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• W2897069969 abstract "Polyamines are polycationic organic amines that are required for all eukaryotic life, exemplified by the polyamine spermidine, which plays an essential role in translation. They also play more specialized roles that differ across species, and their chemical versatility has been fully exploited during the evolution of protozoan pathogens. These eukaryotic pathogens, which cause some of the most globally widespread infectious diseases, have acquired species-specific polyamine-derived metabolites with essential cellular functions and have evolved unique mechanisms that regulate their core polyamine biosynthetic pathways. Many of these parasitic species have lost enzymes and or transporters from the polyamine metabolic pathway that are found in the human host. These pathway differences have prompted drug discovery efforts to target the parasite polyamine pathways, and indeed, the only clinically approved drug targeting the polyamine biosynthetic pathway is used to manage human African trypanosomiasis. This Minireview will primarily focus on polyamine metabolism and function in Trypanosoma, Leishmania, and Plasmodium species, which are the causative agents of human African trypanosomiasis (HAT) and Chagas disease, Leishmaniasis, and malaria, respectively. Aspects of polyamine metabolism across a diverse group of protozoan pathogens will also be explored. Polyamines are polycationic organic amines that are required for all eukaryotic life, exemplified by the polyamine spermidine, which plays an essential role in translation. They also play more specialized roles that differ across species, and their chemical versatility has been fully exploited during the evolution of protozoan pathogens. These eukaryotic pathogens, which cause some of the most globally widespread infectious diseases, have acquired species-specific polyamine-derived metabolites with essential cellular functions and have evolved unique mechanisms that regulate their core polyamine biosynthetic pathways. Many of these parasitic species have lost enzymes and or transporters from the polyamine metabolic pathway that are found in the human host. These pathway differences have prompted drug discovery efforts to target the parasite polyamine pathways, and indeed, the only clinically approved drug targeting the polyamine biosynthetic pathway is used to manage human African trypanosomiasis. This Minireview will primarily focus on polyamine metabolism and function in Trypanosoma, Leishmania, and Plasmodium species, which are the causative agents of human African trypanosomiasis (HAT) and Chagas disease, Leishmaniasis, and malaria, respectively. Aspects of polyamine metabolism across a diverse group of protozoan pathogens will also be explored. Polyamines are low-molecular-weight, organic polycations that are synthesized from amino acid precursors (1Michael A.J. Biosynthesis of polyamines and polyamine-containing molecules.Biochem. J. 2016; 473 (27470594): 2315-232910.1042/BCJ20160185Crossref PubMed Scopus (64) Google Scholar, 2Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18 (30181570): 681-69510.1038/s41568-018-0050-3Crossref PubMed Scopus (132) Google Scholar). In eukaryotes, the diamine putrescine is produced by decarboxylation of l-ornithine, and spermidine is synthesized from putrescine by the addition of an aminopropyl group donated by decarboxylated SAM 2The abbreviations used are: SAMS-adenosylmethioninedcAdoMetdecarboxylated SAMHAThuman African trypanosomiasisAdoMetDCSAM decarboxylasePLPpyridoxal-5′-phosphateODCornithine decarboxylasePAOpolyamine oxidaseSSATspermidine/spermine-N1-acetyltransferaseDHSdeoxyhypusine synthaseDFMO2-(difluoromethyl)-dl-ornithineDOHHdeoxyhypusine hydroxylasePDBProtein Data BankSSATspermidine/spermine-N1-acetyltransferasedh-eIF5Adeoxyhypusinated-eIF5Ah-eIF5Ahypusinated eIF5AHTShigh-throughput screenCNScentral nervous system. (dcAdoMet) (Fig. 1A). The core biosynthetic pathway that is common to both higher eukaryotes (e.g. mammals) and many single-cell organisms typically employs three key enzymes: 1) pyridoxal 5′-phosphate (PLP)-dependent ornithine decarboxylase (ODC); 2) pyruvoyl (Pvl)-dependent SAM decarboxylase (AdoMetDC); and 3) spermidine synthase, which conjugates the aminopropyl group from dcAdoMet to putrescine to generate spermidine. In the parasitic protozoa, the complete core polyamine biosynthetic pathway (ODC, AdoMetDC, and spermidine synthase) is present only in Trypanosoma brucei, Leishmania, and Plasmodium species (3Li B. Kim S.H. Zhang Y. Hanfrey C.C. Elliott K.A. Ealick S.E. Michael A.J. Different polyamine pathways from bacteria have replaced eukaryotic spermidine biosynthesis in ciliates Tetrahymena thermophila and Paramecium tetaurelia.Mol. Microbiol. 2015; 97 (25994085): 791-80710.1111/mmi.13066Crossref PubMed Scopus (9) Google Scholar). Mammals and other higher eukaryotes also produce the tetraamine spermine, which is synthesized from spermidine by addition of a second aminopropyl group. Additionally, a catabolic pathway that degrades spermine and spermidine back to putrescine via polyamine oxidase (PAO) and spermidine/spermine-N1-acetyltransferase (SSAT) is also present (2Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18 (30181570): 681-69510.1038/s41568-018-0050-3Crossref PubMed Scopus (132) Google Scholar, 4Pegg A.E. Mammalian polyamine metabolism and function.IUBMB Life. 2009; 61 (19603518): 880-89410.1002/iub.230Crossref PubMed Scopus (423) Google Scholar). These catabolic pathways are largely missing from the protozoa (Fig. 1A). S-adenosylmethionine decarboxylated SAM human African trypanosomiasis SAM decarboxylase pyridoxal-5′-phosphate ornithine decarboxylase polyamine oxidase spermidine/spermine-N1-acetyltransferase deoxyhypusine synthase 2-(difluoromethyl)-dl-ornithine deoxyhypusine hydroxylase Protein Data Bank spermidine/spermine-N1-acetyltransferase deoxyhypusinated-eIF5A hypusinated eIF5A high-throughput screen central nervous system. The polyamine biosynthetic pathway in higher eukaryotes is highly regulated at multiple levels, including transcription, translation, and protein degradation, highlighting the role of polyamines in regulating cell growth (2Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18 (30181570): 681-69510.1038/s41568-018-0050-3Crossref PubMed Scopus (132) Google Scholar, 4Pegg A.E. Mammalian polyamine metabolism and function.IUBMB Life. 2009; 61 (19603518): 880-89410.1002/iub.230Crossref PubMed Scopus (423) Google Scholar). Similar mechanisms are absent in the protozoa, although several unique regulatory strategies have been uncovered and will be discussed. Spermidine serves as a substrate for deoxyhypusine synthase (DHS) in all eukaryotes, which together with deoxyhypusine hydroxylase (DOHH) covalently modifies the translation elongation factor eIF5A with the amino acid hypusine (5Dever T.E. Dinman J.D. Green R. Translation elongation and recoding in eukaryotes.Cold Spring Harb. Perspect. Biol. 2018; 10 (29610120)a03264910.1101/cshperspect.a032649Crossref PubMed Scopus (45) Google Scholar, 6Dever T.E. Gutierrez E. Shin B.S. The hypusine-containing translation factor eIF5A.Crit Rev. Biochem. Mol. Biol. 2014; 49 (25029904): 413-42510.3109/10409238.2014.939608Crossref PubMed Scopus (85) Google Scholar7Park M.H. Nishimura K. Zanelli C.F. Valentini S.R. Functional significance of eIF5A and its hypusine modification in eukaryotes.Amino Acids. 2010; 38 (19997760): 491-50010.1007/s00726-009-0408-7Crossref PubMed Scopus (208) Google Scholar). DHS transfers the aminobutyl portion of spermidine to a conserved lysine residue on eIF5A, which is the sole protein that carries this modification. Both eIF5A and its hypusine modification are essential in eukaryotes, functioning to relieve ribosomal stalling on mRNAs encoding polyproline tracts and to promote translation termination (8Schuller A.P. Wu C.C. Dever T.E. Buskirk A.R. Green R. eIF5A functions globally in translation elongation and termination.Mol. Cell. 2017; 66 (28392174): 194-205.e510.1016/j.molcel.2017.03.003Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). DHS is present in the full range of parasitic protozoa (Fig. 1A). Because polyamines are essential for cell growth, their biosynthesis