1.Application of methyltransferases in microbial synthesis of natural products.
Xiangyan ZHANG ; Xiaolin SHEN ; Xinxiao SUN ; Jia WANG ; Qipeng YUAN
Chinese Journal of Biotechnology 2021;37(6):1869-1886
Methyltransferases (MTs) constitute a large group of enzymes that catalyze the transfer of a methyl moiety, most frequently from S-adenosyl-L-methionine, to their substrates. It plays an essential role in regulation of gene expression and synthesis of many natural compounds. Owing to its broad substrate spectrum, MTs make important contributions to diversify the spectrum of products through methylation modifications. Recently, great progress has been made in application of MTs for the biosynthesis of various natural products including phenylpropane compounds, fragrances, hormones and antibiotics, which is summarized in this review. Moreover, we highlighted the strategies of using MTs for efficient production and for expanding the diversity of these methylated natural products, and discussed the current challenges and future prospects in this area.
Biological Products
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Methylation
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Methyltransferases/metabolism*
2.Research advances on the effects of RNA N6-methyladenosine modification in the relevant pathophysiological processes of wound repair.
Chinese Journal of Burns 2022;38(10):989-993
N6-methyladenosine (m6A) exists widely in eukaryotes as a post-transcriptional modification. This modification is dynamically and reversibly regulated by methyltransferases and demethylases, and is involved in regulating biological effects through m6A binding proteins. Recent studies have elucidated that m6A is involved in embryonic skin morphogenesis, wound repair, and pathophysiological processes such as inflammatory response, angiogenesis, and fibrosis. This review summarizes the role of m6A and its related proteins in the related pathophysiological processes of wound repair, so as to provide a new theoretical basis for the treatment strategy of wound repair.
RNA/metabolism*
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Methylation
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Adenosine/metabolism*
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Methyltransferases/metabolism*
3.RNA methylation and neurovascular unit remodeling.
Xinyi LÜ ; Yishu FAN ; Shuntong KANG ; Bo XIAO ; Mengqi ZHANG
Journal of Central South University(Medical Sciences) 2021;46(5):536-544
RNA methylation is of great significance in the regulation of gene expression, among which the more important methylation modifiers are N6-methyladenosine (m6A) and 5-methylcytosine (m5C). The methylation process is mainly regulated by 3 kinds of proteins: methyltransferase, demethylase, and reader. m6A, m5C, and their related proteins have high abundance in the brain, and they have important roles in the development of the nervous system and the repair and remodeling of the vascular system. The neurovascular unit (NVU) is a unit of brain structure and function composed of neurons, capillaries, astrocytes, supporting cells, and extracellular matrix. The local microenvironment for NVU has an important role in nerve cell function repair, and the remodeling of NVU is of great significance in the prognosis of various neurological diseases.
5-Methylcytosine
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Adenosine/metabolism*
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Methylation
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Methyltransferases/metabolism*
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RNA
4.Synthesis and application of the methyl analogues of S-adenosyl-L-methionine.
Chinese Journal of Biotechnology 2023;39(11):4428-4444
Methylation plays a vital role in biological systems. SAM (S-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation reactions. SAM-dependent methyltransferases (MTase) transfer a methyl group from SAM to substrates, thereby altering their physicochemical properties or biological activities. In recent years, many SAM analogues with alternative methyl substituents have been synthesized and applied to methyltransferases that specifically transfer different groups to the substrates. These include functional groups for labeling experiments and novel alkyl modifications. This review summarizes the recent progress in the synthesis and application of SAM methyl analogues and prospects for future research directions in this field.
S-Adenosylmethionine/metabolism*
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Methionine
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Methyltransferases/metabolism*
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Methylation
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Racemethionine
5.The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications.
Yanjing LI ; Kexue GE ; Tingting LI ; Run CAI ; Yong CHEN
Protein & Cell 2023;14(3):165-179
Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.
Nucleosomes
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Histones/metabolism*
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Histone-Lysine N-Methyltransferase/metabolism*
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Lysine/metabolism*
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Methyltransferases/metabolism*
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Methylation
6.METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis.
Qiuchan XIONG ; Caojie LIU ; Xin ZHENG ; Xinyi ZHOU ; Kexin LEI ; Xiaohan ZHANG ; Qian WANG ; Weimin LIN ; Ruizhan TONG ; Ruoshi XU ; Quan YUAN
International Journal of Oral Science 2022;14(1):26-26
The dorsal lingual epithelium, which is composed of taste buds and keratinocytes differentiated from K14+ basal cells, discriminates taste compounds and maintains the epithelial barrier. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotic cells. How METTL3-mediated m6A modification regulates K14+ basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear. Here we show knockout of Mettl3 in K14+ cells reduced the taste buds and enhanced keratinocytes. Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds. Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization, but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery. Mechanically, we revealed that the most frequent m6A modifications were enriched in Hippo and Wnt signaling, and specific peaks were observed near the stop codons of Lats1 and FZD7. Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.
