Current Medicinal Chemistry

Atta-ur-Rahman, FRS
Honorary Life Fellow
Kings College
University of Cambridge
Cambridge
UK

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Molecular and Enzymatic Profiles of Mammalian DNA Methyltransferases: Structures and Targets for Drugs

Author(s): F. Xu, C. Mao, Y. Ding, C. Rui, L. Wu, A. Shi, H. Zhang, L. Zhang, Z. Xu.

Abstract:

DNA methylation is an epigenetic event involved in a variety array of processes that may be the foundation of genetic phenomena and diseases. DNA methyltransferase is a key enzyme for cytosine methylation in DNA, and can be divided into two functional families (Dnmt1 and Dnmt3) in mammals. All mammalian DNA methyltransferases are encoded by their own single gene, and consisted of catalytic and regulatory regions (except Dnmt2). Via interactions between functional domains in the regulatory or catalytic regions and other adaptors or cofactors, DNA methyltransferases can be localized at selective areas (specific DNA/nucleotide sequence) and linked to specific chromosome status (euchromatin/ heterochromatin, various histone modification status). With assistance from UHRF1 and Dnmt3L or other factors in Dnmt1 and Dnmt3a/Dnmt3b, mammalian DNA methyltransferases can be recruited, and then specifically bind to hemimethylated and unmethylated double-stranded DNA sequence to maintain and de novo setup patterns for DNA methylation. Complicated enzymatic steps catalyzed by DNA methyltransferases include methyl group transferred from cofactor Ado-Met to C5 position of the flipped-out cytosine in targeted DNA duplex. In the light of the fact that different DNA methyltransferases are divergent in both structures and functions, and use unique reprogrammed or distorted routines in development of diseases, design of new drugs targeting specific mammalian DNA methyltransferases or their adaptors in the control of key steps in either maintenance or de novo DNA methylation processes will contribute to individually treating diseases related to DNA methyltransferases.

Keywords: DNA methyltransferase, epigenetics, enzyme catalysis, protein-DNA interactions, DNA MTase, replication- foci targeting, RFT, targeting sequence, TS, methyl-CpG binding protein-2, MeCP2, methyl-CpG binding domain protein, MBD2, MBD3, HDAC1, histone deacetylase-1, HDAC2, H3-K9 methyltransferase, Suv39h1, HP1b, DNMT3A2, ATRX, alpha-thalassemia and mental retardation on X chromosome, TRDMT1, tRNA aspartic acid methyltransferase 1, S-adenosyl-L-homocysteine, UHRF1

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Article Details

VOLUME: 17
ISSUE: 33
Year: 2010
Page: [4052 - 4071]
Pages: 20
DOI: 10.2174/092986710793205372
Price: $58