| Popis: |
The sophistication of proteomic analysis has revealed that protein lysine residues are posttranslationally modified by a variety of acyl groups. Protein lysine acetylation regulates metabolism, gene expression, and microtubule formation and has been extensively studied; however, the understanding of the biological significance of other acyl posttranslational modifications (PTMs) is still in its infancy. The acylation of lysine residues is either mediated by acyltransferase ‘writer’ enzymes or through non-enzymatic mechanisms and hydrolase enzymes, termed ‘erasers’, cleave various acyl PTMs to reverse the modified state. We have studied the human lysine deacylase enzymes, comprising the 11 Zn2+-dependent histone deacetylases (HDACs) and the 7 NAD+-consuming sirtuins (SIRTs), over the last decade. We have thus developed selective inhibitors and molecular probes as well as studied the acyl substrate scope of each enzyme using chemically synthesized peptide substrates and photo-crosslinking probes. Recently, we have turned our attention to lysine PTMs containing a stereogenic center, such as -N--hydroxybutyryllysine (Kbhb) and -N-lactyllysine (Kla), that each comprise a pair of mirror image stereoisomers. Both modifications are found on histones, where they affect gene transcription in response to specific metabolic states, and they are found on cytosolic and mitochondrial enzymes involved in fatty acid oxidation (Kbhb) and glycolysis (Kla), respectively. Thus, chiral modifications to lysine side chains give rise to two distinct diastereomeric products, with separate metabolic origins and potentially different activities exhibited by writer and eraser enzymes. Lysine L-lactylation derives from L-lactate, a major energy carrier produced from pyruvate after glycolysis, and it is highly induced by metabolic states such as the Warburg effect. L-Lactate can possibly be activated by acyl-coenzyme A (CoA) synthetases and transferred to lysine residues by histone acetyltransferases such as p300. D-Lactylation, on the other hand, arises primarily from a non-enzymatic reaction with D-lactylglutathione, an intermediate in the glyoxalase pathway. In addition to their distinct origin, we found that both K(L-la) and K(D-la) modifications are erased by HDACs with different catalytic efficiencies. Also, K(L-bhb) and K(D-bhb) arise from different metabolites but depend on interconnected metabolic pathways, while the two stereoisomers of -N-3-hydroxy-3-methylglutaryllysine (Khmg) derive from a single precursor that may then be regulated differently by eraser enzymes. Distinguishing between the individual stereoisomers of PTMs is therefore of crucial importance. In the present Account, we will (1) revisit the long-standing evidence for distinct production and dynamics of enantiomeric forms of chiral metabolites that serve as epsilon-N-acyllysine PTMs and (2) highlight the outstanding questions that arise from the recent literature on chiral lysine PTMs resulting from these metabolites. |
