Histone enzyme

Chromatin is composed of nucleosomes, where each comprise 147 base pairs of DNA wrapped around an octamer oftwo copies of each histone H2A, H2B, H3, and H4. Nucleosomes are folded into higher-order structures that are stabilized by linker histones. Chromatin structure can be altered by enzymes that posttranslationally modify histones (e.g., through phosphorylation, acetylation, methylation, or ubiquitination) or by ATP-driven chromatin-remodeling complexes that alter nucleosome position and/or composition. 

Due to the large amount of DNA present within the nucleus it must be carefully packaged. In the resting cell DNA is tightly compacted around basic histone proteins, excluding the binding of the enzyme RNA polymerase II, which activates the formation of mRNA. This conformation of the chromatin structure... 

An enzyme activity ascribed to many coactivators, which transfers acetyl groups to lysine residues of histone tails of the nucleosomes and thereby facilitate their disruption and the opening of the chromatin. 

Enzyme activity ascribed to corepressors, which is the removal of acetyl groups from lysine residues of histone tails. Thereby the assembly of nucleosomes is maintained, which leads to a dense, transcriptional inactive chromatin structure. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

AB INITIO QUANTUM MECHANICAL/MOLECULAR MECHANICAL STUDIES OF HISTONE MODIFYING ENZYMES... 

In our simulations of histone modifying enzymes, the computational approaches centered on the pseudobond ab initio quantum mechanical/molecular mechanical (QM/MM) approach. This approach consists of three major components [20,26-29] a pseudobond method for the treatment of the QM/MM boundary across covalent bonds, an efficient iterative optimization procedure which allows for the use of the ab initio QM/MM method to determine the reaction paths with a realistic enzyme environment, and a free energy perturbation method to take account... 

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. 

ENZYME MECHANISM AND CATALYSIS OF HISTONE LYSINE METHYLATION [49,50]... 

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... 

Biel M, Wascholowski V, Giannis A (2005) Epigenetics - an epicenter of gene regulation histones and histone-modifying enzymes. Angew Chem-Int Edit 44 3186-3216... 

Santos-rosa H, Caldas C (2005) Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer 41 2381-2402... 

Holbert MA, Marmorstein R (2005) Structure and activity of enzymes that remove histone modifications. Curr Opin Struct Biol 15 673-680... 

Wang S, Hu P, Zhang Y (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis the case of histone lysine methyltransferase set7/9. J Phys Chem B ASAP... 

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

The nucleus contains a large number of proteins other than histones. These so-called nonhistone proteins may or may not be tightly associated with the chromosomes. For example, the nucleus contains enzymes associated with the synthesis of RNA and DNA these are nonhistone proteins, but they are not part of the structure of chromosomes. One group of nonhistone proteins are the high mobility group (HMG) proteins, named for their rapid movement on polyacryl-amide gel electrophoresis. The HMG proteins, but not histone HI, are associated with the chromatin that is most active in RNA synthesis. 

---