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Estructuras de la fosfructokinasa-1 humana y base atómica de las mutaciones asociadas al cáncer

Bradley A Webb¹, Farhad Forouhar², Fu-En Szu²

¹Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, USA.

|May 19, 2015

Resumen

Los investigadores determinaron las primeras estructuras cristalinas de la fosfofructokinasa-1 plaquetaria humana (PFKP), revelando su formación de tetrámeros y cambios conformacionales. Estas estructuras proporcionan información sobre las mutaciones asociadas con el cáncer y la orientación terapéutica de la glucólisis.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
Enzimología Enzimología.

Sus antecedentes:

La fosfofructokinasa-1 (PFK1) es una enzima glicolítica clave que regula el metabolismo de la glucosa.
Las mutaciones de PFK1 causan la enfermedad de Tarui, y su papel en la reprogramación metabólica del cáncer es significativo.
La estructura tetramérica de PFK1 en mamíferos no se había determinado previamente.

Objetivo del estudio:

Para determinar la estructura cristalina de las plaquetas humanas de la fosfofructokinasa-1 (PFKP) tetramer.
Para entender los cambios conformacionales de la enzima y su interfaz tetrámica.
Para investigar el impacto funcional de las mutaciones de PFK1 asociadas con el cáncer.

Principales métodos:

Cristalografía de rayos X de la fosfofructokinasa-1 de las plaquetas humanas (PFKP).
Formación de complejo con ATP-Mg(2+) y ADP.
Caracterización bioquímica de las mutaciones de PFKP.

Principales resultados:

Las primeras estructuras cristalinas del tetrámero PFK1 de mamíferos (PFKP) se determinaron en 3.1 y 3.4 Å.
Las estructuras revelan cambios conformacionales significativos en la hidrólisis de nucleótidos y una interfaz tetramérica única.
Caracterización de tres mutaciones asociadas al cáncer que muestran efectos distintos en la regulación de las enzimas y la producción de lactato.

Conclusiones:

Las estructuras determinadas proporcionan un plan molecular para comprender la regulación y la función de PFK1.
Los hallazgos aclaran el impacto de las mutaciones somáticas en la actividad de PFK1 en el cáncer.
Esta información estructural puede guiar el desarrollo de terapias dirigidas a PFK1 para el control de enfermedades.

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