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{{Chembox {{Chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 400128403 | verifiedrevid = 400128403
| ImageFile = Lactacystin.svg | ImageFile = Lactacystin.svg
| ImageFile_Ref = {{chemboximage|correct|??}} | ImageFile_Ref = {{chemboximage|correct|??}}
| ImageSize = 244 | ImageSize = 244
| ImageName = Stereo skeletal formula of lactacystin | ImageName = Stereo skeletal formula of lactacystin ((2''R'')-2-amid, (2''R'',3''S'',4''R'')-3-hydrox,-2-((1''S'')-1-hydrox)prop,-4-meth)
| IUPACName = 2-(acetylamino)-3--4-methyl-5-oxopyrrolidin-2-yl}carbonyl)sulfanyl]propanoic acid | SystematicName = (2''R'')-2-Acetamido-3-({(2''R'',3''S'',4''R'')-3-hydroxy-2--4-methyl-5-oxopyrrolidine-2-carbonyl}sulfanyl)propanoic acid
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| CASNo = 133343-34-7 | CASNo = 133343-34-7
| CASNo_Ref = {{cascite|correct|??}} | CASNo_Ref = {{cascite|correct|??}}
| PubChem = 3870 | PubChem = 3870
⚫ | PubChem1 =
| PubChem_Ref = {{Pubchemcite|changed|PubChem}}
⚫ | PubChem1_Comment = <small>-2-((1''S'')-1-hydrox)prop</small>
⚫ | PubChem1 =
| PubChem2 = 45039639
| PubChem1_Ref = {{Pubchemcite|correct|PubChem}}
| PubChem1_Comment = <small>-2-((1''S'')-1-hydrox)prop</small> | PubChem2_Comment = <small>(3''S'',4''R'')-3-hydrox,-2-((1''R'')-1-hydrox)prop,-4-meth</small>
| PubChem2 = 45039639 | PubChem3 = 46782036
⚫ | PubChem3_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''R'')-1-hydrox)prop,-4-meth</small>
| PubChem2_Ref = {{Pubchemcite|correct|PubChem}}
⚫ | PubChem4 = 3034764
⚫ | PubChem2_Comment = <small>(3''S'',4''R'')-3-hydrox,-2-((1''R'')-1-hydrox)prop,-4-meth</small>
⚫ | PubChem4_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''S'')-1-hydrox)prop,-4-meth</small>
| PubChem3 = 46782036
⚫ | ChemSpiderID = 3735
| PubChem3_Ref = {{Pubchemcite|correct|PubChem}}
⚫ | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
⚫ | PubChem3_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''R'')-1-hydrox)prop,-4-meth</small>
⚫ | ChemSpiderID1 = 2299173
⚫ | PubChem4 = 3034764
| ChemSpiderID1_Ref = {{chemspidercite|changed|chemspider}}
| PubChem4_Ref = {{Pubchemcite|correct|PubChem}}
| PubChem4_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''S'')-1-hydrox)prop,-4-meth</small> | ChemSpiderID1_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''S'')-1-hydrox)prop,-4-meth</small>
⚫ | MeSHName = Lactacystin
⚫ | ChemSpiderID = 3735
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChEBI_Ref = {{ebicite|changed|EBI}}
⚫ | ChEBI = 52722
⚫ | ChemSpiderID1 = 2299173
⚫ | ChEMBL = 374308
⚫ | ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}
⚫ | ChEMBL_Ref = {{ebicite|changed|EBI}}
⚫ | ChemSpiderID1_Comment = <small>(2''R'')-2-amid, (3''S'',4''R'')-3-hydrox,-2-((1''S'')-1-hydrox)prop,-4-meth</small>
⚫ | SMILES = CC(C)C(O)C1(NC(=O)C(C)C1O)C(=O)SCC(NC(C)=O)C(O)=O
⚫ | MeSHName = Lactacystin
⚫ | SMILES1 = CC(=O)NC(CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O)C(=O)O
⚫ | ChEBI = 52722
⚫ | SMILES2 = OC1C(C)C(=O)NC1(C(=O)SCC(NC(C)=O)C(O)=O)C(O)C(C)C
⚫ | ChEMBL = 374308
⚫ | StdInChI = 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)
⚫ | ChEMBL_Ref = {{ebicite|correct|EBI}}
⚫ | StdInChI_Ref = {{stdinchicite|changed|chemspider}}
⚫ | SMILES = CC(C)C(O)C1(NC(=O)C(C)C1O)C(=O)SCC(NC(C)=O)C(O)=O
⚫ | 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)
⚫ | SMILES1 = CC(=O)NC(CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O)C(=O)O
⚫ | StdInChIKey = DAQAKHDKYAWHCG-UHFFFAOYSA-N
⚫ | SMILES2 = OC1C(C)C(=O)NC1(C(=O)SCC(NC(C)=O)C(O)=O)C(O)C(C)C
⚫ | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
⚫ | StdInChI = 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)
⚫ | InChIKey = DAQAKHDKYAWHCG-WBMULXAQBF
⚫ | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
⚫ | 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)
⚫ | StdInChIKey = DAQAKHDKYAWHCG-UHFFFAOYSA-N
⚫ | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
⚫ | InChIKey = DAQAKHDKYAWHCG-WBMULXAQBF
}} }}
| Section2 = {{Chembox Properties |Section2={{Chembox Properties
| C=15 | H=24 | N=2 | O=7 | S=1
| C = 15
| H = 24 | LogP = 0.086
| N = 2 | pKa = 3.106
| O = 7 | pKb = 10.891
| S = 1
| ExactMass = 376.130421822 g mol<sup>-1</sup>
| LogP = 0.086
| pKa = 3.106
| pKb = 10.891
}} }}
}} }}


