Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog

Erin K. Willert, Richard Fitzpatrick, Margaret A. Phillips

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

African sleeping sickness is a fatal disease that is caused by the protozoan parasite Trypanosoma brucei. Polyamine biosynthesis is an essential pathway in the parasite and is a validated drug target for treatment of the disease. S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in polyamine biosynthesis. Here, we show that trypanosomatids uniquely contain both a functional AdoMetDC and a paralog designated prozyme that has lost catalytic activity. The T. brucei prozyme forms a high-affinity heterodimer with AdoMetDC that stimulates its activity by 1,200-fold. Both genes are expressed in T. brucei, and analysis of AdoMetDC activity in T. brucei extracts supports the finding that the heterodimer is the functional enzyme in vivo. Thus, prozyme has evolved to be a catalytically dead but allosterically active subunit of AdoMetDC, providing an example of how regulators of multimeric enzymes can evolve through gene duplication and mutational drift. These data identify a distinct mechanism for regulating AdoMetDC in the parasite that suggests new strategies for the development of parasite-specific inhibitors of the polyamine biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)8275-8280
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number20
DOIs
StatePublished - May 15 2007

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Adenosylmethionine Decarboxylase
Allosteric Regulation
Trypanosomiasis
Polyamines
Trypanosoma brucei brucei
Parasites
Enzymes
African Trypanosomiasis
Gene Duplication
Biosynthetic Pathways
Pharmaceutical Preparations
Genes

Keywords

  • Gene duplication
  • Prozyme
  • S-adenyosylmethionine decarboxylase
  • Trypanosoma brucei

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog. / Willert, Erin K.; Fitzpatrick, Richard; Phillips, Margaret A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 20, 15.05.2007, p. 8275-8280.

Research output: Contribution to journalArticle

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