8YT1

Crystal structure of ACMSD in complex with malonate

8YT1 の概要

• エントリーDOI: 10.2210/pdb8yt1/pdb
• 分子名称: 2-amino-3-carboxymuconate 6-semialdehyde decarboxylase, ZINC ION, MALONIC ACID, ... (4 entities in total)
• 機能のキーワード: kynurenine, decarboxylase, nad homeostasis, tryptophan metabolism, metalloenzyme, lyase
• 由来する生物種: Pseudomonas fluorescens
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 119452.28

構造登録者

Yang, Y.,Liu, A. (登録日: 2024-03-24, 公開日: 2024-10-16, 最終更新日: 2025-04-30)

主引用文献

Yang, Y.,Davis, I.,Altman, R.A.,Liu, A.
alpha-Amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase catalyzes enol/keto tautomerization of oxaloacetate.
J.Biol.Chem., 300:107878-107878, 2024

PubMed Abstract: ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodegenerative disorders. However, unraveling its enzyme-substrate complex has been challenging due to its high catalytic efficiency. Here, we present a combined biochemical and structural study wherein we determined the crystal structure of ACMSD in complex with malonate. Our analysis revealed significant rearrangements in the active site, particularly in residues crucial for ACMS decarboxylation, including Arg51, Arg239∗ (a residue from an adjacent subunit), His228, and Trp194. Docking modeling studies proposed a putative ACMS binding mode. Additionally, we found that ACMSD catalyzes oxaloacetic acid (OAA) tautomerization at a rate of 6.51 ± 0.42 s but not decarboxylation. The isomerase activity of ACMSD on OAA warrants further investigation in future biological studies. Subsequent mutagenesis studies and crystallographic analysis of the W194A variant shed light on the roles of specific second-coordination sphere residues. Our findings indicate that Arg51 and Arg239∗ are crucial for OAA tautomerization. Moreover, our comparative analysis with related isomerase superfamily members underscores a general strategy employing arginine residues to promote OAA isomerization. Given the observed isomerase activity of ACMSD on OAA and its structural similarity to ACMS, we propose that ACMSD may facilitate isomerization to ensure ACMS is in the optimal tautomeric form for subsequent decarboxylation initiated by the zinc-bound hydroxide ion. Overall, these findings deepen the understanding of the structure and function of ACMSD, offering insights into potential therapeutic interventions.

PubMed: 39395800
DOI: 10.1016/j.jbc.2024.107878

実験手法

X-RAY DIFFRACTION (2.22 Å)