Chemical mechanisms of histone lysine and arginine modifications

Abstract

Histone lysine and arginine residues are subject to a wide array of post-translational modifications including methylation, citrullination, acetylation, ubiquitination, and sumoylation. The combinatorial action of these modifications regulates critical DNA processes including replication, repair, and transcription. In addition, enzymes that modify histone lysine and arginine residues have been correlated with a variety of human diseases including arthritis, cancer, heart disease, diabetes, and neurodegenerative disorders. Thus, it is important to fully understand the detailed kinetic and chemical mechanisms of these enzymes. Here, we review recent progress towards determining the mechanisms of histone lysine and arginine modifying enzymes. In particular, the mechanisms of S-adenosyl-methionine (AdoMet) dependent methyltransferases, FAD-dependent demethylases, iron dependent demethylases, acetyl-CoA dependent acetyltransferases, zinc dependent deacetylases, NAD(+) dependent deacetylases, and protein arginine deiminases are covered. Particular attention is paid to the conserved active-site residues necessary for catalysis and the individual chemical steps along the catalytic pathway. When appropriate, areas requiring further work are discussed.

Fig. 1

Proposed general chemical mechanism of AdoMet-dependent histone lysine methyltransferases. SET domain, Dot1/KMT4, and protein arginine methyltransferases use a similar mechanism of methyl transfer.

Fig. 2

Proposed chemical mechanism of LSD1/KDM1. This figure was adapted from Culhane et al. [53].

Fig. 3

Proposed chemical mechanism of JHDM enzymes.

Fig. 4

Proposed chemical mechanism of histone acetyltransferases.

Fig. 5

Proposed chemical mechanism of class I/II/IV HDACs.

Fig. 6

Proposed chemical mechanism of class III HDACs (or sirtuins).

Fig. 7

Proposed chemical mechanism of PAD enzymes. This figure was adapted from Thompson et al. [159].