Cross-species activation of trypanosome S-adenosylmethionine decarboxylase by the regulatory subunit prozyme

Erin K. Willert, Margaret A. Phillips

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease (American trypanosomiasis), a neglected disease of Central and South America. Polyamines are small organic cations that are required for cell growth and their biosynthesis has been the target of drug discovery efforts in both T. cruzi and the related Trypanosoma brucei parasites. Here we show that, as previously demonstrated for T. brucei, S-adenosylmethionine decarboxylase (AdoMetDC) from T. cruzi forms a heterodimer with prozyme, an inactive homolog that arose by gene duplication of the canonical enzyme uniquely in the trypanosomatids. The T. cruzi AdoMetDC/prozyme heterodimer is 110-fold more active than homodimeric AdoMetDC. Unlike for T. brucei AdoMetDC, the activity of the T. cruzi heterodimer is further stimulated by putrescine to generate an enzyme with similar catalytic efficiency to the fully activated T. brucei enzyme. The effects of prozyme on T. cruzi AdoMetDC are mediated by an increase in kcat, while the predominant effect of putrescine is to lower the Km. Finally we demonstrate that the cross-species heterodimers of T. cruzi and T. brucei AdoMetDC and prozyme pairs are functional, and that putrescine is required for prozyme to fully activate the mixed species heterodimers. These data demonstrate that prozyme mediated activation of AdoMetDC is a common mechanism required to regulate AdoMetDC activity in the trypanosomatids.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalMolecular and Biochemical Parasitology
Volume168
Issue number1
DOIs
StatePublished - Nov 2009

Fingerprint

Adenosylmethionine Decarboxylase
Trypanosomiasis
Trypanosoma cruzi
Trypanosoma brucei brucei
Putrescine
Chagas Disease
Parasites
Enzymes
Neglected Diseases
Central America
Gene Duplication
South America
Polyamines
Drug Discovery
Cations

Keywords

  • Polyamines
  • Putrescine
  • Regulation
  • Trypanosoma brucei
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Molecular Biology
  • Parasitology

Cite this

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title = "Cross-species activation of trypanosome S-adenosylmethionine decarboxylase by the regulatory subunit prozyme",
abstract = "The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease (American trypanosomiasis), a neglected disease of Central and South America. Polyamines are small organic cations that are required for cell growth and their biosynthesis has been the target of drug discovery efforts in both T. cruzi and the related Trypanosoma brucei parasites. Here we show that, as previously demonstrated for T. brucei, S-adenosylmethionine decarboxylase (AdoMetDC) from T. cruzi forms a heterodimer with prozyme, an inactive homolog that arose by gene duplication of the canonical enzyme uniquely in the trypanosomatids. The T. cruzi AdoMetDC/prozyme heterodimer is 110-fold more active than homodimeric AdoMetDC. Unlike for T. brucei AdoMetDC, the activity of the T. cruzi heterodimer is further stimulated by putrescine to generate an enzyme with similar catalytic efficiency to the fully activated T. brucei enzyme. The effects of prozyme on T. cruzi AdoMetDC are mediated by an increase in kcat, while the predominant effect of putrescine is to lower the Km. Finally we demonstrate that the cross-species heterodimers of T. cruzi and T. brucei AdoMetDC and prozyme pairs are functional, and that putrescine is required for prozyme to fully activate the mixed species heterodimers. These data demonstrate that prozyme mediated activation of AdoMetDC is a common mechanism required to regulate AdoMetDC activity in the trypanosomatids.",
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