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Control and regulation of S‐Adenosylmethionine biosynthesis by the regulatory β subunit and quinolone‐based compounds
Author(s) -
Panmanee Jiraporn,
BradleyClarke Jack,
Mato Jose M.,
O'Neill Paul M.,
Antonyuk Svetlana V.,
Hasnain S. Samar
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14790
Subject(s) - allosteric regulation , methionine adenosyltransferase , active site , methionine , biochemistry , enzyme , mutant , regulator , chemistry , protein subunit , gating , biology , microbiology and biotechnology , biophysics , amino acid , gene
Methylation is an underpinning process of life and provides control for biological processes such as DNA synthesis, cell growth, and apoptosis. Methionine adenosyltransferases ( MAT ) produce the cellular methyl donor, S‐Adenosylmethionine ( SAM e). Dysregulation of SAM e level is a relevant event in many diseases, including cancers such as hepatocellular carcinoma and colon cancer. In addition, mutation of Arg264 in MAT α1 causes isolated persistent hypermethioninemia, which is characterized by low activity of the enzyme in liver and high level of plasma methionine. In mammals, MAT α1/α2 and MAT βV1/V2 are the catalytic and the major form of regulatory subunits, respectively. A gating loop comprising residues 113–131 is located beside the active site of catalytic subunits ( MAT α1/α2) and provides controlled access to the active site. Here, we provide evidence of how the gating loop facilitates the catalysis and define some of the key elements that control the catalytic efficiency. Mutation of several residues of MAT α2 including Gln113, Ser114, and Arg264 lead to partial or total loss of enzymatic activity, demonstrating their critical role in catalysis. The enzymatic activity of the mutated enzymes is restored to varying degrees upon complex formation with MAT βV1 or MAT βV2, endorsing its role as an allosteric regulator of MAT α2 in response to the levels of methionine or SAM e. Finally, the protein–protein interacting surface formed in MAT α2: MAT β complexes is explored to demonstrate that several quinolone‐based compounds modulate the activity of MAT α2 and its mutants, providing a rational for chemical design/intervention responsive to the level of SAM e in the cellular environment. Enzymes Methionine adenosyltransferase ( EC.2.5.1.6 ). Database Structural data are available in the RCSB PDB database under the PDB ID 6FBN (Q113A), 6FBP (S114A: P22 1 2 1 ), 6FBO (S114A: I222), 6FCB (P115G), 6FCD (R264A), 6FAJ ( wt MATα2: apo), 6G6R ( wt MATα2: holo)