Journal
FEBS JOURNAL
Volume 279, Issue 11, Pages 2012-2021Publisher
WILEY
DOI: 10.1111/j.1742-4658.2012.08586.x
Keywords
catallytic metal; gluconeogenic pathway; glycolytic pathway; phosphoglycerate mutase; Trypanosoma brucei
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [575933/2008-9]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [06/55686-4]
- FAPESP at the Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo
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Phosphoglycerate mutases (PGAMs) participate in both the glycolytic and the gluconeogenic pathways in reversible isomerization of 3-phosphoglycerate and 2-phosphoglycerate. PGAMs are members of two distinct protein families: enzymes that are dependent on or independent of the 2,3-bisphosphoglycerate cofactor. We determined the X-ray structure of the monomeric Trypanosoma brucei independent PGAM (TbiPGAM) in its apoenzyme form, and confirmed this observation by small angle X-ray scattering data. Comparing the TbiPGAM structure with the Leishmania mexicana independent PGAM structure, previously reported with a phosphoglycerate molecule bound to the active site, revealed the domain movement resulting from active site occupation. The structure reported here shows the interaction between Asp319 and the metal bound to the active site, and its contribution to the domain movement. Substitution of the metal-binding residue Asp319 by Ala resulted in complete loss of independent PGAM activity, and showed for the first time its involvement in the enzymes function. As TbiPGAM is an attractive molecular target for drug development, the apoenzyme conformation described here provides opportunities for its use in structure-based drug design approaches.
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