組蛋白甲基轉移酶

組蛋白甲基轉移酶（Histone methyltransferase，簡稱為HMT）是包括組蛋白-賴氨酸N-甲基轉移酶與組蛋白-精氨酸N-甲基轉移酶在內的是一大類組蛋白修飾酶類，它們催化將一個、兩個或三個甲基轉移到組蛋白的賴氨酸或精氨酸殘基上。被添加上的甲基基團主要位於組蛋白H3和H4的特定賴氨酸或精氨酸上。

**種類**
賴氨酸特異性組蛋白甲基轉移酶類可被細分為含SET結構域的和不含SET結構域的兩類。顧名思義，它們之間的區別在於存不存在SET這樣一種結構域。
人類基因所編碼的具有組蛋白甲基轉移酶活性的蛋白質包括：- ASH1L- DOT1L- EHMT1、EHMT2、EZH1、EZH2- MLL、MLL2、MLL3、MLL4、MLL5- NSD1- PRDM2- SET、SETBP1、SETD1A、SETD1B、SETD2、SETD3、SETD4、SETD5、SETD6、SETD7、SETD8、SETD9、SETDB1、SETDB2- SETMAR、SMYD1、SMYD2、SMYD3、SMYD4、SMYD5、SUV39H1、SUV39H2、SUV420H1、SUV420H2

**含SET結構域的賴氨酸特異性組蛋白甲基轉移酶**

**結構**
影響甲基轉移酶活性的結構包括：SET結構域（包括130個氨基酸）、前SET和後SET結構域。前SET區域包括半胱氨酸殘基，可形成三角鋅簇，緊密結合鋅原子並使結構穩定。SET結構域本身包含一個富含β-股的催化核心，從而形成幾個β摺疊區域。 一般在前SET結構域發現的β-股將形成的β-摺疊，它帶有SET結構域的β-股，導致SET結構域結構的細微變化。
These small changes alter the target residue site specificity for methylation and allow the SET domain methyltransferases to target many different residues. This interplay between the pre-SET domain and the catalytic core is critical for enzyme function.

**催化機制**
In order for the reaction to proceed, S-Adenosyl methionine (SAM) and the lysine residue of the substrate histone tail must first be bound and properly oriented in the catalytic pocket of the SET domain.  Next, a nearby tyrosine residue deprotonates the ε-amino group of the lysine residue.  The lysine chain then makes a nucleophilic attack on the methyl group on the sulfur atom of the SAM molecule, transferring the methyl group to the lysine side chain.
Active site of Histone Lysine N-Methyltransferase.  Lysine residue (in yellow) and S-Adenosyl methionine (SAM) (in blue) clearly visible.

**不含SET結構域的賴氨酸特異性組蛋白甲基轉移酶**
Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1.  Unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in the globular core of the histone, and is the only enzyme known to do so. A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies.

**結構**
The N terminal of Dot1 contains the active site.   A loop serving as the binding site for SAM links the N-terminal and the C-terminal domains of the Dot1 catalytic domain.  The C-terminal is important for the substrate specificity and binding of Dot1 because the region carries a positive charge, allowing for a favorable interaction with the negatively charged backbone of DNA.  Due to structural constraints, Dot1 is only able to methylate histone H3.

**精氨酸特異性組蛋白甲基轉移酶**
There are two different types of protein arginine methyltransferases (PRMTs) and three types of methylation that can occur at arginine residues on histone tails.  The first type of PRMTs (PRMT1, PRMT3, CARM1⧸PRMT4, and Rmt1⧸Hmt1) produce monomethylarginine and asymmetric dimethylarginine.  The second type (JBP1⧸PRMT5) produces monomethyl or symmetric dimethylarginine.  The differences in the two types of PRMTs arise from restrictions in the arginine binding pocket. 

**結構**
The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total).  Each PRMT has a unique N-terminal region and a catalytic core.  The arginine residue and SAM must be correctly oriented within the binding pocket.  SAM is secured inside the pocket by a hydrophobic interaction between an adenine ring and a phenyl ring of a phenylalanine.  

**催化機制**
A glutamate on a nearby loop interacts with nitrogens on the target arginine residue. This interaction redistributes the positive charge and leads to the deprotonation of one nitrogen group, which can then make a nucleophilic attack on the methyl group of SAM.  Differences between the two types of PRMTs determine the next methylation step: either catalyzing the dimethylation of one nitrogen or allowing the symmetric methylation of both groups.  However, in both cases the proton stripped from the nitrogen is dispersed through a histidine–aspartate proton relay system and released into the surrounding matrix.

**在基因調控中的作用**
Histone methylation plays an important role in epigenetic gene regulation.  Methylated histones can either repress or activate transcription as different experimental findings suggest. For example, it is likely that the methylation of lysine 9 on histone H3 (H3K9me3) in the promoter region of genes prevents excessive expression of these genes and, therefore, delays cell cycle transition and/or proliferation.  See Histone#Chromatin regulation.

**疾病的相關性**
Abnormal expression or activity of methylation-regulating enzymes has been noted in some types of human cancers, suggesting associations between histone methylation and malignant transformation of cells or formation of tumors.   In recent years, epigenetic modification of the histone proteins, especially the methylation of the histone H3, in cancer development has been an area of emerging research.  It is now generally accepted that in addition to genetic aberrations, cancer can be initiated by epigenetic changes in which gene expression is altered without genomic abnormalities.  These epigenetic changes include loss or gain of methylations in both DNA and histone proteins.
There is not yet compelling evidence that suggests cancers develop purely by abnormalities in histone methylation or its signaling pathways, however they may be a contributing factor. For example, down-regulation of methylation of lysine 9 on histone 3 (H3K9me3) has been observed in several types of human cancer (such as colorectal cancer, ovarian cancer, and lung cancer), which arise from either the deficiency of H3K9 methyltransferases or elevated activity or expression of H3K9 demethylases.

**進一步研究**
組蛋白甲基轉移酶可以用作癌症的診斷和預後的生物標誌物。 另外，關於組蛋白甲基轉移酶在細胞的惡性轉化，組織的癌發生和腫瘤發生中的功能和調節仍然存在許多問題。

**另見**
Histone-modifying enzymes
*組蛋白乙酰轉移酶（HAT）
*組蛋白脫乙酰酶（HDAC）
*組蛋白甲基化
*核小體
*染色質

**參考文獻**

**深入閱讀**
  url = -  doi = 10.1534/genetics.109.101899  

**外部鏈接**
   GeneReviews/NCBI/NIH/UW entry on Kleefstra Syndrome- Histone-Lysine+N-Methyltransferase- Protein-Arginine+N-Methyltransferase