has been extensively studied for its potential to be targeted by drugs that could be used against proliferative diseases. Significant effort has been focused on cancer chemotherapy, but it has proven difficult to identify compounds with sufficient efficacy for this application (2Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18 (30181570): 681-69510.1038/s41568-018-0050-3Crossref PubMed Scopus (132) Google Scholar, 9Murray-Stewart T.R. Woster P.M. Casero Jr., R.A. Targeting polyamine metabolism for cancer therapy and prevention.Biochem. J. 2016; 473 (27679855): 2937-295310.1042/BCJ20160383Crossref PubMed Scopus (73) Google Scholar). The availability of dietary polyamines and polyamine transporters reduces the efficacy of biosynthetic inhibitors. Recently, combinations of biosynthetic inhibitors and transport inhibitors are being explored to determine whether more complete cellular polyamine reductions can be obtained for the treatment of cancer, but it remains to be seen whether this strategy will be effective (2Casero Jr., R.A. Murray Stewart T. Pegg A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities.Nat. Rev. Cancer. 2018; 18 (30181570): 681-69510.1038/s41568-018-0050-3Crossref PubMed Scopus (132) Google Scholar). Efforts to study polyamine synthesis and function in protozoan parasites grew from the early work in the cancer field as researchers sought to translate the mammalian discoveries to single-celled eukaryotic pathogens. Two high-impact discoveries paved the way for both therapeutic applications and for the uncovering of unique biology in these parasitic pathogens. The first of these was the discovery in 1980 by Bacchi et al. (10Bacchi C.J. Nathan H.C. Hutner S.H. McCann P.P. Sjoerdsma A. Polyamine metabolism: a potential therapeutic target in trypanosomes.Science. 1980; 210 (6775372): 332-33410.1126/science.6775372Crossref PubMed Scopus (295) Google Scholar), who showed the irreversible ODC inhibitor 2-(difluoromethyl)-dl-ornithine (DFMO) (Figure 2, Figure 3, A and B) cured Trypanosoma brucei infections in mice. This finding led to the eventual registration of DFMO for treatment of late-stage human African trypanosomiasis (HAT) as a combination therapy with nifurtimox (11Yun O. Priotto G. Tong J. Flevaud L. Chappuis F. NECT is next: implementing the new drug combination therapy for Trypanosoma brucei gambiense sleeping sickness.PLoS Negl. Trop. Dis. 2010; 4 (20520803): e72010.1371/journal.pntd.0000720Crossref PubMed Scopus (88) Google Scholar, 12Priotto G. Kasparian S. Mutombo W. Ngouama D. Ghorashian S. Arnold U. Ghabri S. Baudin E. Buard V. Kazadi-Kyanza S. Ilunga M. Mutangala W. Pohlig G. Schmid C. Karunakara U. et al.Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.Lancet. 2009; 374 (19559476): 56-6410.1016/S0140-6736(09)61117-XAbstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar), and to its inclusion on the World Health Organization essential medicines list (World Health Organization (WHO) model list of essential medicines accessed August, 2018 (http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017_FINAL_amendedAug2017.pdf?ua=1)). 3Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site. The second key discovery was the observation by Fairlamb et al., in 1985 (13Fairlamb A.H. Blackburn P. Ulrich P. Chait B.T. Cerami A. Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids.Science. 1985; 227 (3883489): 1485-148710.1126/science.3883489Crossref PubMed Scopus (566) Google Scholar), that trypanosomatids conjugate two molecules of GSH to spermidine to generate a unique cofactor called trypanothione (N1,N8-bis(glutathionyl)spermidine), which is used in place of GSH (l-γ-Glu-Cys-Gly) to maintain redox balance in these cells (Fig. 1B). More recent work has uncovered a number of examples of atypical enzyme arrangements and novel regulatory strategies, including bifunctional enzymes and enzyme complexes, that require inactive pseudoenzymes to activate their cognate paralogous enzyme (14Willert E. Phillips M.A. Regulation and function of polyamines in African trypanosomes.Trends Parasitol. 