Document Detail


Trypanosoma brucei S-adenosylmethionine decarboxylase N terminus is essential for allosteric activation by the regulatory subunit prozyme.
MedLine Citation:
PMID:  23288847     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human African trypanosomiasis is caused by a single-celled protozoan parasite, Trypanosoma brucei. Polyamine biosynthesis is a clinically validated target for the treatment of human African trypanosomiasis. Metabolic differences between the parasite and the human polyamine pathway are thought to contribute to species selectivity of pathway inhibitors. S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in the production of the polyamine spermidine. We previously showed that trypanosomatid AdoMetDC differs from other eukaryotic enzymes in that it is regulated by heterodimer formation with a catalytically dead paralog, designated prozyme, which binds with high affinity to the enzyme and increases its activity by up to 10(3)-fold. Herein, we examine the role of specific residues involved in AdoMetDC activation by prozyme through deletion and site-directed mutagenesis. Results indicate that 12 key amino acids at the N terminus of AdoMetDC are essential for prozyme-mediated activation with Leu-8, Leu-10, Met-11, and Met-13 identified as the key residues. These N-terminal residues are fully conserved in the trypanosomatids but are absent from other eukaryotic homologs lacking the prozyme mechanism, suggesting co-evolution of these residues with the prozyme mechanism. Heterodimer formation between AdoMetDC and prozyme was not impaired by mutation of Leu-8 and Leu-10 to Ala, suggesting that these residues are involved in a conformational change that is essential for activation. Our findings provide the first insight into the mechanisms that influence catalytic regulation of AdoMetDC and may have potential implications for the development of new inhibitors against this enzyme.
Authors:
Nahir Velez; Chad A Brautigam; Margaret A Phillips
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-18     Completed Date:  2013-04-29     Revised Date:  2014-02-18    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5232-40     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosylmethionine Decarboxylase / chemistry*
Alanine / chemistry
Allosteric Site
Amino Acid Sequence
Catalysis
Dimerization
Escherichia coli / metabolism
Humans
Kinetics
Models, Biological
Molecular Sequence Data
Peptides / chemistry
Polyamines / chemistry
Protein Conformation
Protein Structure, Tertiary
Sequence Homology, Amino Acid
Trypanosoma brucei brucei / enzymology*,  metabolism
Trypanosomiasis, African / metabolism
Grant Support
ID/Acronym/Agency:
R01 AI034432/AI/NIAID NIH HHS; R01 AI34432/AI/NIAID NIH HHS; R37 AI034432/AI/NIAID NIH HHS; R37AI034432/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Peptides; 0/Polyamines; EC 4.1.1.50/Adenosylmethionine Decarboxylase; OF5P57N2ZX/Alanine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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