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• W2899762972 abstract "A critical function of spermidine is in the formation of hypusine, an essential post-translational modification of eukaryotic initiation factor eIF5A. In this issue of Structure, Afandor et al. (2018) determine the crystal structure of trypanosomal deoxyhypusine synthase, which shows that gene duplication and subsequent mutations provide significant differences from the mammalian equivalent exploitable for drug design. A critical function of spermidine is in the formation of hypusine, an essential post-translational modification of eukaryotic initiation factor eIF5A. In this issue of Structure, Afandor et al. (2018) determine the crystal structure of trypanosomal deoxyhypusine synthase, which shows that gene duplication and subsequent mutations provide significant differences from the mammalian equivalent exploitable for drug design. Polyamines are small basic molecules that bind to many cellular components including nucleic acids, membranes, and proteins. By virtue of these interactions, polyamines have a wide variety of cellular functions. The two polyamines present in mammals are spermidine and spermine. Spermidine is well established to be essential for the viability of eukaryotes. Inactivation of any one of the genes needed for its synthesis prevents development past the early embryonic stages. It has a unique feature, described below, its action as a precursor of hypusine. Spermine cannot take part in this reaction but performs many similar functions to spermidine with different potency. It is essential for normal growth and development in mammals. The phenotypes of Gyro mice and human patients with the X-linked genetic condition Snyder-Robinson syndrome, both lacking normal spermine synthase activity, show clearly that the correct spermine:spermidine ratio is critical (Pegg and Michael, 2010Pegg A.E. Michael A.J. Spermine synthase.Cell. Mol. Life Sci. 2010; 67: 113-121Crossref PubMed Scopus (106) Google Scholar). It is now 40 years since the discovery that polyamines are needed for mammalian cell growth. Reports that their synthesis and content were enhanced in proliferative diseases led to the search for inhibitors of polyamine synthesis, which might prove to be useful drugs (Pegg and McCann, 1982Pegg A.E. McCann P.P. Polyamine metabolism and function.Am. J. Physiol. 1982; 243: C212-C221Crossref PubMed Google Scholar). Although there are potent inactivators of every step in the polyamine biosynthesis pathway, by far the most widely studied of these inhibitors is DFMO (Eflornithine), a mechanism-based inactivator of ornithine decarboxylase (ODC) first described in 1978. Although at that time no structural information was available on the enzymes involved in polyamine metabolism, DFMO (and many other inhibitors) were conceived and synthesized by scientists in the Merrell Dow Research Institute directed by Al Sjoerdsma to provide potent inactivators based on known enzyme mechanisms. Studies with cultured tumor cells showed that DFMO was profoundly antiproliferative, but initial clinical trials in malignant diseases were not promising. More recently, some success has been achieved in clinical trials for some cancers such as malignant gliomas and neuroblastoma and for chemoprevention in patients at high risk for gastrointestinal cancer (Casero et al., 2018Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18: 681-695Crossref PubMed Scopus (320) Google Scholar). Despite the lack of success of DFMO for treating malignancies, studies showed that it was effective against African sleeping sickness caused by T. b. gambiense. It is an important part of the current treatments, particularly when combined with nifurtimox that generates reactive oxygen species (Kennedy, 2013Kennedy P.G. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness).Lancet Neurol. 