Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors

Makino, Yuko; Oe, Chihiro; Iwama, Kazuya; Suzuki, Satoshi; Nishiyama, Akie; Hasegawa, Kazuya; Okuda, Haruka; Hirata, Kazushige; Ueno, Makoto; Kawaji, Kumi; Sasano, Mina; Usui, Emiko; Hosaka, Toshiaki; Yabuki, Yukako; Shirouzu, Mikako; Katsumi, Makoto; Murayama, Kazutaka; Hayashi, Hironori

doi:10.1038/s42003-022-03555-x

Cited by 14 publications

(11 citation statements)

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“…Therefore, drugs targeting SHMT can disrupt multiple metabolic pathways of DNA and RNA synthesis, and SHMT is now considered a potential target of therapeutics against various pathogenic infections. [59] Glycolysis is a conserved metabolic mechanism for energy production in which glucose is converted to pyruvate and lactate under both aerobic and anaerobic conditions. It is known that P. falciparum relies exclusively on glycolysis for energy production and meets its energy needs through anaerobic metabolism.…”

Section: Parasite Cytosolmentioning

confidence: 99%

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Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

Ramli,

Mohd Faudzi

2023

Archiv der Pharmazie

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Asia is a hotspot for infectious diseases, including malaria, dengue fever, tuberculosis, and the pandemic COVID‐19. Emerging infectious diseases have taken a heavy toll on public health and the economy and have been recognized as a major cause of morbidity and mortality, particularly in Southeast Asia. Infectious disease control is a major challenge, but many surveillance systems and control strategies have been developed and implemented. These include vector control, combination therapies, vaccine development, and the development of new anti‐infectives. Numerous newly discovered agents with pharmacological anti‐infective potential are being actively and extensively studied for their bioactivity, toxicity, selectivity, and mode of action, but many molecules lose their efficacy over time due to resistance developments. These facts justify the great importance of the search for new, effective, and safe anti‐infectives. Diarylpentanoids, a curcumin derivative, have been developed as an alternative with better bioavailability and metabolism as a therapeutic agent. In this review, the mechanisms of action and potential targets of antimalarial drugs as well as the classes of antimalarial drugs are presented. The bioactivity of diarylpentanoids as a potential scaffold for a new class of anti‐infectives and their structure–activity relationships are also discussed in detail.

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Section: Parasite Cytosolmentioning

confidence: 99%

Section: Mechanisms Of Action and Possible Targets Of Antimalarialsmentioning

confidence: 99%

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

Ramli,

Mohd Faudzi

2023

Archiv der Pharmazie

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“…The data may be analyzed using Eqn (1), which is analogous to the 2-substrate enzyme kinetic model described by Florini and Vestling [11] and that was implemented in linearized form by Schirch and Ropp to study SHMT.…”

Section: Ligand Binding Assaysmentioning

confidence: 99%

“…Soybean serine hydroxymethyltransferase (SHMT) is a conserved enzyme in the folate cycle, providing 1-carbon units for multiple pathways including DNA synthesis, cellular methylation, and plant defense. Due to its key role in metabolism, SHMT from various organisms is a target for antimicrobial, antimalarial, chemotherapeutic and herbicide design [1][2][3][4]. In the soybean cv.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional analysis of two SHMT8 variants associated with soybean cyst nematode resistance

