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• W2898092351 endingPage "e1007404" @default.
• W2898092351 startingPage "e1007404" @default.
• W2898092351 abstract "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 (TbAdoMetDC) 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 TbAdoMetDC prozyme has evolved. We previously demonstrated that prozyme protein levels increase in response to loss of TbAdoMetDC 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 TbAdoMetDC protein and decarboxylated AdoMet (dcAdoMet) act as suppressors of prozyme translation. In TbAdoMetDC null cells expressing the human AdoMetDC enzyme, prozyme levels are constitutively upregulated. Wild-type prozyme levels are restored by complementation with either TbAdoMetDC or an active site mutant, suggesting that TbAdoMetDC possesses an enzyme activity-independent function that inhibits prozyme translation. Depletion of dcAdoMet pools by three independent strategies: inhibition/knockdown of TbAdoMetDC, 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." @default.
• W2898092351 created "2018-11-02" @default.
• W2898092351 creator A5008866938 @default.
• W2898092351 creator A5020789318 @default.
• W2898092351 creator A5026350486 @default.
• W2898092351 creator A5036761832 @default.
• W2898092351 creator A5087750390 @default.
• W2898092351 date "2018-10-26" @default.
• W2898092351 modified "2023-10-14" @default.
• W2898092351 title "A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei" @default.
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• W2898092351 doi "https://doi.org/10.1371/journal.ppat.1007404" @default.
• W2898092351 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6221367" @default.
• W2898092351 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30365568" @default.
• W2898092351 hasPublicationYear "2018" @default.
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