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Assessment of deoxyhypusine hydroxylase as a putative, novel drug target

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Abstract

Antimalarial drug resistance has nowadays reached each drug class on the market for longer than 10 years. The focus on validated, classical targets has severe drawbacks. If resistance is arising or already present in the field, a target-based High-Throughput-Screening (HTS) with the respective target involves the risk of identifying compounds to which field populations are also resistant. Thus, it appears that a rewarding albeit demanding challenge for target-based drug discovery is to identify novel drug targets. In the search for new targets for antimalarials, we have investigated the biosynthesis of hypusine, present in eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine hydroxylase (DOHH), which has recently been cloned and expressed from P. falciparum, completes the modification of eIF5A through hydroxylation. Here, we assess the present druggable data on Plasmodium DOHH and its human counterpart. Plasmodium DOHH arose from a cyanobacterial phycobilin lyase by loss of function. It has a low FASTA score of 27 to its human counterpart. The HEAT-like repeats present in the parasite DOHH differ in number and amino acid identity from its human ortholog and might be of considerable interest for inhibitor design.

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Abbreviations

DHS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

eIF5A:

Eukaryotic initiation factor 5A

HUVEC:

Human vascular endothelial cells

OPA:

Ortho-phtaldialdehyde

SDS–PAGE:

Sodium dodecylsulfate

DEAE FF:

Diethylaminoethyl cellulose fast flow

GC/MS:

Gas chromatography/mass spectrometry

SCRATCH:

A protein structure and structural feature prediction server

HEAT:

Huntingtin protein, elongation factor 3, the protein phosphatase subunit 2A and the target of rapamycin

References

  • Abbruzzese A (1988) Developmental pattern for deoxyhypusine hydroxylase in rat brain. J Neurochem 50:695–699

    Article  CAS  PubMed  Google Scholar 

  • Abbruzzese A, Park MH, Folk JE (1985) Deoxyhypusine hydroxylase from rat testis. J Biol Chem 261:3085–3089

    Google Scholar 

  • Andrus L, Szabo P, Grady RW, Hanauske RW, Hanauske AR, Huima-Byron T, Slowinska B, Zagulska S, Hanauske-Abel HM (1998) Antiretroviral effects of deoxyhypusine hydroxylase inhibitors: a hypusine-dependent host cell mechanism for replication of human immunodeficiency virus type 1 (HIV-1). Biochem Pharmacol 55:1807–1818

    Article  CAS  PubMed  Google Scholar 

  • Beninati S, Abbruzzese A, Folk JE (1990) High-performance liquid chromatographic method for determination of hypusine and deoxyhypusine. Anal Biochem 184:16–20

    Article  CAS  PubMed  Google Scholar 

  • Clement HM, Hanauske-Abel HM, Wolff EC, Kleinman HK, Park MH (2003) The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Cancer 106:458–459

    Article  Google Scholar 

  • Cuff JA, Clamp ME, Siddiqui AS, Finlay M, Barton GJ (1998) JPred: a consensus secondary structure prediction server. Bioinformatics 14:892–893

    Article  CAS  PubMed  Google Scholar 

  • Duguay J, Jamal S, Liu Z, Wang TW, Thompson JE (2007) Leaf-specific suppression of deoxyhypusine synthase in Arabidopsis thaliana enhances growth without negative pleiotropic effects. J Plant Physiol 164:408–420

    Article  CAS  PubMed  Google Scholar 

  • Frommholz F, Kusch P, Blavid R, Scheer H, Tu JM, Marcus K, Zhao KH, Atemnkeng V, Marciniak J, Kaiser AE (2009) Completing the hypusine pathway in Plasmodium: deoxyhypusine hydroxylase is an E-Z-HEAT repeat protein. FEBS J 276:5881–5891. doi:10.1111/j.1742-4658.2009.07272.x

    Article  CAS  PubMed  Google Scholar 

  • Goebel T, Ulmer D, Projahn H, Kloeckner J, Heller E, Glaser M, Ponte-Sucre A, Specht SR, Hoerauf A, Hauber I, Hauber J, Holzgrabe U (2008) In search of novel agents for therapy of tropical diseases and human immunodeficiency virus. J Med Chem 51:238–250

    Article  CAS  PubMed  Google Scholar 

  • Gregio AP, Cano VP, Avaca JS, Valentini SR, Zanelli CF (2009) EIF5A has a function in the elongation step of translation in yeast. Biochem Biophys Res Commun 20:785–790

