Targeting the polyamine biosynthetic pathway in parasitic protozoa

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

Malaria, trypanosomiasis, and leishmaniasis are life-threatening parasitic diseases for which safe and more effective medicines are urgently needed. The polyamine biosynthetic pathway in protozoan pathogens is a validated target for the development of drugs, as demonstrated by the current use of a-difluoromethylornithine (DFMO) to treat patients diagnosed with human African trypanosomias (HAT). These parasites have evolved novel polyamine metabolic pathways that are considerably different from those of the human host. For example, trypanosomes contain a novel spermidine/glutathione conjugate termed trypanothione, and uniquely in these parasites S -adenosylmethionine decarboxylase (AdoMetDC) is activated by heterodimer formation with a catalytically dead homologue. In Plasmodium parasites, AdoMetDC and ODC are fused as a bifunctional protein. Trypanosoma cruzi lacks ODC and relies on polyamine transporters. In this chapter, we discuss these differences and highlight additional aspects of these organisms that could be exploited as potential therapeutic strategies, including differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds.

Original languageEnglish (US)
Title of host publicationPolyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism
PublisherSpringer Japan
Pages315-330
Number of pages16
ISBN (Print)9784431552123, 9784431552116
DOIs
StatePublished - Jan 1 2015

Fingerprint

Protozoa
Biosynthetic Pathways
Polyamines
Adenosylmethionine Decarboxylase
Parasites
Trypanosomiasis
Eflornithine
Parasitic Diseases
Leishmaniasis
Spermidine
Plasmodium
Trypanosoma cruzi
Pathogens
Metabolic Networks and Pathways
Malaria
Medicine
Glutathione
Proteins
Pharmaceutical Preparations

Keywords

  • Chaga’s disease
  • Human African trypanosomiasis (HAT)
  • Leishmaniasis
  • Malaria
  • Ornithine decarboxylase (ODC)
  • Polyamines
  • S-Adenosylmethionine decarboxylase (AdoMetDC)
  • Spermidine synthase (SpdSyn)
  • α-Difluoromethylornithine (DFMO)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Velez, N., & Phillips, M. A. (2015). Targeting the polyamine biosynthetic pathway in parasitic protozoa. In Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism (pp. 315-330). Springer Japan. https://doi.org/10.1007/978-4-431-55212-3_24

Targeting the polyamine biosynthetic pathway in parasitic protozoa. / Velez, Nahir; Phillips, Margaret A.

Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism. Springer Japan, 2015. p. 315-330.

Research output: Chapter in Book/Report/Conference proceedingChapter

Velez, N & Phillips, MA 2015, Targeting the polyamine biosynthetic pathway in parasitic protozoa. in Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism. Springer Japan, pp. 315-330. https://doi.org/10.1007/978-4-431-55212-3_24
Velez N, Phillips MA. Targeting the polyamine biosynthetic pathway in parasitic protozoa. In Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism. Springer Japan. 2015. p. 315-330 https://doi.org/10.1007/978-4-431-55212-3_24
Velez, Nahir ; Phillips, Margaret A. / Targeting the polyamine biosynthetic pathway in parasitic protozoa. Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism. Springer Japan, 2015. pp. 315-330
@inbook{488f9867dda14d53a6748c593895ca9d,
title = "Targeting the polyamine biosynthetic pathway in parasitic protozoa",
abstract = "Malaria, trypanosomiasis, and leishmaniasis are life-threatening parasitic diseases for which safe and more effective medicines are urgently needed. The polyamine biosynthetic pathway in protozoan pathogens is a validated target for the development of drugs, as demonstrated by the current use of a-difluoromethylornithine (DFMO) to treat patients diagnosed with human African trypanosomias (HAT). These parasites have evolved novel polyamine metabolic pathways that are considerably different from those of the human host. For example, trypanosomes contain a novel spermidine/glutathione conjugate termed trypanothione, and uniquely in these parasites S -adenosylmethionine decarboxylase (AdoMetDC) is activated by heterodimer formation with a catalytically dead homologue. In Plasmodium parasites, AdoMetDC and ODC are fused as a bifunctional protein. Trypanosoma cruzi lacks ODC and relies on polyamine transporters. In this chapter, we discuss these differences and highlight additional aspects of these organisms that could be exploited as potential therapeutic strategies, including differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds.",
keywords = "Chaga’s disease, Human African trypanosomiasis (HAT), Leishmaniasis, Malaria, Ornithine decarboxylase (ODC), Polyamines, S-Adenosylmethionine decarboxylase (AdoMetDC), Spermidine synthase (SpdSyn), α-Difluoromethylornithine (DFMO)",
author = "Nahir Velez and Phillips, {Margaret A.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1007/978-4-431-55212-3_24",
language = "English (US)",
isbn = "9784431552123",
pages = "315--330",
booktitle = "Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism",
publisher = "Springer Japan",

