Structural insights into auxiliary cofactor usage by radical S-adenosylmethionine enzymes

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Radical S-adenosylmethionine (SAM) enzymes are a versatile class catalyzing diverse biochemical transformations.
• All radical SAM enzymes share a conserved catalytic core and bind a [4Fe-4S] cluster via a tri-cysteine motif.
• Many radical SAM enzymes incorporate additional metal cofactors or utilize cosubstrates like methylcobalamin.

Purpose of the Study:

• To investigate the structural diversity and cofactor binding strategies of radical SAM enzymes.
• To elucidate the role of N- and C-terminal domains in anchoring auxiliary metal cofactors.
• To understand the importance of protein-protein interactions in radical SAM enzyme catalysis.

Main Methods:

• Analysis of recently reported structures of radical SAM enzymes.
• Examination of enzyme complexes involved in sulfur insertion and metallocofactor assembly.
• Comparative structural analysis of auxiliary cofactor docking surfaces.

Main Results:

• Auxiliary metal cofactors and cosubstrates are anchored by variable N- and C-terminal domains.
• Despite domain variability, a common surface is utilized for auxiliary cofactor docking.
• Interactions with iron-sulfur cluster assembly proteins and scaffold proteins are integral to catalysis.

Conclusions:

• Architectural diversity in radical SAM enzymes is accommodated by conserved cofactor docking mechanisms.
• Structural insights into these complexes open new avenues for understanding radical SAM enzyme function.
• The study highlights the significance of protein-protein interactions in the catalytic pathways of radical SAM enzymes.