Catalytic Space Engineering as a Strategy to Activate C–H Oxidation on 5-Methylcytosine in Mammalian Genome | Zendy

Sushma Sappa | Zendy; Debasis Dey | Zendy; Babu Sudhamalla | Zendy; Kabirul Islam | Zendy

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Catalytic Space Engineering as a Strategy to Activate C–H Oxidation on 5-Methylcytosine in Mammalian Genome

Author(s) -

Sushma Sappa,

Debasis Dey,

Babu Sudhamalla,

Kabirul Islam

Publication year - 2021

Publication title -

journal of the american chemical society

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 7.115

H-Index - 612

eISSN - 1520-5126

pISSN - 0002-7863

DOI - 10.1021/jacs.1c03815

Subject(s) - chemistry , 5 methylcytosine , catalysis , enzyme , dna , active site , genome , chromosomal translocation , chemical space , suppressor , gene , biochemistry , computational biology , gene expression , dna methylation , drug discovery , biology

Conditional remodeling of enzyme catalysis is a formidable challenge in protein engineering. Herein, we have undertaken a unique active site engineering tactic to command catalytic outcomes. With ten-eleven translocation (TET) enzyme as a paradigm, we show that variants with an expanded active site significantly enhance multistep C-H oxidation in 5-methylcytosine (5mC), whereas a crowded cavity leads to a single-step catalytic apparatus. We further identify an evolutionarily conserved residue in the TET family with a remarkable catalysis-directing ability. The activating variant demonstrated its prowess to oxidize 5mC in chromosomal DNA for potentiating expression of genes including tumor suppressors.

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