Crystal Structure of 4-Hydroxybutyryl-CoA Synthetase (ADP-forming): A Key Enzyme in the Thaumarchaeal Hydroxypropionate/Hydroxybutyrate cycle

The 3-hydroxypropionate/4-hydroxybutyrate (3HP/4HB) cycle from ammonia-oxidizing Thaumarchaeota is currently considered the most energy-efficient aerobic carbon fixation pathway. The Nitrosopumilus maritimus 4-hydroxybutyryl-CoA synthetase (ADP-forming) (Nmar\_0206) from this cycle represents one of a number of proteins that exhibit increased efficiency over its crenarchaeal counterparts. Nmar\_0206 catalyzes the conversion of 4-hydroxybutyrate (4HB) and Coenzyme-A (CoA) to 4-hydroxybutyryl-CoA through the dephosphorylation of ATP to ADP, as opposed to AMP as seen in Crenarchaeota. This enzyme reduces energy requirements on the cell, thus reflecting thaumarchaeal success in adapting to low-nutrient environments. The first high-resolution structure of Nmar_0206 from Nitrosopumilus maritimus SCM1 reveals a highly conserved interdomain stabilizing loop between the CoA-binding and ATP-grasp domains. Phylogenetic analysis suggests the widespread prevalence of this loop and highlights its underrepresentation within the PDB and its structural importance within the ATP-forming Acetyl-CoA superfamily (ACD). ### Competing Interest Statement The authors have declared no competing interest.