}

TY - CHAP

T1 - Targeting the polyamine biosynthetic pathway in parasitic protozoa

AU - Velez, Nahir

AU - Phillips, Margaret A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Malaria, trypanosomiasis, and leishmaniasis are life-threatening parasitic diseases for which safe and more effective medicines are urgently needed. The polyamine biosynthetic pathway in protozoan pathogens is a validated target for the development of drugs, as demonstrated by the current use of a-difluoromethylornithine (DFMO) to treat patients diagnosed with human African trypanosomias (HAT). These parasites have evolved novel polyamine metabolic pathways that are considerably different from those of the human host. For example, trypanosomes contain a novel spermidine/glutathione conjugate termed trypanothione, and uniquely in these parasites S -adenosylmethionine decarboxylase (AdoMetDC) is activated by heterodimer formation with a catalytically dead homologue. In Plasmodium parasites, AdoMetDC and ODC are fused as a bifunctional protein. Trypanosoma cruzi lacks ODC and relies on polyamine transporters. In this chapter, we discuss these differences and highlight additional aspects of these organisms that could be exploited as potential therapeutic strategies, including differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds.

AB - Malaria, trypanosomiasis, and leishmaniasis are life-threatening parasitic diseases for which safe and more effective medicines are urgently needed. The polyamine biosynthetic pathway in protozoan pathogens is a validated target for the development of drugs, as demonstrated by the current use of a-difluoromethylornithine (DFMO) to treat patients diagnosed with human African trypanosomias (HAT). These parasites have evolved novel polyamine metabolic pathways that are considerably different from those of the human host. For example, trypanosomes contain a novel spermidine/glutathione conjugate termed trypanothione, and uniquely in these parasites S -adenosylmethionine decarboxylase (AdoMetDC) is activated by heterodimer formation with a catalytically dead homologue. In Plasmodium parasites, AdoMetDC and ODC are fused as a bifunctional protein. Trypanosoma cruzi lacks ODC and relies on polyamine transporters. In this chapter, we discuss these differences and highlight additional aspects of these organisms that could be exploited as potential therapeutic strategies, including differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds.

KW - Chaga’s disease

KW - Human African trypanosomiasis (HAT)

KW - Leishmaniasis

KW - Malaria

KW - Ornithine decarboxylase (ODC)

KW - Polyamines

KW - S-Adenosylmethionine decarboxylase (AdoMetDC)

KW - Spermidine synthase (SpdSyn)

KW - α-Difluoromethylornithine (DFMO)

UR - http://www.scopus.com/inward/record.url?scp=84967221989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84967221989&partnerID=8YFLogxK

U2 - 10.1007/978-4-431-55212-3_24

DO - 10.1007/978-4-431-55212-3_24

M3 - Chapter

AN - SCOPUS:84967221989

SN - 9784431552123

SN - 9784431552116

SP - 315

EP - 330

BT - Polyamines: A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism

PB - Springer Japan

ER -