Cited by 18Amino Acid Enzymes and MetabolismBiochemical and Molecular ResearchFolate and B Vitamins Research

Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes

Tramonti, Angela, Paiardini, Alessandro, Paone, Alessio, Bouzidi, Amani, Giardina, Giorgio, Guiducci, Giulia, Magnifico, Maria Chiara, Rinaldo, Serena +4 more·2018·Archives of Biochemistry and Biophysics

Abstract

Serine hydroxymethyltransferase (SHMT) is a pivotal enzyme in one-carbon metabolism that catalyses the reversible conversion of serine and tetrahydrofolate into glycine and methylenetetrahydrofolate. It exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. Research on one-carbon metabolism in cancer cell lines has shown that SHMT1 preferentially catalyses serine synthesis, whereas in mitochondria SHMT2 is involved in serine breakdown. Recent research has focused on the identification of inhibitors that bind at the folate pocket. We have previously found that a representative derivative of the pyrazolopyran scaffold, namely 2.12, inhibits both SHMT isoforms, with a preference for SHMT1, causing apoptosis in lung cancer cell lines. Here we show that the affinity of 2.12 for SHMT depends on the identity of the amino acid substrate bound to the enzyme. The dissociation constant of 2.12 is 50-fold lower when it binds to SHMT1 enzyme-serine complex, as compared to the enzyme-glycine complex. Evidence is presented for a similar behaviour of compound 2.12 in the cellular environment. These findings suggest that the presence and identity of the amino acid substrate should be considered when designing SHMT inhibitors. Moreover, our data provide the proof-of-concept that SHMT inhibitors selectively targeting the directionality of one-carbon metabolism flux could be designed.

Integrity signals

Registry

Crossref · 10.1016/j.abb.2018.07.001

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Prior to Nonaka and co-worker's study, only marginal selectivity between the two SHMT isoforms had been achieved, with inhibitors being selective for SHMT1 by 2- to 3-fold.

    “Prior to Nonaka and co-worker’s study, generally, only marginal selectivity between the two SHMT isoforms has been achieved, with the inhibitors being selective for SHMT1 by 2- to 3-fold.”

Cites

Flagged first, then by citations

1 of the 29 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Authors
Tramonti, A., Paiardini, A., Paone, A., Bouzidi, A., Giardina, G., Guiducci, G., Magnifico, M. C., Rinaldo, S., McDermott, L., Menendez, J. A., Contestabile, R., & Cutruzzolà, F.
Affiliations
  • Institute of Molecular Biology and Pathology (IT)
  • Sapienza University of Rome (IT)
  • University of Pittsburgh (US)
Corresponding author
  • Contestabile, Roberto
  • Cutruzzolà, Francesca
Venue
Archives of Biochemistry and Biophysics
Publisher
Elsevier BV
Published
2018-09
Volume
653
Pages
71-79
ISSN
0003-9861 (ISSN-L)
OpenAlex
W2810955549
Cited by
18
References
29
Citations by year
2026: 4 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 1
FWCI
0.97
Type
journal article
Language
en
Open access
closed
Locations
  • Archives of Biochemistry and Biophysics (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
Funders
  • Associazione Italiana per la Ricerca sul Cancro (AIRC-IG2015 n. 16720)
  • Sapienza University of Rome (RP11715C644A5CCE)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
Keywords
serine hydroxymethyltransferase, SHMT1, SHMT2, one-carbon metabolism, enzyme-substrate complex, enzyme inhibition, lung cancer, inhibitor design, tetrahydrofolate
MeSH terms
Enzyme Inhibitors, Glycine, Humans, Hydrogen Bonding, Lung Neoplasms, Pyrans, Pyrazoles, Serine, Glycine Hydroxymethyltransferase, Spectrometry, Fluorescence, Substrate Specificity, Apoptosis, Cell Line, Tumor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review