IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
artículos
Título:
Crystallographic and kinetic study of riboflavin synthase from Brucella abortus, a chemotherapeutic target with an enhanced intrinsic flexibility
Autor/es:
MARÍA I. SERER; HERNÁN R. BONOMI; BEATRIZ G. GUIMARÃES; ROLANDO C. ROSSI; FERNANDO A. GOLDBAUM; SEBASTIÁN KLINKE
Revista:
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Lugar: Londres; Año: 2014 vol. 70 p. 1419 - 1434
ISSN:
0907-4449
Resumen:
Riboflavin synthase (RS) catalyzes the last step of riboflavinbiosynthesis in microorganisms and plants, which correspondsto the dismutation of two molecules of 6,7-dimethyl-8-ribityllumazine to yield one molecule of riboflavin and onemolecule of 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione.Owing to the absence of this enzyme in animals andthe fact that most pathogenic bacteria show a strictdependence on riboflavin biosynthesis, RS has been proposedas a potential target for antimicrobial drug development.Eubacterial, fungal and plant RSs assemble as homotrimerslacking C3 symmetry. Each monomer can bind two substratemolecules, yet there is only one active site for the wholeenzyme, which is located at the interface between twoneighbouring chains. This work reports the crystallographicstructure of RS from the pathogenic bacterium Brucellaabortus (the aetiological agent of the disease brucellosis) inits apo form, in complex with riboflavin and in complex withtwo different product analogues, being the first time that thestructure of an intact RS trimer with bound ligands has beensolved. These crystal models support the hypothesis ofenhanced flexibility in the particle and also highlight the roleof the ligands in assembling the unique active site. Kinetic andbinding studies were also performed to complement thesefindings. The structural and biochemical information generatedmay be useful for the rational design of novel RSinhibitors with antimicrobial activity.