2013; 12: 186-194Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar). This finding has led to increased interest in targeting the polyamine pathway for treatment of other forms of trypanosomiasis and other parasitic diseases including malaria, leshmaniasis, and Chagas disease. However, the studies have not yet advanced to major clinical trials. Several reasons for this include the opportunity to take up endogenous polyamines that are available to parasites that have intracellular locations, although it is likely that a major reason is the lack of highly species-specific compounds. It is not entirely clear why DFMO has profound anti-trypanosomal activity without significant toxicity. Host toxicity is minimized by the rapid turnover of the mammalian ODC protein providing rapid replacement of the inactivated enzyme and by the profound upregulation of both the polyamine biosynthetic pathway and the polyamine uptake system. Three possible contributing reasons for the sensitivity of trypanosomes are: (1) trypanosomal ODC is much more stable than the mammalian equivalent, (2) trypanosomes contain a unique molecule trypanothione which counteracts oxidative damage and is synthesized from spermidine, (3) the rapid changes in antigenic determinants that allow the parasite to escape the immune system may be slowed by the reduction in polyamine content. Currently structures of all of the key enzymes in polyamine metabolism in mammals are known and there are many structures from their parasite equivalents. The work of the Phillips laboratory including the current paper in Structure (Afanador et al., 2018Afanador G.A. Tomchick D.R. Phillips M.A. Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.Structure. 2018; 26 (this issue): 1499-1512Scopus (11) Google Scholar) provides real promise that there are exploitable differences and that parasite-specific inactivators can be produced. Polyamines play multiple important roles in a variety of critical cellular processes, but the absolute requirement for spermidine in many organisms appears to be due to its use in the synthesis of hypusine (Park and Wolff, 2018Park M.H. Wolff E.C. Hypusine, a polyamine-derived amino acid critical for eukaryotic translation.J. Biol. Chem. 2018; (Published online on September 26, 2018. jbc.TM118.003341)Crossref Scopus (76) Google Scholar). Hypusine is a post-translational modification of a specific lysine residue in the eukaryotic initiation factor eIF5A essential for different functions of this protein. eIF5A allows translocation at ribosome pausing sites including those involving polyproline sequences and it stimulates peptide release at some translation termination sites. Hypusine is produced by the sequential action of two enzymes. Deoxyhypusine synthase (DHS) catalyzes the conversion of a specific lysine residue in eIF5A to deoxyhypusine [Nε-4-aminobutyl(lysine)], which is subsequently hydroxylated to hypusine [Nε-4-amino-2-hydroxybutyl(lysine)]. This hydroxylation is needed for viability of mice, D. melanogaster, C. elegans, and T. brucei but not S. cerevisiae. DHS catalyzes a complex reaction that occurs in two stages: first, the NAD-dependent cleavage of spermidine to form an enzyme-butylimine intermediate and enzyme-bound NADH, and second, the transfer of the butylimine moiety to the eIF5A precursor and subsequent reduction by enzyme-bound NADH to form deoxyhypusine [Nε-4-aminobutyl(lysine)]. Mammalian DHS is a tetramer of four identical subunits having two active sites located at each of the dimer interfaces with critical residues contributed by both subunits (Umland et al., 2004Umland T.C. Wolff E.C. Park M.H. Davies D.R. 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. 2004; 279: 28697-28705Crossref PubMed Scopus (65) Google Scholar). Spermidine is anchored in the active site by interactions with three acidic residues. At present, the only available inhibitor of DHS is GC7 (N1-guanyl1,7-diaminoheptane), which binds tightly to the spermidine binding site. Its strict specificity toward DHS is not fully established, but this competitive inhibitor is effective against all DHS that have been tested. The potential value of selective prevention of the hypusine modification is quite clear and it may well be preferred to interference with polyamine synthesis since functions of polyamines are multifaceted. Trypanosomal DHS has been studied extensively in the Phillips laboratory. Their paper in this issue of Structure (Afanador et al., 2018Afanador G.A. Tomchick D.R. Phillips M.A. Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.Structure. 