Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD+ synthesis pathway and plays an important role in maintaining NAD+ homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a Ki value of 0.85 ± 0.22 nM and binds in the catalytic site, interacting with the Zn2+ metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.

Structural Basis of Human Dimeric α-Amino-β-Carboxymuconate-ε-Semialdehyde Decarboxylase Inhibition With TES-1025 / Cianci, M.; Giacche, N.; Cialabrini, L.; Carotti, A.; Liscio, P.; Rosatelli, E.; De Franco, F.; Gasparrini, M.; Robertson, J.; Amici, A.; Raffaelli, N.; Pellicciari, R.. - In: FRONTIERS IN MOLECULAR BIOSCIENCES. - ISSN 2296-889X. - ELETTRONICO. - 9:(2022). [10.3389/fmolb.2022.834700]

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

Cianci M.
Co-primo
Supervision
;
Cialabrini L.;Gasparrini M.;Amici A.;Raffaelli N.;
2022-01-01

Abstract

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD+ synthesis pathway and plays an important role in maintaining NAD+ homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a Ki value of 0.85 ± 0.22 nM and binds in the catalytic site, interacting with the Zn2+ metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.
2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/300075
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