One lysine, two acyl marks: 2-hydroxyisobutyrylation and acetylation of G6PD differ in outcome and regulation

Authentic 2-hydroxyisobutyrylation of human G6PD is strongly site-dependent, abolishing activity at K171, K205, K360, and K288 while reducing efficiency and destabilizing at K386.

• Why it matters: Site-specific consequences of lysine 2-hydroxyisobutyrylation are unclear because prior approaches relied on substitutions or mixed, heterogeneous protein preparations.
• What they did: Using genetic code expansion, homogeneous G6PD variants carrying an authentic 2-hydroxyisobutyryl group at nine lysines were tested for activity and stability, and K386 was compared with acetylation at the same residue.
• The result: AcK386 destabilized without strongly impairing catalysis, whereas 2-hydroxyisobutyrylation at K386 impaired both; SIRT2 removed both marks and restored activity, while SIRT1 deacetylated but poorly removed the 2-hydroxyisobutyryl group.

AI summary of the abstract · may contain errors · not medical advice · read the paper.