Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin

Fenteany, Gabriel; Standaert, Robert F.; Lane, William S.; Choi, Soongyu; Corey, E. J.; Schreiber, Stuart L.

doi:10.1126/science.7732382

Cited by 1,583Ubiquitin and proteasome pathwaysProtease and Inhibitor MechanismsHeat shock proteins research

Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin

Fenteany, Gabriel, Standaert, Robert F., Lane, William S., Choi, Soongyu, Corey, E. J., Schreiber, Stuart L.·1995·Science

DOI 10.1126/science.7732382

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Abstract

Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces neurite outgrowth in a murine neuroblastoma cell line. Tritium-labeled lactacystin was used to identify the 20S proteasome as its specific cellular target. Three distinct peptidase activities of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities) were inhibited by lactacystin, the first two irreversibly and all at different rates. None of five other proteases were inhibited, and the ability of lactacystin analogs to inhibit cell cycle progression and induce neurite outgrowth correlated with their ability to inhibit the proteasome. Lactacystin appears to modify covalently the highly conserved amino-terminal threonine of the mammalian proteasome subunit X (also called MB1), a close homolog of the LMP7 proteasome subunit encoded by the major histocompatibility complex. This threonine residue may therefore have a catalytic role, and subunit X/MB1 may be a core component of an amino-terminal-threonine protease activity of the proteasome.

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These nucleophilic centers are also present in DNA and other biologically relevant compounds, such as glutathione.
“These nucleophilic centers are also present in DNA and other biologically relevant compounds, such as glutathione.116–121”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [117]

Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.
Rock, K. L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D., & Goldberg, A. L. (1994) · Cell · doi:10.1016/s0092-8674(94)90462-6 · Cited by 2,524 · see citing works
Cyclin is degraded by the ubiquitin pathway
Glotzer, M., Murray, A. W., & Kirschner, M. W. (1991) · Nature · doi:10.1038/349132a0 · Cited by 2,381 · see citing works
The ubiquitinproteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB
Palombella, V. J., Rando, O. J., Goldberg, A. L., & Maniatis, T. (1994) · Cell · doi:10.1016/s0092-8674(94)90482-0 · Cited by 2,097 · see citing works
A useful 12-I-5 triacetoxyperiodinane (the Dess-Martin periodinane) for the selective oxidation of primary or secondary alcohols and a variety of related 12-I-5 species
Dess, D. B., & Martin, J. C. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00019a027 · Cited by 2,091 · see citing works
The ubiquitin-proteasome proteolytic pathway
Ciechanover, A. J. (1994) · Cell · doi:10.1016/0092-8674(94)90396-4 · Cited by 1,804 · see citing works
Crystal Structure of the 20 S Proteasome from the Archaeon T. acidophilum at 3.4 Å Resolution
Löwe, J., Stock, D., Jap, B. K., Zwickl, P., Baumeister, W. P., & Huber, R. (1995) · Science · doi:10.1126/science.7725097 · Cited by 1,527 · see citing works
THE UBIQUITIN SYSTEM FOR PROTEIN DEGRADATION
Hershko, A., & Ciechanover, A. J. (1992) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.61.070192.003553 · Cited by 1,419 · see citing works
The role of cyclin synthesis and degradation in the control of maturation promoting factor activity
Murray, A. W., Solomon, M. J., & Kirschner, M. W. (1989) · Nature · doi:10.1038/339280a0 · Cited by 1,107 · see citing works
Proteasome from Thermoplasma acidophilum : a Threonine Protease
Seemüller, E., Lupas, A. N., Stock, D., Löwe, J., Huber, R., & Baumeister, W. P. (1995) · Science · doi:10.1126/science.7725107 · Cited by 634 · see citing works
Proteolysis, proteasomes and antigen presentation
Goldberg, A. L., & Rock, K. L. (1992) · Nature · doi:10.1038/357375a0 · Cited by 576 · see citing works
Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells.
Ōmura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., & Sasaki, Y. (1991) · The Journal of Antibiotics · doi:10.7164/antibiotics.44.113 · Cited by 510 · see citing works
The multicatalytic and 26 S proteases.
RECHSTEINER, M. C., Hoffman, L. M., & Dubiel, W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53218-x · Cited by 472 · see citing works
The multicatalytic proteinase complex, a major extralysosomal proteolytic system
Orłowski, M. (1990) · Biochemistry · doi:10.1021/bi00497a001 · Cited by 459 · see citing works
Penicillin acylase has a single-amino-acid catalytic centre
Duggleby, H. J., Tolley, S. P., Hill, C. P., Dodson, E. J., Dodson, G. G., & Moody, P. C. E. (1995) · Nature · doi:10.1038/373264a0 · Cited by 449 · see citing works
Ubiquitination
Finley, D., & Chau, V. (1991) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.07.110191.000325 · Cited by 442 · see citing works
Proteasomes: protein degradation machines of the cell
Peters, J. (1994) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(94)90115-5 · Cited by 311 · see citing works
The multicatalytic proteinase (prosome) is ubiquitous from eukaryotes to archaebacteria
Dahlmann, B., Kopp, F., Kuehn, L., et al. (1989) · FEBS Letters · doi:10.1016/0014-5793(89)81441-3 · Cited by 278 · see citing works
Structure of lactacystin, a new microbial metabolite which induces differentiation of neuroblastoma cells.
Ōmura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., FUJITA, S., & Nakagawa, A. (1991) · The Journal of Antibiotics · doi:10.7164/antibiotics.44.117 · Cited by 271 · see citing works
PRE2, highly homologous to the human major histocompatibility complex-linked RING10 gene, codes for a yeast proteasome subunit necessary for chrymotryptic activity and degradation of ubiquitinated proteins.
Heinemeyer, W., Gruhler, A., Möhrle, V., Mahé, Y., & Wolf, D. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53509-2 · Cited by 258 · see citing works
Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene
Martinez, C. K., & Monaco, J. J. (1991) · Nature · doi:10.1038/353664a0 · Cited by 257 · see citing works
Methylated ubiquitin inhibits cyclin degradation in clam embryo extracts.
Hershko, A., Ganoth, D., Pehrson, J. R., et al. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55308-4 · Cited by 243 · see citing works
Natural substrates of the Ubiquitin proteolytic pathway
RECHSTEINER, M. C. (1991) · Cell · doi:10.1016/0092-8674(91)90104-7 · Cited by 236 · see citing works
Primary structure of the Thermoplasma proteasome and its implications for the structure, function, and evolution of the multicatalytic proteinase
Zwickl, P., Grziwa, A., Pühler, G., Dahlmann, B., Lottspeich, F., & Baumeister, W. P. (1992) · Biochemistry · doi:10.1021/bi00119a004 · Cited by 232 · see citing works
A beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line.
Fenteany, G., Standaert, R. F., Reichard, G. A., et al. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.8.3358 · Cited by 224 · see citing works
Self-citation
cDNA Cloning and Interferon γ Down-Regulation of Proteasomal Aubunits X and Y
Akiyama, K., Yokota, K.-Y., Kagawa, S., et al. (1994) · Science · doi:10.1126/science.8066462 · Cited by 186 · see citing works
Subunit stoichiometry and three‐dimensional arrangement in proteasomes from Thermoplasma acidophilum.
Pühler, G., Weinkauf, S., Bachmann, L., Müller, S., Engel, A. H., Hegerl, R., & Baumeister, W. P. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05206.x · Cited by 178 · see citing works
Proteasome components with reciprocal expression to that of the MHC-encoded LMP proteins
Belich, M. P., Glynne, R. J., Senger, G., Sheer, D., & Trowsdale, J. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00174-3 · Cited by 155 · see citing works
Localization of subunits in proteasomes from Thermoplasma acidophilum by immunoelectron microscopy
Grziwa, A., Baumeister, W. P., Dahlmann, B., et al. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)81256-8 · Cited by 123 · see citing works
Purification and Characterization of a Z-Leu-Leu-Leu-MCA Degrading Protease Expected to Regulate Neurite Formation: A Novel Catalytic Activity in Proteasome
Tsubuki, S., Kawasaki, H., Saito, Y., Miyashita, N., Inomata, M., & Kawashima, S. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.2378 · Cited by 120 · see citing works
Alternative exon usage and processing of the major histocompatibility complex-encoded proteasome subunits.
Früh, K., Yang, Y. M., Arnold, D., et al. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41645-6 · Cited by 115 · see citing works
Proteasomes: protein and gene structures.
Tanaka, K., Tamura, T., Yoshimura, T., et al. (1992) · PubMed · Cited by 106 · see citing works
Relationships among the subunits of the high molecular weight proteinase, macropain (proteasome)
Lee, L. W., Moomaw, C. R., Orth, K., et al. (1990) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(90)90165-c · Cited by 65 · see citing works
N‐Terminal sequence similarities between components of the multicatalytic proteinase complex
Lilley, K. S., Davison, M. D., & Rivett, A. J. (1990) · FEBS Letters · doi:10.1016/0014-5793(90)80220-d · Cited by 54 · see citing works
Nucleotide sequence ofPUP1encoding a putative proteasome subunit inSaccharomyces cerevisiae
Haffter, P., & Fox, T. D. (1991) · Nucleic Acids Research · doi:10.1093/nar/19.18.5075 · Cited by 33 · see citing works

