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Abstract Nat/Ivy is a diverse and ubiquitous CoA‐binding evolutionary lineage that catalyzes acyltransferase reactions, primarily converting thioesters into amides. At the heart of the Nat/Ivy fold is a phosphate‐binding loop that bears a striking resemblance to that of P‐loop NTPases—both are extended, glycine‐rich loops situated between a β‐strand and an α‐helix. Nat/Ivy, therefore, represents an intriguing intersection between thioester chemistry, a putative primitive energy currency, and an ancient mode of phospho‐ligand binding. Current evidence suggests that Nat/Ivy emerged independently of other cofactor‐utilizing enzymes, and that the observed structural similarity—particularly of the cofactor binding site—is the product of shared constraints instead of shared ancestry. The reliance of Nat/Ivy on a β‐α‐β motif for CoA‐binding highlights the extent to which this simple structural motif may have been a fundamental evolutionary “nucleus” around which modern cofactor‐binding domains condensed, as has been suggested for HUP domains, Rossmanns, and P‐loop NTPases. Finally, by dissecting the patterns of conserved interactions between Nat/Ivy families and CoA, the coevolution of the enzyme and the cofactor was analyzed. As with the Rossmann, it appears that the pyrophosphate moiety at the center of the cofactor predates the enzyme, suggesting that Nat/Ivy emerged sometime after the metabolite dephospho‐CoA.
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This content will become publicly available on December 1, 2025
Crystal structure of the 4-hydroxybutyryl-CoA synthetase (ADP-forming) from nitrosopumilus maritimus
Abstract The 3-hydroxypropionate/4-hydroxybutyrate (3HP/4HB) cycle from ammonia-oxidizing Thaumarchaeota is currently considered the most energy-efficient aerobic carbon fixation pathway. TheNitrosopumilus maritimus4-hydroxybutyryl-CoA synthetase (ADP-forming; Nmar_0206) represents one of several enzymes from this cycle that exhibit increased efficiency over crenarchaeal counterparts. This enzyme reduces energy requirements on the cell, reflecting thaumarchaeal success in adapting to low-nutrient environments. Here we show the structure of Nmar_0206 fromNitrosopumilus maritimusSCM1, which reveals a highly conserved interdomain linker loop between the CoA-binding and ATP-grasp domains. Phylogenetic analysis suggests the widespread prevalence of this loop and highlights both its underrepresentation within the PDB and structural importance within the (ATP-forming) acyl-CoA synthetase (ACD) superfamily. This linker is shown to have a possible influence on conserved interface interactions between domains, thereby influencing homodimer stability. These results provide a structural basis for the energy efficiency of this key enzyme in the modified 3HP/4HB cycle of Thaumarchaeota.
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- Award ID(s):
- 1231306
- PAR ID:
- 10586739
- Publisher / Repository:
- Nature
- Date Published:
- Journal Name:
- Communications Biology
- Volume:
- 7
- Issue:
- 1
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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