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ATP allosterically regulates an acyl-CoA oxidase
David H Perez1, Arup Mondal1, Weijie Xu1
1Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA.
Nature Communications
|August 8, 2025
Summary
Adenosine triphosphate (ATP) allosterically regulates Acyl-CoA oxidase (ACOX) by enhancing its binding to the FAD cofactor. This discovery reveals a novel regulatory mechanism linking ATP levels to fatty acid and secondary metabolism.
Area of Science:
- Biochemistry
- Enzymology
- Metabolic Regulation
Background:
- Acyl-CoA oxidase (ACOX) enzymes are crucial in peroxisomal fatty acid metabolism and secondary metabolism in various organisms.
- These enzymes bind adenosine triphosphate (ATP) at unique sites within the dimer interface, distinct from typical substrate-binding sites.
Purpose of the Study:
- To elucidate the mechanism by which ATP regulates ACOX enzyme activity.
- To investigate the specificity of ATP binding and its effect on cofactor affinity.
Main Methods:
- X-ray crystallography was employed to study the apo dimeric enzyme structure.
- Molecular dynamics simulations were utilized to understand ATP binding and its effects.
- Site-directed mutagenesis was performed to probe the ATP binding site's role.
Main Results:
- ATP specifically stimulates ACOX activity by increasing the enzyme's affinity for its flavin adenine dinucleotide (FAD) cofactor.
- ATP binding is facilitated by an unprecedented shift in an alpha-helix bundle, allowing access to the buried dimer interface site.
- An allosteric network connects the ATP and FAD binding sites, mediating the stimulatory effect.
Conclusions:
- ATP allosterically controls the binding of ACOX enzymes to FAD, thereby regulating enzymatic activity.
- This regulatory mechanism suggests a potential link between cellular ATP levels and both primary and secondary metabolic pathways.
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