8I09

Crystal structure of serine acetyltransferase from Salmonella typhimurium complexed with butyl gallate

Summary for 8I09

• Entry DOI: 10.2210/pdb8i09/pdb
• Descriptor: Serine acetyltransferase, CYSTEINE, butyl 3,4,5-tris(oxidanyl)benzoate, ... (5 entities in total)
• Functional Keywords: salmonella, serine acetyltransferase, cysteine synthesis, beta-helix, transferase
• Biological source: Salmonella enterica subsp. enterica serovar Typhimurium
• Total number of polymer chains: 12
• Total formula weight: 367616.76

Authors

Toyomoto, T.,Ono, K.,Shiba, T.,Momitani, K.,Zhang, T.,Tsutsuki, H.,Ishikawa, T.,Hoso, K.,Hamada, K.,Rahman, A.,Zhong, H.,Akaike, T.,Yamamoto, K.,Matsuoka, M.,Hanaoka, K.,Niidome, T.,Sawa, T. (deposition date: 2023-01-10, release date: 2023-11-22, Last modification date: 2024-11-13)

Primary citation

Toyomoto, T.,Ono, K.,Shiba, T.,Momitani, K.,Zhang, T.,Tsutsuki, H.,Ishikawa, T.,Hoso, K.,Hamada, K.,Rahman, A.,Wen, L.,Maeda, Y.,Yamamoto, K.,Matsuoka, M.,Hanaoka, K.,Niidome, T.,Akaike, T.,Sawa, T.
Alkyl gallates inhibit serine O -acetyltransferase in bacteria and enhance susceptibility of drug-resistant Gram-negative bacteria to antibiotics.
Front Microbiol, 14:1276447-1276447, 2023

PubMed Abstract: A principal concept in developing antibacterial agents with selective toxicity is blocking metabolic pathways that are critical for bacterial growth but that mammalian cells lack. Serine -acetyltransferase (CysE) is an enzyme in many bacteria that catalyzes the first step in l-cysteine biosynthesis by transferring an acetyl group from acetyl coenzyme A (acetyl-CoA) to l-serine to form -acetylserine. Because mammalian cells lack this l-cysteine biosynthesis pathway, developing an inhibitor of CysE has been thought to be a way to establish a new class of antibacterial agents. Here, we demonstrated that alkyl gallates such as octyl gallate (OGA) could act as potent CysE inhibitors and in bacteria. Mass spectrometry analyses indicated that OGA treatment markedly reduced intrabacterial levels of l-cysteine and its metabolites including glutathione and glutathione persulfide in to a level similar to that found in lacking the gene. Consistent with the reduction of those antioxidant molecules in bacteria, became vulnerable to hydrogen peroxide-mediated bacterial killing in the presence of OGA. More important, OGA treatment intensified susceptibilities of metallo-β-lactamase-expressing Gram-negative bacteria ( and ) to carbapenem. Structural analyses showed that alkyl gallate bound to the binding site for acetyl-CoA that limits access of acetyl-CoA to the active site. Our data thus suggest that CysE inhibitors may be used to treat infectious diseases caused by drug-resistant Gram-negative bacteria not only via direct antibacterial activity but also by enhancing therapeutic potentials of existing antibiotics.

PubMed: 37965540
DOI: 10.3389/fmicb.2023.1276447

Experimental method

X-RAY DIFFRACTION (1.8 Å)