'''Lactacystin''' is an ] naturally ] by ] of the ] '']'' first described in 1991.<ref name="Omura">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.</ref> The first ] of lactacystin was developed by ] in 1992.<ref name="Corey">''"Total Synthesis of Lactacystin"'' Corey, E. J.; Reichard, G. A. '']'' '''1992''', ''114'', 10677.</ref> The molecule is most commonly used as in ] and ] laboratories as a selective inhibitor of the ].<ref name="Fenteany">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'' 268:726-731.</ref><ref name="Orlowski">Orlowski RZ. (1999). The role of the ubiquitin-proteasome pathway in apoptosis. ''Cell Death Differ'' 6: 303-313.</ref> The molecule is a ], or cyclic ]. A number of syntheses of this molecule have been published and there are no less than 1,300 references to this natural product in the literature.<ref name="Brennan">Christopher J. Brennan, Gerald Pattenden, Gwenaella Rescourio . (2003). Formal Synthesis of (+)-Lactacystin Based on a Novel Radical Cyclization of an -Ethynyl-Substituted Serine: C Brennan et al. ''Tetrahedron Lett'' 44 (2003) 49, 8757-8760.</ref> '''Lactacystin''' is an ] naturally ] by ] of the ] '']'' first identified as an inducer of neuritogenesis in neuroblastoma cells in 1991.<ref name="Omura">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.</ref> The target of lactacystin was subsequently found to be the ] on the basis of its affinity for certain catalytic subunits of the proteasome by Fenteany and co-workers in 1995.<ref name="Fenteany1">{{cite journal |vauthors=Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL |title=Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin |journal=Science |volume=268 |issue=5211 |pages=726–31 |year=1995 |pmid=7732382 |doi=10.1126/science.7732382|bibcode=1995Sci...268..726F |s2cid=37779687 }}</ref> 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 ]. The molecule is commonly used in ] and ] laboratories as a selective inhibitor of the ].<ref name="Fenteany1">{{cite journal |vauthors=Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL |title=Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin |journal=Science |volume=268 |issue=5211 |pages=726–31 |year=1995 |pmid=7732382 |doi=10.1126/science.7732382|bibcode=1995Sci...268..726F |s2cid=37779687 }}</ref><ref name="Fenteany2">{{cite journal |vauthors=Fenteany G, Schreiber SL |title=Lactacystin, proteasome function, and cell fate |journal=J. Biol. Chem. |volume=273 |issue=15 |pages=8545–8 |year=1998 |pmid= 9535824 |doi=10.1074/jbc.273.15.8545|doi-access= free}}</ref> The first ] of lactacystin was developed in 1992 by Corey and Reichard,<ref name="Corey">''"Total Synthesis of Lactacystin"'' Corey, E. J.; Reichard, G. A. '']'' '''1992''', ''114'', 10677.</ref> and a number of other syntheses of this molecule have also been published. There are more than 1,660 entries for lactacystin in ] as of January 2019.

==See also==
*]


==References== ==References==
{{Reflist}} {{Reflist}}

{{Biochem-stub}}
{{Organic-compound-stub}}


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Latest revision as of 19:39, 26 March 2024

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--4-methyl-5-oxopyrrolidine-2-carbonyl}sulfanyl)propanoic acid
Identifiers
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
  • 3735
  • 2299173 (2R)-2-amid, (3S,4R)-3-hydrox,-2-((1S)-1-hydrox)prop,-4-meth
MeSH Lactacystin
PubChem CID
  • 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
CompTox Dashboard (EPA)
InChI
  • 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)Key: DAQAKHDKYAWHCG-UHFFFAOYSA-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
SMILES
  • 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
Chemical formula C15H24N2O7S
Molar mass 376.42 g·mol
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 , 100 kPa). ☒N verify (what is  ?) Infobox references
Chemical compound

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. 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. 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. The first total synthesis of lactacystin was developed in 1992 by Corey and Reichard, 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

References

  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. ^ 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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