Histone Methylation Enzymes

The secondary structure of the proteins are shown as dark gray helices and the beta strands and coil regions are in light gray. The zinc ions are shown as spheres, (b) The NAD molecule bound to the enzyme and the acetylated peptide of p53 are shown as ball and sticks. The acetylated lysine is labeled. 

Despite the large amount of biochemical and structural studies of sirtuins in complex with various substrates, cofactors and reaction products, the catalytic mechanism of this class of enzymes is still a matter of debate. SN -like [56] and SN -like [60] mechanisms have been inferred from structural studies but further biochemical and possibly structural studies will be required to clarify which mechanism is used by sirtuins. It should also be noted that another matter of debate concerns the mode of noncompetitive inhibition of sirtuins by the reaction product nicotinamide [62], various structural studies having highlighted different binding pockets for this molecule [63, 64]. 

Protein methylation is one of the most common protein modifications found in a wide range of prokaryotic and eukaryotic proteins that are involved either in regulation of transcription or in translation. Several amino acids can be modified, mainly by either N-methylation or C-methylation. Protein methylation has been 

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Cheng X, Collins RE, Zhang X (2005) Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomolec Struct 34 267-294... 

Figure 3. Schematic representation of the interplay of the various epigenetic marks and its therapeutic potential DNA methylation causes the concomitant deacetylation of the histones, whereby it negatively (—) coixelates with histone acetylation and positively (+) with histone methylation, particularly the repressive marks. The active methylation marks correlate positively with histone acetylation. The loss of activity or the loss or mistargeting of these activities are the most common cause of epigenetic diseases. Shown in the boxes are the small molecular modulators (a, activators or i, inhibitors) of the various enzymes that have potential to develop epigenetic therapeutics...

In contrast, lysine methylation seems to be an exceptionally stable modification. Early studies showed that turnover of histone methyl groups was even slower than turnover of the histones themselves (e.g., [26,27]). No conclusive evidence has yet been found for histone demethylating enzymes, and they may not exist [28]. It may be that removal of methylated histones mostly occurs passively, through post-replication chromatin assembly and replacement of old, methylated histones with new, unmethylated ones. However, the possibility remains that local methylation patterns may be more dynamic and may involve novel mechanisms for removal of methylated tails [28]. 

Transcriptional repression by DNA methylation is achieved by various modes of action. In one such mechanism, DNA methylation simply inhibits the binding of a transcription factor [17[. By a more complex means of action, a number of DNA methyl-binding proteins potentiate transcriptional silencing. In some cases, binding is accompanied by the action of an associated histone-modifying enzyme. 

Histone methylation by methyltransferases is another vddely described modification that also plays an important role in regulation of transcriptional activity. Methylation can occur either on arginine or on lysine residues in the N-termini of histones and therefore this group of enzymes can be separated into protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). 

Our current knowledge regarding histone methylation stems in large part from the study of histone methyltransferases. Several of these enzymes are essential for development, vdth deregulated expression being linked to human disorders such as cancer [4]. Whereas proteins responsible for methylation of histones have been knovm for almost a decade, enzymes with histone demethylase activity (HDM) have only recently been discovered. Here we summarize our current knowledge regarding histone demethylases with a focus on the demethylation mechanisms, potential roles... 

Methylation at K9 is associated with transcriptional inactivation and establishment of a heterochromatin state. K9 methylation by the methyltransferase SUV39 directs binding of the transcriptional repressor HP1, which is a component of transcriptionally inactive heterochromatin (Fig. 1.36). SUV39, HP1 and histone deacetylase enzymes have been found to be associated with inactive, hypophosphorylated complexes between the tumor suppressor pRb and the transcription factor E2F (see Chapter 13). 

Histone-modifying Enzymes are Targeted by Methyl Binding Domains... 

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