Animals
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Epithelium/metabolism*
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Homeostasis
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Methylation
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Methyltransferases/metabolism*
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Mice
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RNA
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Taste Buds/metabolism*
7.Characterization of Lysine Monomethylome and Methyltransferase in Model Cyanobacterium Synechocystis sp. PCC 6803.
Xiaohuang LIN ; Mingkun YANG ; Xin LIU ; Zhongyi CHENG ; Feng GE
Genomics, Proteomics & Bioinformatics 2020;18(3):289-304
Protein lysine methylation is a prevalent post-translational modification (PTM) and plays critical roles in all domains of life. However, its extent and function in photosynthetic organisms are still largely unknown. Cyanobacteria are a large group of prokaryotes that carry out oxygenic photosynthesis and are applied extensively in studies of photosynthetic mechanisms and environmental adaptation. Here we integrated propionylation of monomethylated proteins, enrichment of the modified peptides, and mass spectrometry (MS) analysis to identify monomethylated proteins in Synechocystis sp. PCC 6803 (Synechocystis). Overall, we identified 376 monomethylation sites in 270 proteins, with numerous monomethylated proteins participating in photosynthesis and carbon metabolism. We subsequently demonstrated that CpcM, a previously identified asparagine methyltransferase in Synechocystis, could catalyze lysine monomethylation of the potential aspartate aminotransferase Sll0480 both in vivo and in vitro and regulate the enzyme activity of Sll0480. The loss of CpcM led to decreases in the maximum quantum yield in primary photosystem II (PSII) and the efficiency of energy transfer during the photosynthetic reaction in Synechocystis. We report the first lysine monomethylome in a photosynthetic organism and present a critical database for functional analyses of monomethylation in cyanobacteria. The large number of monomethylated proteins and the identification of CpcM as the lysine methyltransferase in cyanobacteria suggest that reversible methylation may influence the metabolic process and photosynthesis in both cyanobacteria and plants.
Bacterial Proteins/metabolism*
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Lysine/metabolism*
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Methyltransferases/metabolism*
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Photosynthesis
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Protein Processing, Post-Translational
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Synechocystis/growth & development*
8.METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity.
Xiaoyang DOU ; Lulu HUANG ; Yu XIAO ; Chang LIU ; Yini LI ; Xinning ZHANG ; Lishan YU ; Ran ZHAO ; Lei YANG ; Chuan CHEN ; Xianbin YU ; Boyang GAO ; Meijie QI ; Yawei GAO ; Bin SHEN ; Shuying SUN ; Chuan HE ; Jun LIU
Protein & Cell 2023;14(9):683-697
METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
Animals
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Mice
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Methylation
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Chromatin
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Histones/metabolism*
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RNA, Messenger/genetics*
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Methyltransferases/metabolism*
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RNA/metabolism*
9.Research progress of m6A methylation in prostate cancer.
Asian Journal of Andrology 2023;25(2):166-170
N6-methyladenosine (m6A) is a ubiquitous RNA modification in mammals. This modification is "written" by methyltransferases and then "read" by m6A-binding proteins, followed by a series of regulation, such as alternative splicing, translation, RNA stability, and RNA translocation. At last, the modification is "erased" by demethylases. m6A modification is essential for normal physiological processes in mammals and is also a very important epigenetic modification in the development of cancer. In recent years, cancer-related m6A regulation has been widely studied, and various mechanisms of m6A regulation in cancer have also been recognized. In this review, we summarize the changes of m6A modification in prostate cancer and discuss the effect of m6A regulation on prostate cancer progression, aiming to profile the potential relevance between m6A regulation and prostate cancer development. Intensive studies on m6A regulation in prostate cancer may uncover the potential role of m6A methylation in the cancer diagnosis and cancer therapy.
Animals
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Male
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Humans
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Methylation
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Adenosine/metabolism*
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RNA/metabolism*
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Methyltransferases/metabolism*
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Prostatic Neoplasms
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Mammals
10.METTL9 mediated N1-histidine methylation of zinc transporters is required for tumor growth.
Mengyue LV ; Dan CAO ; Liwen ZHANG ; Chi HU ; Shukai LI ; Panrui ZHANG ; Lianbang ZHU ; Xiao YI ; Chaoliang LI ; Alin YANG ; Zhentao YANG ; Yi ZHU ; Kaiguang ZHANG ; Wen PAN
Protein & Cell 2021;12(12):965-970