Structural Basis of Human Dimeric α-Amino-β-Carboxymuconate-ε-Semialdehyde Decarboxylase Inhibition With TES-1025

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) regulates the de novo NAD+ synthesis pathway, crucial for cellular energy and homeostasis.
• ACMSD is an emerging therapeutic target for inflammatory diseases, metabolic disorders, aging, and liver and kidney conditions.

Purpose of the Study:

• To determine the crystal structure of human dimeric ACMSD in complex with the novel nanomolar inhibitor TES-1025.
• To elucidate the binding mode and mechanism of inhibition of TES-1025 at the atomic level.
• To provide structural insights for the development of new ACMSD-targeted therapeutics.

Main Methods:

• X-ray crystallography to determine the structure of the ACMSD-TES-1025 complex.
• Enzyme inhibition assays to quantify the binding affinity of TES-1025.

Main Results:

• The crystal structure reveals TES-1025 binds to the catalytic site of dimeric ACMSD, interacting with a Zn2+ ion and residues from both subunits.
• TES-1025 exhibits a high binding affinity with a K_i value of 0.85 ± 0.22 nM.
• The observed binding conformation differs from previously predicted modes, offering new structural information.

Conclusions:

• TES-1025 is the first identified nanomolar inhibitor of human ACMSD, demonstrating a novel binding mode.
• The structural data provides a foundation for designing potent and selective inhibitors targeting ACMSD for various diseases.
• This research advances the understanding of ACMSD inhibition and its therapeutic implications for liver and kidney diseases.