 18. Homospermidine synthase (A) and deoxyhypusine synthase (B) catalyze analogous reactions. The two enzymes transfer an aminobutyl moiety from spermidine to a primary amino group of putrescine and a proteinous lysyl residue of a protein, respectively...

Fig. 19. Alignment of homospermidine synthase (HSS) amino acid sequence from Senecio ver-nalis (Sv) in comparison to deoxyhypusine synthase amino acid sequences from six different species. Sv, Senecio vernalis Nt, Nicotiana tabacumi Hs, Homo sapiens Sc, Saccharomyces cerevisiae Nc, Neurospora crassa Mj, Methanococcus jannaschii. Black boxes denote identical amino acid residues in all seven sequences, framed boxes conservative replacement...

Chawla B, Jhingran A, Singh S et al (2010) Identification and characterization of a novel deoxyhypusine synthase in Leishmania donovani. J Biol Chem 285 453-463... 

Ober D, Gibas L, Witte L, Hartmann T (2003) Evidence for general occurrence of homospermidine in plants and its supposed origin of deoxyhypusine synthase. Phytochemistry 62 339-344 Orechoff A (1929) The alkaloids of Anabasis aphylla. C R Acad Sci 189 945 Orechoff A, Konowalowa R (1933) Uber die Alkaloide von Convolvulus pseudocantabricus ScHRENK. (l.Mitt.) Arch Pharm 271 145-148... 

HSS exhibits strong sequence similarity to deoxyhypusine synthase (DHS), a ubiquitous enzyme responsible for the activation of eukaryotic initiation factor 5A (elFSA) (Ober and Hartmann 1999). DHS catalyses the transfer of an aminobutyl moiety from spermidine to a lysine residue of elFSA. In contrast, HSS does not accept elFSA as a substrate. However, HSS and DHS both catalyse the formation of homospermidine by the aminobutylation of putrescine, although this reaction is rarely catalysed by DHS in vivo. HSS is thought to have evolved from DHS after duplication of the single-copy dhs gene. The product lost the ability to bind and react with elFSA but retained HSS activity. HSS is a well-documented example of the evolutionary recruitment of a primary metabolic enzyme into a secondary metabolic pathway. 

Ober, D., Harms, R., Witte, L. et al. (2003) Molecular evolution by change of function. Alkaloid-specific homospermidine synthase retained aU properties of deoxyhypusine synthase except binding the elF5A precursor protein. /. Biol Chem., 278, 12805-12812. 

The biosynthesis of hypusine (Scheme 10.1) is catalyzed by two specific enzymes, deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) (Park 2006 Wolff et al. 2007). DHS catalyzes an NAD-dependent cleavage of spermidine with the transfer of its 4-aminobutyl moiety to the terminal N of a specific lysine of elF5A (Lys 50 in human, Lys 51 in yeast) to form an intermediate, deoxyhypusine residue. Importantly, neither putrescine nor spermine can substitute for spermidine as a substrate, emphasizing the critical role of spermidine in cell growth. 

Ishfaq M, Maeta K, Maeda S et al (2012) Acetylation regulates subcellular localization of eukaryotic translation initiation factor 5A (elF5A). FEBS Lett 586 3236-3241 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 JasiuUonis MG, Luchessi AD, Moteira AG et al (2007) Inhibition of eukaryotic translation initiation factor 5A (elF5A) hypusination imptiirs melanoma growth. Cell Biochem Fund 25 109-114... 

Nishimura K, Lee SB, Park JH et al (2012) Essential role of eIE5A-l and deoxyhypusine synthase in mouse embryonic development. Amino Acids 42 703-710 Park MH (2006) The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (elF5A). J Biochem 139 161-169 Park MH, Cooper HL, Polk JE (1981) Identification of hypusine, an unusual amino add, in a protein from human lymphocytes and of spermidine as its biosynthetic precursor. Proc Natl Acad Sci USA 78 2869-2873... 

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

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