2018; 26 (this issue): 1499-1512Scopus (11) Google Scholar) describing the sub-unit composition, structure, and mechanism of action of the enzyme has several interesting features, including the potential implication of this enzyme as an approachable target for drug design. The trypanosomal DHS is a heterotetramer formed by proteins from two separate but related genes. One of these encodes a catalytically impaired enzyme and the other a totally inactive paralog termed a prozyme, which is required to activate the former. The overall structure has similarities to the mammalian DHS but exists as two heterodimers. Each heterodimer contains a shared active site with one catalytic active site and one inactive site at the dimer interface. The functional site contains the essential catalytic lysine residue and a bound NAD+. The other site is inactive due to alteration of many key residues including this lysine but does also contain NAD+. The alteration of many residues derived from the inactive paralog that are involved in the active site provides an opportunity to produce inhibitors which would selectively inactivate the parasite DHS. A high through put screen for new inhibitors of DHS has been previously described (Park and Wolff, 2018Park M.H. Wolff E.C. Hypusine, a polyamine-derived amino acid critical for eukaryotic translation.J. Biol. Chem. 2018; (Published online on September 26, 2018. jbc.TM118.003341)Crossref Scopus (76) Google Scholar). The comparative use of such an assay to screen available libraries with the trypanosomal and human DHS enzymes should identify useful leads for such inhibitors This work by Philips and colleagues (Afanador et al., 2018Afanador G.A. Tomchick D.R. Phillips M.A. Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.Structure. 2018; 26 (this issue): 1499-1512Scopus (11) Google Scholar) provides another interesting example of a pseudoenzyme, lacking key catalytic residues, regulating the catalytic activity of the parent enzyme. These paralogs clearly arise from gene duplications. This is the second example of such gene duplication in the trypanosomal polyamine pathway discovered by the Phillips laboratory. The authors have previously shown that S-adenosylmethionine decarboxylase (AdoMetDC) also requires such activation (Willert et al., 2007Willert E.K. Fitzpatrick R. Phillips M.A. Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog.Proc. Natl. Acad. Sci. USA. 2007; 104: 8275-8280Crossref PubMed Scopus (70) Google Scholar). In this case, the gene that encodes the “active” protein produces a protein with minimal enzyme activity, but this activity is increased more than 1000-fold when it is dimerized with the catalytically inactive proenzyme. AdoMetdDCs require a covalently bound pyruvate co-factor, which is formed from an internal serine residue by an autocatalytic process, producing the α and β chains of the protein with the pyruvate at the N terminus of the α chain (Pegg, 2009Pegg A.E. S-Adenosylmethionine decarboxylase.Essays Biochem. 2009; 46: 25-45Crossref PubMed Google Scholar). The human AdoMetDC is an (αβ)2 dimer with two active sites whereas in the trypanosomal equivalent, the prozyme does not undergo this cleavage and the enzyme is an (αβ)prozyme heterodimer with one active site. This heterodimerization prevents inhibition by a sequence located in the N-terminal region. It is an interesting speculation that such gene duplications may lead to many regulatory functions in multiple pathways. With regard to polyamine metabolism, it is remarkable that human spermine synthase has an N-terminal domain with a structure that is very similar to AdoMetDC (Wu et al., 2008Wu H. Min J. Zeng H. McCloskey D.E. Ikeguchi Y. Loppnau P. Michael A.J. Pegg A.E. Plotnikov A.N. Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism.J. Biol. Chem. 2008; 283: 16135-16146Crossref PubMed Scopus (83) Google Scholar). This domain is absent in spermidine synthase, which has a C-terminal active site domain with many features in common with spermine synthase. It may have some significance in regulating polyamine content in those species that have spermine synthase. The importance of understanding the detailed structure of key enzymes that may prove useful targets for the synthesis of novel species-specific drugs is clearly illustrated by the work described in this issue of Structure (Afanador et al., 2018Afanador G.A. Tomchick D.R. Phillips M.A. Trypanosomatid Deoxyhypusine Synthase Activity Is Dependent on Shared Active-Site Complementation between Pseudoenzyme Paralogs.Structure. 2018; 26 (this issue): 1499-1512Scopus (11) Google Scholar). The possibility that such pseudoenzymes related to the polyamine biosynthetic pathway may also play important regulatory roles raised by this work deserves further experimental investigation." @default.
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• W2899762972 title "Unique Characteristics of the Parasite Polyamine Pathway" @default.
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