| Autor: |
Honami Echizen, Kenjiro Hanaoka, Kazuhito Shimamoto, Ryota Hibi, Sachiko Toma-Fukai, Hisashi Ohno, Eita Sasaki, Toru Komatsu, Tasuku Ueno, Yukihiro Tsuchiya, Yasuo Watanabe, Takao Otsuka, Hiroaki Saito, Satoru Nagatoishi, Kouhei Tsumoto, Hirotatsu Kojima, Takayoshi Okabe, Toshiyuki Shimizu, Yasuteru Urano |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Scientific Reports, Vol 13, Iss 1, Pp 1-11 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-023-43536-6 |
| Popis: |
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 (IC50 = 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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