8J6N

Crystal structure of Cystathionine gamma-lyase in complex with compound 1

Summary for 8J6N

• Entry DOI: 10.2210/pdb8j6n/pdb
• Descriptor: Cystathionine gamma-lyase, [6-methyl-4-[(~{E})-(oxamoylhydrazinylidene)methyl]-5-oxidanyl-pyridin-3-yl]methyl dihydrogen phosphate, GLYCEROL, ... (5 entities in total)
• Functional Keywords: lyase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 12
• Total formula weight: 520647.25

Authors

Hibi, R.,Toma-Fukai, S.,Shimizu, T.,Hanaoka, K. (deposition date: 2023-04-26, release date: 2024-02-14)

Primary citation

Echizen, H.,Hanaoka, K.,Shimamoto, K.,Hibi, R.,Toma-Fukai, S.,Ohno, H.,Sasaki, E.,Komatsu, T.,Ueno, T.,Tsuchiya, Y.,Watanabe, Y.,Otsuka, T.,Saito, H.,Nagatoishi, S.,Tsumoto, K.,Kojima, H.,Okabe, T.,Shimizu, T.,Urano, Y.
Discovery of a cystathionine gamma-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5'-phosphate (PLP) via Schiff base formation.
Sci Rep, 13:16456-16456, 2023

PubMed Abstract: D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5'-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures.

PubMed: 37777556
DOI: 10.1038/s41598-023-43536-6

Experimental method

X-RAY DIFFRACTION (1.9 Å)