Sirtuin activation as a therapeutic approach against inborn errors of metabolism - PubMed (original) (raw)

Review

Sirtuin activation as a therapeutic approach against inborn errors of metabolism

Jeannette C Bleeker et al. J Inherit Metab Dis. 2016 Jul.

Abstract

Protein acylation has emerged as a large family of post translational modifications in which an acyl group can alter the function of a wide variety of proteins, especially in response to metabolic stress. The acylation state is regulated through reversible acylation/deacylation. Acylation occurs enzymatically or non-enzymatically, and responds to acyl-CoA levels. Deacylation on the other hand is controlled through the NAD(+)-dependent sirtuin proteins. In several inborn errors of metabolism (IEMs), accumulation of acyl-CoAs, due to defects in amino acid and fatty acid metabolic pathways, can lead to hyperacylation of proteins. This can have a direct effect on protein function and might play a role in pathophysiology. In this review we describe several mouse and cell models for IEM that display high levels of lysine acylation. Furthermore, we discuss how sirtuins serve as a promising therapeutic target to restore acylation state and could treat IEMs. In this context we examine several pharmacological sirtuin activators, such as resveratrol, NAD(+) precursors and PARP and CD38 inhibitors.

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Figures

Fig. 1

Regulation and chemical structures of lysine acylation modifications, including acetylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, crotonylation, malonylation, succinylation, glutarylation and myristoylation. Lysine acylation is catalyzed by lysine acyltransferase (KAT) and at least partly through non-enzymatic reactions driven by acyl-CoA levels. Lysine deacylation is catalyzed by lysine deacylase (KDAC) enzymes, such as sirtuins. PCC: propionyl-CoA carboxylase; GCDH: glutaryl-CoA dehydrogenase; MCD: malonyl-CoA decarboxylase; SCAD: short-chain acyl-CoA dehydrogenase

Fig. 2

Pharmacological activation of sirtuins. Sirtuins can be activated in multiple ways. Resveratrol activates sirtuins, although the mechanism is still debated. Two proposed modes of activation include (1) activation of AMPK; (2) direct activation. Sirtuins can also be activated through increasing the levels of its substrate NAD+. This can be achieved through (a) boosting NAD+ synthesis from precursors nicotinic acid (NA), nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN); (b) inhibiting the activity of major NAD+ consuming pathways, such as poly(ADP-ribose) polymerases (PARPs) or the cyclic ADP-ribose synthase CD38. Activating sirtuins can improve the acylation state at various levels and mitochondrial function

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Sirtuin activation as a therapeutic approach against inborn errors of metabolism - PubMed (original) (raw)