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Pseudoenzymes as Activators of Enzyme Function: The Prozyme Paradigm in Trypanosomatid Polyamine Metabolism
Author(s) -
Phillips Margaret
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.237.2
Subject(s) - polyamine , ornithine decarboxylase , ornithine decarboxylase antizyme , trypanosoma brucei , biology , biochemistry , enzyme , mechanism (biology) , function (biology) , eflornithine , trypanosoma , microbiology and biotechnology , gene , genetics , philosophy , epistemology
The parasitic protozoa Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). Polyamine metabolism is a proven drug target for the treatment of HAT as eflornithine, an inhibitor of the key biosynthetic enzyme ornithine decarboxylase, is a frontline therapy for late stage disease. Our studies have uncovered an exciting and novel mechanism for regulation of polyamine biosynthesis in the trypanosomatids. We have demonstrated that two enzymes in the pathway, S‐adenosylmethinione decarboxylase (AdoMetDC) and deoxyhypusine synthase (DHS), are activated by oligomerization with catalytically dead paralogs we term prozymes. The trypanosomatids are the only organisms where this mechanism is used to generate the functional forms of both of these enzymes, and while all metazoan genomes contain evidence of “pseudo enzymes”, some with regulatory roles, the sheer magnitude of the enzymatic activation (1000‐3000‐fold) observed for these trypanosomatid enzymes is unprecedented. Additionally in the case of AdoMetDC, changes in AdoMetDC activity levels in the parasite lead to increases in the prozyme protein levels, correlated to the levels of decarboxylated AdoMet, suggesting that regulation of prozyme expression is a novel mechanism for controlling polyamine levels in these parasites. Our finding that this mechanism evolved twice within the same pathway also suggests that the trypanosomatids are under selective pressure to evolve novel mechanisms of regulation, perhaps because of the lack of transcriptional and other mechanisms typically used in eukaryotes to regulate gene expression.