Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog.
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.
Willert
Erin K
EK
Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
Fitzpatrick
Richard
R
Phillips
Margaret A
MA
D012437:Adenosylmethionine Decarboxylase / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D019281:Dimerization; D004789:Enzyme Activation; D018503:Genome, Protozoan / Q000235:genetics; D007700:Kinetics; D008969:Molecular Sequence Data; D010271:Parasites / Q000201:enzymology; D010802:Phylogeny; D011073:Polyamines / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
D011073:Polyamines; D011994:Recombinant Proteins; D012437:Adenosylmethionine Decarboxylase