The catalytic activity of serine hydroxymethyltransferase is essential for <i>de novo</i> nuclear <scp>dTMP</scp> synthesis in lung cancer cells

Giardina, G.; Paone, Alessio; Tramonti, Angela; Lucchi, R.; Marani, Marina; Magnifico, Maria Chiara; Bouzidi, Amani; Pontecorvi, Valentino; Guiducci, Giulia; Zamparelli, Carlotta; Rinaldo, Serena; Paiardini, Alessandro; Contestabile, Roberto; Cutruzzolà, Francesca

doi:10.1111/febs.14610

Cited by 35 publications

(40 citation statements)

References 30 publications

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“…By contrast AP-MS analysis of SHMT2-Flag identified only the cytosolic BRISC complex in agreement with Zheng and Greenberg [2]. This finding suggests that the SHMT2-Flag protein was localized outside mitochondria similar to the SHMT2α isoform [1,45]. Further structural analysis would be required to better understand the apparent cytosolic localization of SHMT2-Flag.…”

Section: Discussionsupporting

confidence: 75%

Cancer proteome and metabolite changes linked to SHMT2

et al. 2020

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Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.

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Section: Discussionsupporting

confidence: 75%

Cancer proteome and metabolite changes linked to SHMT2

et al. 2020

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“…All proteins resulted mainly tetrameric in solution; the K157S-K158S mutant required the addition of 200 μM pyridoxal phosphate (PLP) to the running buffer to fully populate the tetrameric state, whereas in the absence of PLP it eluted as a mixture of tetramer (55%) and dimer (45%) (Supplementary Figure S4A). The dichroic spectra of the two mutants superpose with the wild-type enzyme and their thermal stability is slightly reduced (Supplementary Figure S4B-C), as observed for other mutations located near the active site or the tetrameric interface (11).…”

Section: Methodsmentioning

confidence: 59%

“…SHMT1 and SHMT2 expression levels are cross-related in lung cancer cells (11,13); however, the mechanisms by which their expression is controlled to ensure the appropriate amounts of each isoform are unknown. We hypothesized that the control may involve the interaction of SHMT1 with the 5′UTR region of the SHMT2 transcripts, since it has been shown that SHMT1 can bind its own RNA at the level of 5′UTR.…”

Section: Resultsmentioning

confidence: 99%

“…We found a ∼35% increase in ishmt2-transfected cell viability over equivalent iscr-transfected cells only when MEM was supplemented with serine (Figure 9E). To further show that cell viability is related to SHMT1 activity, we have supplemented MEM with dTMP, a metabolite whose synthesis requires the CH 2 -THF produced in the serine to glycine breakdown mainly catalyzed by SHMT1 (11). Consistent with our hypothesis, dTMP supplementation led to similar cell viability in both iscr- and ishmt2-transfected cells (Figure 9E).…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, SHMT1 is likely to have a more versatile metabolic role, since it can switch the directionality of the reaction depending on cell type and metabolic needs (5,9). In addition, SHMT1, together with SHMT2α, undergoes nuclear localization during the S-phase of the cell cycle to participate in the synthesis of dTMP (10,11).…”

Section: Introductionmentioning

confidence: 99%

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The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

Guiducci

Paone

Tramonti

et al. 2019

Nucleic Acids Research

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Enzymes of intermediary metabolism are often reported to have moonlighting functions as RNA-binding proteins and have regulatory roles beyond their primary activities. Human serine hydroxymethyltransferase (SHMT) is essential for the one-carbon metabolism, which sustains growth and proliferation in normal and tumour cells. Here, we characterize the RNA-binding function of cytosolic SHMT (SHMT1) in vitro and using cancer cell models. We show that SHMT1 controls the expression of its mitochondrial counterpart (SHMT2) by binding to the 5′untranslated region of the SHMT2 transcript (UTR2). Importantly, binding to RNA is modulated by metabolites in vitro and the formation of the SHMT1–UTR2 complex inhibits the serine cleavage activity of the SHMT1, without affecting the reverse reaction. Transfection of UTR2 in cancer cells controls SHMT1 activity and reduces cell viability. We propose a novel mechanism of SHMT regulation, which interconnects RNA and metabolites levels to control the cross-talk between cytosolic and mitochondrial compartments of serine metabolism.

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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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The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells

Abstract: Structural data are available in the PDB under the accession number 6FL5.

Cited by 35 publications

References 30 publications

Cancer proteome and metabolite changes linked to SHMT2

Cancer proteome and metabolite changes linked to SHMT2

The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism

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

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