2012; 28 (22192816): 66-7210.1016/j.pt.2011.11.001Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 15Müller I.B. Das Gupta R. Lüersen K. Wrenger C. Walter R.D. Assessing the polyamine metabolism of Plasmodium falciparum as chemotherapeutic target.Mol. Biochem. Parasitol. 2008; 160 (18455248): 1-710.1016/j.molbiopara.2008.03.008Crossref PubMed Scopus (57) Google Scholar16Nguyen S. Jones D.C. Wyllie S. Fairlamb A.H. Phillips M.A. Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog.J. Biol. Chem. 2013; 288 (23525104): 15256-1526710.1074/jbc.M113.461137Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar).Figure 3X-ray structure of T. brucei ODC. ODC K69A bound to DFMO (PDB code 2TOD) (86Grishin N.V. Osterman A.L. Brooks H.B. Phillips M.A. Goldsmith E.J. The X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with α-difluoromethylornithine.Biochemistry. 1999; 38 (10563800): 15174-1518410.1021/bi9915115Crossref PubMed Scopus (0) Google Scholar). A, ribbon diagram of the dimer with monomers colored in teal and tan. DFMO and PLP are shown as spheres. B, ODC active site showing select residues within the 4 Å shell of PLP and DFMO. DFMO is covalently bound to Cys-360. Catalytic residues with known function in catalysis or substrate binding are displayed.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Protozoan parasites associated with human disease include members of the trypanosomatids (T. brucei, Trypanosoma cruzi, and Leishmania species) (17Stuart K. Brun R. Croft S. Fairlamb A. Gürtler R.E. McKerrow J. Reed S. Tarleton R. Kinetoplastids: related protozoan pathogens, different diseases.J. Clin. Invest. 2008; 118 (18382742): 1301-131010.1172/JCI33945Crossref PubMed Scopus (374) Google Scholar, 18Field M.C. Horn D. Fairlamb A.H. Ferguson M.A. Gray D.W. Read K.D. De Rycker M. Torrie L.S. Wyatt P.G. Wyllie S. Gilbert I.H. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nat. Rev. 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Plasmodium species are responsible for malaria, with the most important species Plasmodium falciparum responsible for nearly half a million deaths per year. For both the trypanosomatid and Plasmodium parasites, drug therapy and disease control are challenged by drug toxicity, drug resistance, and/or difficult treatment regiments. Thus, the polyamine pathway has been explored in these parasites for the potential to identify new enzymatic targets for drug discovery. The metabolic pathways, both typical and novel, the essentiality of genes in these pathways, and their utility for being exploited for drug discovery, have all been investigated and will be discussed (reviewed previously in Refs. 14Willert E. Phillips M.A. Regulation and function of polyamines in African trypanosomes.Trends Parasitol. 2012; 28 (22192816): 66-7210.1016/j.pt.2011.11.001Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 19Jacobs R.T. Nare B. 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Invest. 2008; 118 (18382742): 1301-131010.1172/JCI33945Crossref PubMed Scopus (374) Google Scholar, 18Field M.C. Horn D. Fairlamb A.H. Ferguson M.A. Gray D.W. Read K.D. De Rycker M. Torrie L.S. Wyatt P.G. Wyllie S. Gilbert I.H. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nat. Rev. Microbiol. 2017; 15 (28239154): 217-23110.1038/nrmicro.2016.193Crossref PubMed Scopus (173) Google Scholar). All three pathogenic trypanosomatids have also evolved two paralogous gene products for both AdoMetDC and DHS that are required to form the active enzymes providing a unique example of how pseudoenzymes evolve to be enzyme regulators (16Nguyen S. Jones D.C. Wyllie S. Fairlamb A.H. Phillips M.A. Allosteric activation of trypanosomatid deoxyhypusine synthase by a catalytically dead paralog.J. Biol. Chem. 2013; 288 (23525104): 15256-1526710.1074/jbc.M113.461137Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 27Afanador G.A. Tomchick D.R. 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Phillips M.A. Pyrimidine salvage enzymes are essential for de novo biosynthesis of deoxypyrimidine nucleotides in Trypanosoma brucei.PLoS Pathog. 