AdoMet-dependent methylation, DNA methyltransferases and base flipping

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Twenty AdoMet-dependent methyltransferases (MTases) have been structurally characterized using X-ray crystallography and NMR.
• These enzymes include DNA, RNA, protein, and small molecule MTases, highlighting their diverse biological roles.

Purpose of the Study:

• To elucidate the common structural features of AdoMet-dependent MTases.
• To identify conserved structural folds for recognizing hypothetical MTases in structural proteomics.
• To understand the mechanistic basis of substrate recognition and catalysis, particularly DNA base flipping.

Main Methods:

• X-ray crystallography
• Nuclear Magnetic Resonance (NMR) spectroscopy

Main Results:

• A common 'AdoMet-dependent MTase fold' comprising a seven-stranded beta-sheet was identified in most characterized MTases.
• An exception is a protein arginine MTase with a distinct consensus fold lacking antiparallel hairpin strands.
• The conserved fold accommodates diverse substrates, from small molecules to macromolecules like DNA and RNA.
• DNA MTases utilize a 'base flipping' mechanism to access specific DNA bases within a catalytic pocket.

Conclusions:

• The conserved MTase fold is a key feature for enzyme classification and identification.
• The 'base flipping' mechanism is crucial for DNA MTases and likely relevant for other enzymes acting on DNA and RNA.
• Newly discovered eukaryotic MTase families present ongoing research opportunities in methyltransferase biology.