Histone catalytic mechanism

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

Corminboeuf C, Hu P, Tuckerman ME, Zhang Y (2006) Unexpected catalytic mechanism for histone deacetylase suggested by a density functional theory QM/MM study. J Am Chem Soc 128 4530 1531... 

Hu P, Zhang Y (2006) Catalytic mechanism and product specificity of the histone lysine methyl-transferase set7/9 An ab initio QM/MM-FE study with multiple initial structures. J Am Chem Soc... 

Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ (2003) Structure and catalytic mechanism of the human histone methyltransferase set7/9. Nature 421 652-656... 

It has been shown that JHDMIA demethylates only mono- and dimethyl lysine of histone H3 (H3K36). This was rather unexpected given that the catalytic mechanism of a Jmj C domain does not require a protonated nitrogen, unlike LS D1, and therefore could also have the ability to remove the methyl in all three states. So far, two crystal structures have been deposited in the protein database but without any publication underlining the work. The crystal structures describe two forms of the human JHDMIA lysine demethylase, apo and in a complex with a-ketoglutarate (PDB codes 2yul and 2yu2). 

Tanner, KG., Trievel, R.C., Kuo, M.H., Howard, R.M., Berger, S.L., Albs, C.D., Marmorstein, R. and Denu, J.M. (1999) Catalytic mechanism and function of invariant glutamic acid 173 from the histone acetyltransferase GCN5 transcriptional coactivator. The Journal of Biological Chemistry, 274 (26), 18157-18160. 

Yan, Y, Harper, S., Speicher, D.W. and Marmorstein, R. (2002) The catalytic mechanism of the ESAl histone acetyltransferase involves a self-acetylated intermediate. Nature Structural Biology,... 

Figure 9 Proposed catalytic mechanisms for histone deacetylases using a (a) GABO pair mechanism or (b) single bifunctional GABO mechanism.

The identities of several protein arginine methyltransferases are now known, but only a few have been shown to have specificity for histone proteins. The mammalian PRMT1, JBP1, and CARMI, as well as the Saccharomyces Rmtl, have histone methyltransferase activity (McBride and Silver, 2001). However, the catalytic mechanism for the methyl group transfer as well as the makeup of the active sites of PRMTs differ somewhat from SET domain proteins. 

SIRT2) in complex with carba-NAD and a histone H4 acetyllysine peptide (PDB code ISZD) (b) outline catalytic mechanism of lysine deacetylation by SIRT deacetylases, which proceeds by activation of the acetyl group by 0-glycosylation (c) representative SIRT inhibitor chemotypes. 

With the characterized mechanism, the next key question is the origin of its catalytic power. A prerequisite for this investigation is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio QM/MM approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9... 

Fig. 4. Domain structure of mammalian DNA methyltransferases. (a) The domain structure of the known DNA methyltransferases, depicting the conserved catalytic domain (dark box) and other identified domains. Conserved aminoacid motifs in the catalytic domain are shown in lighter shade of gray. (b) Schematic representation of the reported protein-protein interactions of Dnmtl with a number of regulatory proteins interactions that modulate Dnmtl methyitransferase activity (darker rectangles) or mediate methylation-independent transcriptional repression mechanisms (lighter rectangles). When Dnmtl represses transcription through its enzymatic activity, it has been described to interact with some proteins PCNA [37] and an oncogenic transcription factor PML-RAR [25]. Note that in the case of the PML-RAR transcription factor, histone deacetylase 1 (HDACl) is also bound to the complex. When Dnmtl represses transcription via methylation-independent pathways, it binds to HDACs either directly [34] or indirectly through other proteins the corepressor DMAPl [33], the retinoblastoma protein, and a gene-specific transcription factor [31].

So far 18 different members of HDACs have been discovered in humans and classified into four classes based on their homology to yeast histone deacetylases [33]. Class I includes four different subtypes (HDACl, 2, 3, 8), class II contains six subtypes tvhich are divided into two subclasses class Ila with subtypes HDAC4, 5, 7, 9 and class Ilb with HDAC6, 10. Class I and class II HDAC share significant structural homology, especially within the highly conserved catalytic domains. HDACs 6 and 10 are unique as they have two catalytic domains. HDACll is referred to as class IV. While the activity of class I, II and IV HDACs depends on a zinc based catalysis mechanism, the class III enzymes, also called sirtuins, require nicotinamide adenine dinucleotide as a cofactor for their catalysis. 

This theory most directly applies to carcinogenesis induced by Ni(ll), since Ni(ll) binds preferentially to histones (proteins of the cell nucleus) rather than to DNA (354—373). The Ni -protein complexes can then catalyze oxidative DNA damage by ROS (149). Catalytic rather than stoichiometric action of Ni(ll) complexes in oxidative DNA damage is consistent with significant genotoxic effects caused by small concentrations of the metal ion (350-368). Indirect (i.e., ROS mediated) oxidative mechanisms are also considered among the major causes of Cd(ll) and Cr(Vl) induced carcinogenicity (351, 353). 

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