We searched for specific inhibitors of the futalosine pathway, non-canonical pathway of menaquinone biosynthesis operating in Helicobacter pylori, from metabolites produced by actinomycetes. Aplasmomycin, a boron-containing macrodiolide, was isolated from Streptomyces sp. K15-0223 as a specific inhibitor of the futalosine pathway. We also showed boromycin, an analog of aplasmomycin, had similar activity.
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Exploring the Substrate-Assisted Dehydration of Chorismate Catalyzed by Dehydratase MqnA from QM/MM Calculations: The Role of Pocket Residues and the Hydrolysis Mechanism of N17D Mutant.
J Chem Inf Model
December 2023
School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China.
MqnA is the first enzyme on the futalosine pathway to menaquinone, which catalyzes the dehydration of chorismate to yield 3-enolpyruvyl-benzoate (3-EPB). MqnA is also the only chorismate dehydratase known so far. In this work, based on the recently determined crystal structures, we constructed the enzyme-substrate complex models and conducted quantum mechanics/molecular mechanics (QM/MM) calculations to elucidate the reaction details of MqnA and the critical roles of pocket residues.
View Article and Find Full Text PDFBiosynthesis and function of microbial methylmenaquinones.
Adv Microb Physiol
July 2023
Microbial Energy Conversion and Biotechnology, Department of Biology, Technical University of Darmstadt, Schnittspahnstraße 10, Darmstadt, Germany; Centre for Synthetic Biology, Technical University of Darmstadt, Darmstadt, Germany. Electronic address:
The membranous quinone/quinol pool is essential for the majority of life forms and its composition has been widely used as a biomarker in microbial taxonomy. The most abundant quinone is menaquinone (MK), which serves as an essential redox mediator in various electron transport chains of aerobic and anaerobic respiration. Several methylated derivatives of MK, designated methylmenaquinones (MMKs), have been reported to be present in members of various microbial phyla possessing either the classical MK biosynthesis pathway (Men) or the futalosine pathway (Mqn).
View Article and Find Full Text PDFExploring Connections between Oral Microbiota, Short-Chain Fatty Acids, and Specific Cancer Types: A Study of Oral Cancer, Head and Neck Cancer, Pancreatic Cancer, and Gastric Cancer.
Cancers (Basel)
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Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, 323 Ilsandong-gu, Goyang-si 10408, Gyeonggi-do, Republic of Korea.
Article Synopsis
- Recent research indicates that the oral microbiome might significantly contribute to the initiation and progression of cancer, though the exact causal mechanisms remain unclear.
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MAT Gain of Activity Mutation in Is Associated with Resistance to MTAN Transition State Analogues.
ACS Infect Dis
April 2023
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
is found in the gut lining of more than half of the world's population, causes gastric ulcers, and contributes to stomach cancers. Menaquinone synthesis in relies on the rare futalosine pathway, where 5'-methylthioadenosine nucleosidase (MTAN) is proposed to play an essential role. Transition state analogues of MTAN, including BuT-DADMe-ImmA (BTDIA) and MeT-DADMe-ImmA (MTDIA), exhibit bacteriostatic action against numerous diverse clinical isolates of with minimum inhibitory concentrations (MIC's) of <2 ng/mL.
View Article and Find Full Text PDFMechanism of chorismate dehydratase MqnA, the first enzyme of the futalosine pathway, proceeds via substrate-assisted catalysis.
J Biol Chem
December 2022
Institut für Biochemie und Biotechnologie, Charles-Tanford-Proteinzentrum, Martin-Luther-Universität - Halle-Wittenberg, Halle/Saale, Germany. Electronic address:
MqnA, the only chorismate dehydratase known so far, catalyzes the initial step in the biosynthesis of menaquinone via the futalosine pathway. Details of the MqnA reaction mechanism remain unclear. Here, we present crystal structures of Streptomyces coelicolor MqnA and its active site mutants in complex with chorismate and the product 3-enolpyruvyl-benzoate, produced during heterologous expression in Escherichia coli.
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