Clasto-Lactacystin β-lactone
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| Category | Enzyme inhibitors |
| Catalog number | BBF-04159 |
| CAS | 154226-60-5 |
| Molecular Weight | 213.23 |
| Molecular Formula | C10H15NO4 |
| Purity | ≥95% |
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Description
Clasto-Lactacystin β-lactone is a microbial metabolite isolated from Streptomyces that is now widely used as a selective inhibitor of the 20S proteasome. Clasto-lactacystin β-lactone was later identified as the active metabolite of lactacystin, resulting from the elimination of cysteine and the formation of a reactive β-lactone. It is 20-fold more potent than Lactacystin.
Specification
| Synonyms | β-Clastolactacystin; Omuralide |
| Storage | Store at -20°C |
| IUPAC Name | (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione |
| Canonical SMILES | CC1C2C(C(=O)O2)(NC1=O)C(C(C)C)O |
| InChI | InChI=1S/C9H13NO4/c1-4(2)7(12)9-5(14-8(9)13)3-6(11)10-9/h4-5,7,12H,3H2,1-2H3,(H,10,11)/t5-,7-,9-/m0/s1 |
| InChI Key | FWPWHHUJACGNMZ-NBBQQVJHSA-N |
Properties
| Boiling Point | 440.8±40.0°C at 760 mmHg |
| Density | 1.3±0.1 g/cm3 |
| Solubility | Soluble in DMSO (25 mg/mL) |
Reference Reading
1. Direct proteasome inhibition by clasto-lactacystin beta-lactone permits the detection of ubiquitinated p21(waf1) in ML-1 cells
K Fukuchi, Y Takagi, H Maruyama, K Gomi Biochim Biophys Acta . 1999 Aug 12;1451(1):206-10. doi: 10.1016/s0167-4889(99)00081-6.
The ubiquitin proteasome pathway regulates the expression of major cellular regulatory proteins. The ubiquitin proteasome system has been demonstrated to be involved in the expression of the cyclin kinase inhibitor, p21. Ubiquitinated p21 is degraded immediately by 26S proteasome, therefore, the detection of p21 is difficult. We report here an improvement for the detection of ubiquitinated p21 using a proteasome inhibitor, clasto-lactacystin beta-lactone. A p21-enriched cell lysate is obtained by pretreating the cells with deferoxamine to induce p21 mRNA expression followed by treatment with 1x10(-6) M beta-lactone. The concentration of p21 from the cell lysate was performed using an anti-p21 antibody crosslinked to protein G Sepharose. Ubiquitinated p21 was detected on Western blots of the concentrated sample using an anti-ubiquitin antibody. This detection system will be used for further analysis of the regulation of p21 ubiquitination.
2. Prediction of the mechanism of action of omuralide (clasto-lactacystin beta-lactone) on human cathepsin A based on a structural model of the yeast proteasome beta5/PRE2-subunit/omuralide complex
Fumiko Matsuzawa, Kohji Itoh, Yoshito Kadota, Sei-ichi Aikawa, Hirofumi Doi, Yurie Satoh Biochim Biophys Acta . 2006 Aug;1764(8):1372-80. doi: 10.1016/j.bbapap.2006.05.008.
Cathepsin A (CathA) is a lysosomal serine carboxypeptidase that exhibits homology and structural similarity to the yeast and wheat serine carboxypeptidases (CPY and CPW) belonging to the alpha/beta-hydrolase fold family. Human CathA (hCathA) and CPW have been demonstrated to be inhibited by a proteasome (threonine protease) inhibitor, lactacystin, and its active derivative, omuralide (clasto-lactacystin beta-lactone), as well as chymostatin. A hCathA/omuralide complex model constructed on the basis of the X-ray crystal structures of the CPW/chymostatin complex and the yeast proteasome beta-subunit (beta5/PRE2)/omuralide one predicted that the conformation of omuralide in the active-site cleft of proteasome beta5/PRE2 should be very similar to that of chymostatin at the S1 catalytic subsites in the hCathA- and CPW-complexes. The relative positions of the glycine residues, i.e., Gly57 in hCathA, Gly53 in CPW, and Gly47 in beta5/PRE2, present in the oxyanion hole of each enzyme were also highly conserved. These results suggest that omuralide might inhibit hCathA and CPW at the S1 subsite in their active-site clefts through direct binding to the active serine residue.
3. Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation
A Craiu, G Fenteany, K L Rock, T Akopian, M Gaczynska, A L Goldberg, C F Gramm J Biol Chem . 1997 May 16;272(20):13437-45. doi: 10.1074/jbc.272.20.13437.
The antibiotic lactacystin was reported to covalently modify beta-subunit X of the mammalian 20 S proteasome and inhibit several of its peptidase activities. However, we demonstrate that [3H]lactacystin treatment modifies all the proteasome's catalytic beta-subunits. Lactacystin and its more potent derivative beta-lactone irreversibly inhibit protein breakdown and the chymotryptic, tryptic, and peptidylglutamyl activities of purified 20 S and 26 S particles, although at different rates. Exposure to these agents for 1 to 2 h reduced the degradation of short- and long-lived proteins in four different mammalian cell lines. Unlike peptide aldehyde inhibitors, lactacystin and the beta-lactone do not inhibit lysosomal degradation of an endocytosed protein. These agents block class I antigen presentation of a model protein, ovalbumin (synthesized endogenously or loaded exogenously), but do not affect presentation of the peptide epitope SIINFEKL, which does not require proteolysis for presentation. Generation of most peptides required for formation of stable class I heterodimers is also inhibited. Because these agents inhibited protein breakdown and antigen presentation similarly in interferon-gamma-treated cells (where proteasomes contain LMP2 and LMP7 subunits in place of X and Y), all beta-subunits must be affected similarly. These findings confirm our prior conclusions that proteasomes catalyze the bulk of protein breakdown in mammalian cells and generate the majority of class I-bound epitopes for immune recognition.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