Korasick,

Owuocha,

Kandoth

et al. 2023

The FEBS Journal

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Two amino acid variants in soybean serine hydroxymethyltransferase 8 (SHMT8) are associated with resistance to the soybean cyst nematode (SCN), a devastating agricultural pathogen with worldwide economic impacts for soybean production. SHMT8 is a cytoplasmic enzyme that catalyzes the PLP‐dependent conversion of serine and tetrahydrofolate (THF) to glycine and 5,10‐methylenetetrahydrofolate. A previous study of the P130R/N358Y double variant of SHMT8, identified in the SCN‐resistant soybean cultivar (cv.) Forrest, showed profound impairment of folate binding affinity and reduced THF‐dependent enzyme activity, relative to the highly active SHMT8 in cv. Essex, which is susceptible to SCN. Given the importance of SCN‐resistance in soybean agriculture, we report here biochemical and structural characterization of the P130R and N358Y single variants to elucidate their individual effects on soybean SHMT8. We find that both single variants have reduced THF‐dependent catalytic activity relative to Essex SHMT8 (10 to 50‐fold decrease in kcat/Km) but are significantly more active than the P130R/N368Y double variant. The kinetic data also show that the single variants lack THF‐substrate inhibition as found in Essex SHMT8, an observation with implications for regulation of the folate cycle. Five crystal structures of the P130R and N358Y variants in complex with various ligands (resolutions from 1.49 to 2.30 Å) reveal distinct structural impacts of the mutations and provide new insights into allosterism. Our results support the notion that the P130R/N358Y double variant in Forrest SHMT8 produces unique and unexpected effects on the enzyme, which cannot be easily predicted from the behavior of the individual variants.

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“…This enzyme is ubiquitous, present in both of procaryotes and eucaryotes. Therefore, it is an important target for anticancer (Ubonprasert et al 2019 ; Geeraerts et al 2021 ; García-Cañaveras et al 2021 ), antiplasmodial (Witschel et al 2015 ) and antibacterial (Makino and Iwama 2022 ). SHMT belongs to the aspartate aminotransferase superfamily (Type I fold PLP-dependent enzymes) along with threonine aldolase and alanine racemase.…”

Section: Introductionmentioning

confidence: 99%

Characterization of thermostable serine hydroxymethyltransferase for β-hydroxy amino acids synthesis

et al. 2022

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Abstractβ-hydroxy amino acids, such as serine, threonine, and phenylserine, are important compounds for medical purposes. To date, there has been only limited exploration of thermostable serine hydroxylmethyltransferase (SHMT) for the synthesis of these amino acids, despite the great potential that thermostable enzymes may offer for commercial use due to their high stability and catalytic efficiencies. ITBSHMT_1 (ITB serine hydroxylmethyltransferase clone number 1) from thermophilic and methanol-tolerant bacteria Pseudoxanthomonas taiwanensis AL17 was successfully cloned. Biocomputational analysis revealed that ITBSHMT_1 contains Pyridoxal-3′-phosphate and tetrahydrofolatebinding residues. Structural comparisons show that ITBSHMT_1 has 5 additional residues VSRQG on loop near PLP-binding site as novel structural feature which distinguish this enzyme with other characterized SHMTs. In silico mutation revealed that the fragment might have very essential role in maintaining of PLP binding on structure of ITBSHMT_1. Recombinant protein was produced in Escherichia coli Rosetta 2(DE3) in soluble form and purified using NiNTA affinity chromatography. The purified protein demonstrated the best activity at 80 °C and pH 7.5 based on the retro aldol cleavage of phenylserine. Activity decreased significantly in the presence of 3 mM transition metal ions but increased in the presence of 30 mM β-mercaptoethanol. ITBSHMT_1 demonstrated Vmax, Km, Kcat, and Kcat/Km at 242 U/mg, 23.26 mM, 186/s, and 8/(mM.s), respectively. The aldol condensation reaction showed the enzyme’s best activity at 80 °C for serine, threonine, or phenylserine, with serine synthesis showing the highest specific activity. Biocomputational analysis revealed that high intramolecular interaction within the 3D structure of ITBSHMT_1 might be correlated with the enzyme’s high thermal stability. The above data suggest that ITBSHMT_1 is a potential and novel enzyme for the production of various β-hydroxy amino acids.

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Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors

Cited by 14 publications

References 50 publications

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

Structural and functional analysis of two SHMT8 variants associated with soybean cyst nematode resistance

Characterization of thermostable serine hydroxymethyltransferase for β-hydroxy amino acids synthesis

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