Lactacystin

Lactacystin
Stereo skeletal formula of lactacystin ((2R)-2-amid, (2R,3S,4R)-3-hydrox,-2-((1S)-1-hydrox)prop,-4-meth)
Names
Systematic IUPAC name
(2R)-2-Acetamido-3-({(2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxopyrrolidine-2-carbonyl}sulfanyl)propanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
  • 3735 ☒N
  • 2299173 (2R)-2-amid, (3S,4R)-3-hydrox,-2-((1S)-1-hydrox)prop,-4-meth ☒N
MeSH Lactacystin
  • 3870
  • 45039639 (3S,4R)-3-hydrox,-2-((1R)-1-hydrox)prop,-4-meth
  • 46782036 (2R)-2-amid, (3S,4R)-3-hydrox,-2-((1R)-1-hydrox)prop,-4-meth
  • 3034764 (2R)-2-amid, (3S,4R)-3-hydrox,-2-((1S)-1-hydrox)prop,-4-meth
  • InChI=1S/C15H24N2O7S/c1-6(2)10(19)15(11(20)7(3)12(21)17-15)14(24)25-5-9(13(22)23)16-8(4)18/h6-7,9-11,19-20H,5H2,1-4H3,(H,16,18)(H,17,21)(H,22,23) ☒N
    Key: DAQAKHDKYAWHCG-UHFFFAOYSA-N ☒N
  • InChI=1/C15H24N2O7S/c1-6(2)10(19)15(11(20)7(3)12(21)17-15)14(24)25-5-9(13(22)23)16-8(4)18/h6-7,9-11,19-20H,5H2,1-4H3,(H,16,18)(H,17,21)(H,22,23)
    Key: DAQAKHDKYAWHCG-WBMULXAQBF
  • CC(C)C(O)C1(NC(=O)C(C)C1O)C(=O)SCC(NC(C)=O)C(O)=O
  • CC(=O)NC(CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O)C(=O)O
  • OC1C(C)C(=O)NC1(C(=O)SCC(NC(C)=O)C(O)=O)C(O)C(C)C
Properties
C15H24N2O7S
Molar mass 376.42 g·mol−1
log P 0.086
Acidity (pKa) 3.106
Basicity (pKb) 10.891
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Lactacystin is an organic compound naturally synthesized by bacteria of the genus Streptomyces first identified as an inducer of neuritogenesis in neuroblastoma cells in 1991.[1] The target of lactacystin was subsequently found to be the proteasome on the basis of its affinity for certain catalytic subunits of the proteasome by Fenteany and co-workers in 1995.[2] The proteasome is a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. Lactacystin was the first non-peptidic proteasome inhibitor discovered and is widely used as a research tool in biochemistry and cell biology. The transformation product of lactacystin clasto-lactacystin β-lactone (also known as omuralide) covalently modifies the amino-terminal threonine of specific catalytic subunits of the proteasome, a discovery that helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease. The molecule is commonly used in biochemistry and cell biology laboratories as a selective inhibitor of the proteasome.[2][3] The first total synthesis of lactacystin was developed in 1992 by Corey and Reichard,[4] and a number of other syntheses of this molecule have also been published. There are more than 1,660 entries for lactacystin in PubMed as of January 2019.

See also

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References

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  1. ^ Omura S, Fujimoto T, Otoguro K, Matsuzaki K, Moriguchi R, Tanaka H, Sasaki Y. (1991). Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells: S. Omura, et al. J. Antibiot. 44(1):113-6.
  2. ^ a b Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL (1995). "Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin". Science. 268 (5211): 726–31. Bibcode:1995Sci...268..726F. doi:10.1126/science.7732382. PMID 7732382. S2CID 37779687.
  3. ^ Fenteany G, Schreiber SL (1998). "Lactacystin, proteasome function, and cell fate". J. Biol. Chem. 273 (15): 8545–8. doi:10.1074/jbc.273.15.8545. PMID 9535824.
  4. ^ "Total Synthesis of Lactacystin" Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114, 10677.
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