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Polyamines are essential for cell growth of eukaryotes including the etiologic agent of human African trypanosomiasis (HAT),  Trypanosoma brucei . In trypanosomatids, a key enzyme in the polyamine biosynthetic pathway,  S -adenosylmethionine decarboxylase ( Tb AdoMetDC) heterodimerizes with a unique catalytically-dead paralog called prozyme to form the active enzyme complex. In higher eukaryotes, polyamine metabolism is subject to tight feedback regulation by spermidine-dependent mechanisms that are absent in trypanosomatids. Instead, in  T .  brucei  an alternative regulatory strategy based on  Tb AdoMetDC prozyme has evolved. We previously demonstrated that prozyme protein levels increase in response to loss of  Tb AdoMetDC activity. Herein, we show that prozyme levels are under translational control by monitoring incorporation of deuterated leucine into nascent prozyme protein. We furthermore identify pathway factors that regulate  prozyme  mRNA translation. We find evidence for a regulatory feedback mechanism in which  Tb AdoMetDC protein and decarboxylated AdoMet (dcAdoMet) act as suppressors of  prozyme  translation. In  Tb AdoMetDC null cells expressing the human AdoMetDC enzyme, prozyme levels are constitutively upregulated. Wild-type prozyme levels are restored by complementation with either  Tb AdoMetDC or an active site mutant, suggesting that  Tb AdoMetDC possesses an enzyme activity-independent function that inhibits prozyme translation. Depletion of dcAdoMet pools by three independent strategies: inhibition/knockdown of  Tb AdoMetDC, knockdown of AdoMet synthase, or methionine starvation, each cause prozyme upregulation, providing independent evidence that dcAdoMet functions as a metabolic signal for regulation of the polyamine pathway in  T .  brucei . These findings highlight a potential regulatory paradigm employing enzymes and pseudoenzymes that may have broad implications in biology.

plos pathogens

A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei