Differential 3-bromopyruvate inhibition of cytosolic and mitochondrial human serine hydroxymethyltransferase isoforms, key enzymes in cancer metabolic reprogramming
Abstract
The cytosolic and mitochondrial isoforms of serine hydroxymethyltransferase (SHMT1 and SHMT2, respectively) are well-recognized targets of cancer research, since their activity is critical for purine and pyrimidine biosynthesis and because of their prominent role in the metabolic reprogramming of cancer cells. Here we show that 3-bromopyruvate (3BP), a potent novel anti-tumour agent believed to function primarily by blocking energy metabolism, differentially inactivates human SHMT1 and SHMT2. SHMT1 is completely inhibited by 3BP, whereas SHMT2 retains a significant fraction of activity. Site directed mutagenesis experiments on SHMT1 demonstrate that selective inhibition relies on the presence of a cysteine residue at the active site of SHMT1 (Cys204) that is absent in SHMT2. Our results show that 3BP binds to SHMT1 active site, forming an enzyme-3BP complex, before reacting with Cys204. The physiological substrate l-serine is still able to bind at the active site of the inhibited enzyme, although catalysis does not occur. Modelling studies suggest that alkylation of Cys204 prevents a productive binding of l-serine, hampering interaction between substrate and Arg402. Conversely, the partial inactivation of SHMT2 takes place without the formation of a 3BP-enzyme complex. The introduction of a cysteine residue in the active site of SHMT2 by site directed mutagenesis (A206C mutation), at a location corresponding to that of Cys204 in SHMT1, yields an enzyme that forms a 3BP-enzyme complex and is completely inactivated. This work sets the basis for the development of selective SHMT1 inhibitors that target Cys204, starting from the structure and reactivity of 3BP.
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The cysteine-reactive inhibitor 3-bromopyruvate is selective for SHMT1 due to the absence of a cysteine residue in SHMT2's active site.
“The cysteine-reactive inhibitor 3-bromopyruvate is selective for SHMT1 due to the absence of a cysteine residue in SHMT2’s active site.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [157]
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Kim, H. M., Kim, E.-S., & Koo, J. S. (2018) · PubMed Central · Cited by 2 · see citing works
A systematic review of genes affecting mitochondrial processes in cancer
Sepúlveda-Villegas, M., Rojo, R., Garza-Hernandez, D., de la Rosa-Garza, M., & Treviño, V. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165846 · Cited by 2 · see citing works
Chen, Z., Zhou, H., Hu, H., & Chen, L. (2022) · Pathology & Oncology Research · doi:10.3389/pore.2022.1610337 · Cited by 1 · see citing works
Pharmacological interventions part II
Koltai, T., Reshkin, S. J., & Harguindey, S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819059-3.00014-9
Liao, Y., Wang, F., Zhang, Y., Cai, H., Song, F., & Hou, J. (2021) · Figshare · doi:10.6084/m9.figshare.14443317
Liao, Y., Wang, F., Zhang, Y., Cai, H., Song, F., & Hou, J. (2021) · Figshare · doi:10.6084/m9.figshare.14443314
Liao, Y., Wang, F., Zhang, Y., Cai, H., Song, F., & Hou, J. (2021) · Figshare · doi:10.6084/m9.figshare.14443311
Liao, Y., Wang, F., Zhang, Y., Cai, H., Song, F., & Hou, J. (2021) · Figshare · doi:10.6084/m9.figshare.14443308
Serine Hydroxymethyltransferase in Cancer Cells
Гаврилюк, Л. А. (2025) · Biochemistry (Moscow) Supplement Series B Biomedical Chemistry · doi:10.1134/s1990750824601371
Li, M., Xu, Y. N., Su, X., & Wen, J. (2026) · PeerJ · doi:10.7717/peerj.21570
- Authors
- Paiardini, A., Tramonti, A., Schirch, D., Guiducci, G., di Salvo, M. L., Fiascarelli, A., Giorgi, A., Maras, B., Cutruzzolà, F., & Contestabile, R.
- Affiliations
- Sapienza University of Rome (IT)
- Institute of Molecular Biology and Pathology (IT)
- Corresponding author
- Cutruzzolà, Francesca
- Contestabile, Roberto
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 1864
- Issue
- 11
- Pages
- 1506-1517
- ISSN
- 1570-9639 (ISSN-L)
- OpenAlex
- W2507335544
- Cited by
- 44
- References
- 60
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 6
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Regione Lazio (FILAS-RU-2014–1020)
- Sapienza University of Rome (2015-C26A155WEE, C26A149EC4)
- Associazione Italiana Ricerca sul Cancro (AIRC-IG2015, 16720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- 3-bromopyruvate, serine hydroxymethyltransferase, SHMT1, SHMT2, enzyme inhibition, active site cysteine, selective inhibitors, tumor metabolic reprogramming, pyrimidine synthesis, purine biosynthesis, alkylation, anticancer agents
- MeSH terms
- Protein Domains, Amino Acid Sequence, Antineoplastic Agents, Cloning, Molecular, Cysteine, Cytosol, Escherichia coli, Humans, Kinetics, Mitochondria, Protein Binding, Pyruvates, Recombinant Proteins, Serine, Glycine Hydroxymethyltransferase, Structure-Activity Relationship, Gene Expression, Mutagenesis, Site-Directed, Protein Structure, Secondary, Catalytic Domain, Enzyme Assays, Molecular Docking Simulation
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