    Article  Google Scholar 

  • Hanauske-Abel HM, Park MH, Hanauske AR, Popowicz AM, Lalande M, Folk JE (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 

  • Huang JK, Cui Y, Chen CH, Clampitt D, Lin CT, Wen L (2007) Molecular cloning and functional expression of bovine deoxyhypusine hydroxylase cDNA and homologs. Protein Expr Purif 54:126–133

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kaiser A, Gottwald A, Maier W, Seitz HM (2003) Targeting enzymes involved in spermidine metabolism of parasitic protozoa—a possible, new strategy for antiparasitic treatment. Parasitol Res 91:508–516

    Article  CAS  PubMed  Google Scholar 

  • Kaiser A, Hammels I, Gottwald A, Nassar M, Zaghloul MS, Motaal BA, Hauber J, Hoerauf A (2007) Modification of eukaryotic initiation factor 5A from Plasmodium vivax by a truncated deoxyhypusine synthase from Plasmodium falciparum: an enzyme with dual enzymatic properties. Biorg Med Chem 15:6200–6207

    Article  CAS  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

    Article  CAS  PubMed  Google Scholar 

  • Kim YS, Kang KR, Wolff EC, Bell JK, McPhie P, Park MH (2006) Deoxyhypusine hydroxylase is an Fe(II)-Heat-repeat enzyme. J Biol Chem 281:13217–13225

    Article  CAS  PubMed  Google Scholar 

  • Liao DI, Wolff EC, Park MH, Davies DR (1998) Crystal structure of the NAD complex of human deoxyhypusine synthase: an enzyme with a ball-and chain-mechanism for blocking the active site. Structure 15:23–32

    Article  Google Scholar 

  • Maréchal E, Cesbron-Delauw MF (2001) The apicoplast: a new member of the plastid family. Trends Plant Sci 6:200–205

    Article  PubMed  Google Scholar 

  • Ober D, Hartmann T (1999) Deoxyhypusine synthase from tobacco, cDNA isolation, characterization and bacterial expression of an enzyme with extended substrate specificity. J Biol Chem 274:32040–32047

    Article  CAS  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  Google Scholar 

  • Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH (2006) Molecular cloning, expression and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci U S A 103:51–56

    Article  CAS  PubMed  Google Scholar 

  • Patel PH, Costa-Mattioli M, Schulze KL, Bellen HJ (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  Google Scholar 

  • Saeftel M, Sarite RS, Njuguna T, Holzgrabe U, Ulmer D, Hoerauf A, Kaiser A (2006) Piperidones with activity against Plasmodium falciparum. Parasitol Res 99:281–286

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Scheer H, Zhao KH (2008) Biliprotein maturation: the chromophore attachment. Mol Microbiol 68:263–276

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Thompson GM, Cano VS (2003) Mapping of eIF5A binding sites for Dys 1 and Lia1: in vivo evidence for regulation of eIF5A hypusination. FEBS Lett 553:464–468

    Article  Google Scholar 

  • Umland TC, Wolff EC, Park MH, Davies DR (2004) A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme NAD inhibitor ternary complex. J Biol Chem 279:28697–28705

    Article  CAS  PubMed  Google Scholar 

  • Wang TW, Zhang CG, Wu W, Nowack LM, Madey E, Thompson JE (2005) Antisense suppression of deoxyhypusine synthase in tomato delays fruit softening and alters growth and development. Plant Physiol 138:1372–1382

    Article  CAS  PubMed  Google Scholar 

  • Weir BA, Yaffe MP (2004) Mmd1p, a novel, conserved protein essential for normal mitochondrial morphology and distribution in the fission yeast Schizosaccharomyces pombe. Mol Biol of the Cell 15:1656–1665

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. University of Applied Sciences Bonn-Rhein-Sieg, Von Liebig Strasse 20, 53359, Rheinbach, Germany

    B. Kerscher & E. Nzukou

  2. University of Applied Sciences Cologne, Betzdorfer Str. 2, 50679, Cologne, Germany

    A. Kaiser

Authors
  1. B. Kerscher
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  2. E. Nzukou
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  3. A. Kaiser
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Correspondence to A. Kaiser.

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Kerscher, B., Nzukou, E. & Kaiser, A. Assessment of deoxyhypusine hydroxylase as a putative, novel drug target. Amino Acids 38, 471–477 (2010). https://doi.org/10.1007/s00726-009-0406-9

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  • DOI: https://doi.org/10.1007/s00726-009-0406-9

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