Protein lysine acylation and cysteine succination by intermediates of energy metabolism

Abstract

In the past few years, several new protein post-translational modifications that use intermediates in metabolism have been discovered. These include various acyl lysine modifications (formylation, propionylation, butyrylation, crotonylation, malonylation, succinylation, myristoylation) and cysteine succination. Here, we review the discovery and the current understanding of these modifications. Several of these modifications are regulated by the deacylases, sirtuins, which use nicotinamide adenine dinucleotide (NAD), an important metabolic small molecule. Interestingly, several of these modifications in turn regulate the activity of metabolic enzymes. These new modifications reveal interesting connections between metabolism and protein post-translational modifications and raise many questions for future investigations.

Figure 1

Structures of PTMs that will be discussed. The post-translationally added parts are colored in blue.

Figure 2

Metabolic pathways that provided the donors for the PTMs shown in Figure 1, except for lysine formylation.

Figure 3

(A) Protein lysine acetylation and deacetylation are controlled by acetyltransferases (HATs) and deacetylases (HDACs and sirtuins). (B) The NAD-dependent deacetylation reaction catalyzed by sirtuins.

Figure 4

General model of how metabolic enzyme acetylation changes according to glucose concentration.

Figure 5

Different pathways for lysine formylation. Formyl-THF could be the formyl donor for a hypothetical enzymatic pathway.

Figure 6

Possible pathways for lysine crotonylation.

Figure 7

Schematic representation of Sirt5 active site structure with thioacetyllysine and CHES bound. This structure led to the hypothesis that Sirt5 is a demalonylase or desuccinylase.

Figure 8

Cysteine succination. (A) Michael reaction for the formation of (2-succinyl)cysteine. (B) A general base can potentially promote the reversal of (2-succinyl)cysteine.