Regulation of protein activity by reversible acetylation

Details Regulation of protein activity by reversible acetylation Regulation of protein activity by reversible acetylation

C - Chemistry, Metallurgy

12

Q

C12Q 1/34 (2006.01) A61K 45/00 (2006.01) C12N 9/00 (2006.01) C12N 9/78 (2006.01) C12Q 1/25 (2006.01)

Patent

CA 2654458

This invention discloses the first cellular acetylated substrate protein of SIRT3, Acetyl-CoA synthetase 2 (AceCS2), which is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at lysine 642 (Lys642) in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. Thus, a mammalian sirtuin directly controls the activity of a metabolic enzyme via reversible lysine acetylation. Modulators of the acetylation status or the activity of AceCS2 are useful for the treatment of pathological conditions, such as type II diabetes, hypercholesterolemia, hyperlipidemia, and obesity.

L'invention présente la première protéine substrat cellulaire acétylée du SIRT3, l'acétyl-CoA synthétase 2 (AceCS2), qui est une protéine de la matrice mitochondriale. L'AceCS2 est acétylée de manière réversible au niveau de la lysine 642 (Lys642) dans le site actif de l'enzyme. La sirtuine mitochondriale SIRT3 interagit avec l'AceCS2 et désacétyle la Lys642 à la fois in vitro et in vivo. La désacétylation de l'AceCS2 par la SIRT3 active l'activité d'acétyl-CoA synthétase de l'AceCS2. Ainsi, une sirtuine de mammifère contrôle directement l'activité d'une enzyme métabolique par une acétylation réversible de la lysine. Les modulateurs de l'état d'acétylation ou de l'activité de l'AceCS2 sont utiles pour traiter des états pathologiques tels que le diabète de type II, l'hypercholestérolémie, l'hyperlipidémie et l'obésité.

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