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Estimulación directa de la síntesis de NADP a través de la fosforilación mediada por Akt de la NAD quinasa

Gerta Hoxhaj¹, Issam Ben-Sahra², Sophie E Lockwood¹

¹Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Science (New York, N.Y.)

|March 9, 2019

Resumen

La señalización del factor de crecimiento activa la NAD quinasa (NADK) a través de la fosforilación de Akt, aumentando la producción de NADP+ esencial para el metabolismo. Esta regulación mejora la disponibilidad de NADPH para los procesos celulares reductivos.

Área de la Ciencia:

El metabolismo celular
Transducción de señales
Regulación de las enzimas

Sus antecedentes:

El fosfato de nicotinamida adenina dinucleótido (NADP +) es crucial para el metabolismo reductor, principalmente a través de su forma reducida, NADPH.
Las vías de señalización del factor de crecimiento juegan un papel importante en la regulación metabólica celular.
La NAD quinasa (NADK) es la enzima clave responsable de la síntesis de NADP+.

Objetivo del estudio:

Investigar el papel de la vía de la fosfoinositida 3-cinasa (PI3K) -Akt en la regulación de la síntesis de NADP+ y NADPH.
Aclarar el mecanismo por el cual Akt influye en la actividad de NADK.
Comprender cómo la producción de NADP+ está modulada agudamente por la señalización del factor de crecimiento.

Principales métodos:

Efectos de señalización del factor de crecimiento en los niveles de NADP+ y NADPH en las células.
Se utilizaron ensayos bioquímicos para estudiar la fosforilación de NADK por Akt in vitro.
Analizó la actividad de las isoformas de NADK, incluida una que carece del dominio amino-terminal regulador.

Principales resultados:

La señalización del factor de crecimiento a través de la vía PI3K-Akt aumenta agudamente la síntesis de NADP+ y NADPH.
Akt fosforila directamente NADK en residuos específicos de serina (Ser44, Ser46, Ser48), mejorando su actividad enzimática.
Una isoforma natural de NADK (isoforma 3) que carece del sitio de fosforilación muestra una alta actividad constitutiva, lo que sugiere autoinhibición.

Conclusiones:

La fosforilación mediada por Akt de NADK es un mecanismo crítico para estimular la producción de NADP+.
Esta fosforilación alivia una función autoinhibidora de la terminación amino de NADK, aumentando su eficiencia catalítica.
Los hallazgos revelan un vínculo directo entre la señalización del factor de crecimiento y la regulación de los cofactores metabólicos clave.

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