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Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases
Powers, J. C., Asgian, J. L., Ekici, Ö. D., & James, K. E. (2002) · Chemical Reviews · doi:10.1021/cr010182v · Cited by 1,090 · see citing works
Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus
Duan, D., Yue, Y., Yan, Z., Yang, J., & Engelhardt, J. F. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8317 · Cited by 391 · see citing works
Major histocompatibility complex class II‐restricted presentation of a cytosolic antigen by autophagy
Nimmerjahn, F., Milosevic, S., Behrends, U., Jaffee, E. M., Pardoll, D. M., Bornkamm, G. W., & Mautner, J. (2003) · European Journal of Immunology · doi:10.1002/eji.200323730 · Cited by 359 · see citing works
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Owa, T., Yoshino, H., Okauchi, T., Yoshimatsu, K., Ozawa, Y., Sugi, N. H., Nagasu, T., Koyanagi, N., & Kitoh, K. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm9902638 · Cited by 322 · see citing works
The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase.
Haspel, R. L., Salditt‐Georgieff, M., & Darnell, J. E. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01016.x · Cited by 312 · see citing works
Apoptotic Pathway and MAPKs Differentially Regulate Chemotropic Responses of Retinal Growth Cones
Campbell, D. S., & Holt, C. E. (2003) · Neuron · doi:10.1016/s0896-6273(03)00158-2 · Cited by 303 · see citing works
Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: Implications for degradation of oxidized proteins
Iwai, K., Drake, S. K., Wehr, N. B., Weissman, A. M., LaVaute, T., Minato, N., Klausner, R. D., Levine, R. L., & Rouault, T. A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4924 · Cited by 293 · see citing works
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Fenical, W., Jensen, P. R., Palladino, M. A., Lam, K. S., Lloyd, G. K., & Potts, B. C. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2008.10.075 · Cited by 291 · see citing works
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Ratner, J. N., Balasubramanian, B., Corden, J., Warren, S. L., & Bregman, D. B. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.5184 · Cited by 233 · see citing works
Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2
Iwai, K., Klausner, R. D., & Rouault, T. A. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00219.x · Cited by 211 · see citing works
Mechanisms for Generating the Autonomous cAMP-Dependent Protein Kinase Required for Long-Term Facilitation in Aplysia
Chain, D. G., Casadio, A., Schacher, S., Hegde, A. N., Valbrun, M., Yamamoto, N., Goldberg, A. L., Bartsch, D., Kandel, E. R., & Schwartz, J. H. (1999) · Neuron · doi:10.1016/s0896-6273(00)80686-8 · Cited by 186 · see citing works
Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblasts: The role of ferritin
Pourzand, C., Watkin, R. D., Brown, J. E., & Tyrrell, R. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.12.6751 · Cited by 176 · see citing works
Extended peptide-based inhibitors efficiently target the proteasome and reveal overlapping specificities of the catalytic β-subunits
Kessler, B. M., Tortorella, D., Altun, M., Kisselev, A. F., Fiebiger, E., Hekking, B. G., Ploegh, H. L., & Overkleeft, H. S. (2001) · Chemistry & Biology · doi:10.1016/s1074-5521(01)00069-2 · Cited by 163 · see citing works
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Schröter, F., & Adjaye, J. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt413 · Cited by 38 · see citing works
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Authors: Fenteany, G., Standaert, R. F., Lane, W. S., Choi, S., Corey, E. J., & Schreiber, S. L.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Fenteany, Gabriel
Standaert, Robert F.
Corey, E. J.
Schreiber, Stuart L.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1995-05-05
Volume: 268
Issue: 5211
Pages: 726-731
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.7732382
OpenAlex: W2066284211
Cited by: 1,583
References: 34
Citations by year: 2026: 8 · 2025: 18 · 2024: 12 · 2023: 13 · 2022: 13 · 2021: 21 · 2020: 20 · 2019: 23 · 2018: 20 · 2017: 24 · 2016: 22 · 2015: 25 · 2014: 35 · 2013: 34 · 2012: 34
FWCI: 38.03
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords: lactacystin, proteasome inhibition, 20S proteasome, LMP7, trypsin-like activity, chymotrypsin-like activity, cell cycle progression, neurite outgrowth, Streptomyces metabolites, covalent modification
MeSH terms: Acetylcysteine, Amino Acid Sequence, Animals, Carrier Proteins, Cattle, Chromatography, High Pressure Liquid, Cysteine Endopeptidases, Electrophoresis, Polyacrylamide Gel, Molecular Sequence Data, Multienzyme Complexes, Nerve Tissue Proteins, Neurons, Threonine, Tumor Cells, Cultured, Cysteine Proteinase Inhibitors, Proteasome Endopeptidase Complex, Mice

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Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin

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