2016; 12 (27820863)e100601010.1371/journal.ppat.1006010Crossref PubMed Scopus (15) Google Scholar), but their function and biosynthetic origin are both unknown. T. brucei encodes an arginase-like enzyme, but it was found to lack key catalytic residues and to be inactive (39Hai Y. Kerkhoven E.J. Barrett M.P. Christianson D.W. Crystal structure of an arginase-like protein from Trypanosoma brucei that evolved without a binuclear manganese cluster.Biochemistry. 2015; 54 (25536859): 458-47110.1021/bi501366aCrossref PubMed Scopus (12) Google Scholar, 40Vincent I.M. Creek D.J. Burgess K. Woods D.J. Burchmore R.J. Barrett M.P. Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.PLoS Negl. Trop. Dis. 2012; 6 (22563508)e161810.1371/journal.pntd.0001618Crossref PubMed Scopus (77) Google Scholar). Labeling studies suggest T. brucei can convert l-arginine to l-ornithine, but the enzymatic machinery used to catalyze this reaction is unknown, and it has been postulated that the primary source of l-ornithine is salvage (40Vincent I.M. Creek D.J. Burgess K. Woods D.J. Burchmore R.J. Barrett M.P. Untargeted metabolomics reveals a lack of synergy between nifurtimox and eflornithine against Trypanosoma brucei.PLoS Negl. Trop. Dis. 2012; 6 (22563508)e161810.1371/journal.pntd.0001618Crossref PubMed Scopus (77) Google Scholar).Table 1X-ray structures of polyamine biosynthetic enzymes from protozoan pathogensEnzymeSpeciesPDB no.Bound inhibitors, mutations, notesODCT. brucei1QU4NoneODCT. brucei2TODDFMO; K69AODCT. brucei1NJJd-Ornithine + G418ODCT. brucei1SZRd-Ornithine; K294AODCT. brucei1F3TPutrescineODCE. histolytica4AIBNoneAdoMetDCT. brucei5TVOInactive monomerAdoMetDC/prozymeT. brucei5TVMActive heterodimer with prozymeAdoMetDC/prozymeT. brucei5TVFActive heterodimer with prozyme; CGP 40215AAdoMetDC/prozymeT. brucei6BM7Active heterodimer with prozyme; UTSAM568 (compound 44)SpdSynP falciparum2PWP, 4CXM, 2HTE, 1I7C, 2PSS, 2PT6, 3B7P, 4BP1, 4CWA, 2PT9, 3RIE, 4BP3, 4UOEVarious ligandsSpdSynT. cruzi4YUV, 4YUW, 4YUY, 3BWB, 3BWC, 4YUX, 4YUZ, 4YV1, 4YV2, 5B1S, 5Y4Q, 4YV0, 5Y4PVarious ligandsDHSc/DHSpT. brucei6DFTActive heterodimer complex; NAD+ArginaseLeishmania4ITY, 4IU0, 4IU1, 4IU4, 4IU5, 5HJ9, 5HJAVarious ligandsTrySLeishmania2VOB, 2VPM, 2VPSVarious ligandsTryRLeishmania2JK6, 2W0H, 2X50, 2YAU, 4ADW, 4APN, 5EBKVarious ligandsTryRT. brucei2WBA, 2WOI, 2WOV, 2WOW, 2WP5, 2WP6, 2WPC, 2WPE, 2WPF, 4NEV, 6BTL, 6BU7Various ligandsTryRT. cruzi1AOG, 1BZL, 1GXF, 1NDA, 4NEWVarious ligands Open table in a new tab In contrast, both Leishmania and T. cruzi are intracellular parasites with access to polyamines within the cell of their mammalian host. Thus, as for mammalian cells polyamine transport plays a role in meeting the cellular needs for these nutrients, which has implications for drug discovery. T. cruzi has lost its ODC and relies on salvage to supply putrescine (41Ariyanayagam M.R. Fairlamb A.H. Diamine auxotrophy may be a universal feature of Trypanosoma cruzi epimastigotes.Mol. Biochem. Parasitol. 1997; 84 (9041526): 111-12110.1016/S0166-6851(96)02788-0Crossref PubMed Scopus (0) Google Scholar), although it still retains an active AdoMetDC (42Willert E.K. Phillips M.A. Cross-species activation of trypanosome S-adenosylmethionine decarboxylase by the regulatory subunit prozyme.Mol. Biochem. Parasitol. 2009; 168 (19523496): 1-610.1016/j.molbiopara.2009.05.009Crossref PubMed Scopus (17) Google Scholar) and SpdSyn (43Yamasaki K. Tani O. Tateishi Y. Tanabe E. Namatame I. Niimi T. Furukawa K. Sakashita H. An NMR biochemical assay for fragment-based drug discovery: evaluation of an inhibitor activity on spermidine synthase of Trypanosoma cruzi.J. Med. Chem. 2016; 59 (26881725): 2261-226610.1021/acs.jmedchem.5b01769Crossref PubMed Scopus (6) Google Scholar). It is auxotrophic for putrescine and spermidine and encodes both saturable and unsaturable transport mechanisms for these amines and for the product of lysine decarboxylation, cadaverine (44Hasne M.P. Coppens I. Soysa R. Ullman B. A high-affinity putre" @default.
• W2897069969 created "2018-10-26" @default.
• W2897069969 creator A5008866938 @default.
• W2897069969 date "2018-11-01" @default.
• W2897069969 modified "2023-10-13" @default.
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