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Hymeglusin

(Synonyms: Antibiotic 1233A) 目录号 : GC43883

An HMG-CoA synthase inhibitor

Hymeglusin Chemical Structure

Cas No.:29066-42-0

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500μg
¥2,038.00
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1mg
¥3,667.00
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2.5mg
¥7,641.00
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产品描述

Hymeglusin is a fungal β-lactone antibiotic that inhibits HMG-CoA synthase (IC50 = 0.12 μM) by covalently modifying the active Cys129 residue of the enzyme.[1][2] At a dose of 25 mg/kg, hymeglusin inhibits cholesterol biosynthesis in rats by 45%. Chiral studies indicate that the (2R,3R)-β-lactone moiety of hymeglusin is important for eliciting the specific inhibition of HMG-CoA synthase.[3] As a cell-wall targeting antibiotic, hymeglusin has been used to investigate the role of a gene important for controlling S. aureus virulence in a mouse sepsis model of infection.[4]

Reference:
[1]. Greenspan, M.D., Yudkovitz, J.B., Lo, C.Y., et al. Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proc. Natl. Acad. Sci. U.S.A. 84(21), 7488-7492 (1987).
[2]. Tomoda, H., Ohbayashi, N., Morikawa, Y., et al. Binding site for fungal β-lactone hymeglusin on cytosolic 3- hydroxy-3-methylglutaryl coenzyme A synthase. Biochim. Biophys. Acta 1636(1), 22-28 (2004).
[3]. Tomoda, H., Ohbayashi, N., Kumagai, H., et al. Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of β-lactone DU-6622. Biochem. Bioph. Res. Commun. 265(2), 536-540 (1999).
[4]. Balibar, C.J., Shen, X., McGuire, D., et al. cwrA, a gene that specifically responds to cell wall damage in Staphylococcus aureus. Microbiology 156(Pt 5), 1372-1383 (2010).

Chemical Properties

Cas No. 29066-42-0 SDF
别名 Antibiotic 1233A
Canonical SMILES OC[C@@H](C1=O)[C@H](O1)CCCC[C@@H](C)C/C(C)=C/C(C)=C/C(O)=O
分子式 C18H28O5 分子量 324.4
溶解度 Soluble in ethanol, or in methanol, or in DMSO, or in chloroform 储存条件 Store at -20°C
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1 mM 3.0826 mL 15.4131 mL 30.8261 mL
5 mM 0.6165 mL 3.0826 mL 6.1652 mL
10 mM 0.3083 mL 1.5413 mL 3.0826 mL
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Research Update

Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia

Front Oncol 2022 Jun 29;12:864430.PMID:35847946DOI:10.3389/fonc.2022.864430.

Venetoclax is used for the priority treatment of elderly patients with acute myeloid leukemia (AML). Resistance or intolerance to venetoclax offsets its clinical benefits in some patients. Combination strategies with other drugs are promising alternatives to overcome the current complications associated with venetoclax use. Hymeglusin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), regulates the mevalonate pathway, which is vital for AML growth and chemosensitivity. The effects of the combination of venetoclax and Hymeglusin on AML were explored in this study. The correlations between HMGCS1 and apoptosis-related genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 and The Cancer Genome Atlas databases. Apoptosis and cell viability were detected in HL-60 and KG-1 cells after treatment with gradient concentrations of venetoclax or Hymeglusin. The transcriptomic profiles of HL-60 and KG-1 cells were compared via RNA-Seq analysis. The effects of venetoclax and Hymeglusin on apoptosis were validated in primary cells. The results showed that HMGCS1 expression was closely associated with apoptosis-related genes based on the data from large clinical databases. B cell lymphoma (BCL)-2 expression was elevated in AML and negatively associated with overall survival. Hymeglusin decreased BCL2 expression levels in HL-60 and KG-1 cells. Venetoclax and Hymeglusin inhibited cell viability in both cell lines, but induced apoptosis in HL-60 cells. This discrepancy in sensitivity to Hymeglusin may be attributed to the positive increase in the expression levels of HMGCS1 and multiple upregulated pro-leukemia genes in KG-1 cells. Combination treatment with venetoclax and Hymeglusin significantly increased the apoptotic rates compared to single-agent treatment in both AML cell lines and primary AML cells. Furthermore, the combination strategy did not result in remarkably enhanced toxicity in normal mononuclear cells. Collectively, Hymeglusin enhanced the effects of venetoclax on apoptosis. This combination strategy showed enhanced antileukemic activity with acceptable toxicity in AML.

HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis

Biomed Pharmacother 2021 May;137:111378.PMID:33601148DOI:10.1016/j.biopha.2021.111378.

Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.

Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of β-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus

ChemMedChem 2021 Jul 6;16(13):2106-2111.PMID:33783142DOI:10.1002/cmdc.202100219.

Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitor, was identified as circumventing the β-lactam drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). We describe the concise total syntheses of a series of natural products, which enabled determination of the absolute configuration of fusarilactone A and provided structure-activity relationship information. Based on previous reports, we speculated that the target protein of this circumventing effect may be MRSA bacterial HMG-CoA synthase (mvaS). We found that this enzyme was dose-dependently inhibited by Hymeglusin. Furthermore, overexpression of the MRSA mvaS gene and site-directed mutagenesis studies suggested its binding site and the mechanism of action.

Binding site for fungal beta-lactone Hymeglusin on cytosolic 3-hydroxy-3-methylglutaryl coenzyme A synthase

Biochim Biophys Acta 2004 Feb 27;1636(1):22-8.PMID:14984735DOI:10.1016/j.bbalip.2003.11.005.

We studied the molecular mechanism through which the fungal beta-lactone, Hymeglusin, potently and specifically inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase. [(14)C]Hymeglusin covalently bound to purified rat liver and to recombinant hamster cytosolic HMG-CoA synthases. The enzyme activity was completely inhibited at a binding ratio of 1.6-2.0 mol [(14)C]Hymeglusin/mol HMG-CoA synthase. Incubating the enzyme with 2 mM iodoacetamide (IAA) or 2 mM N-ethylmaleimide (NEM) but not with 1.0 mM diisopropyl fluorophosphates (DFP) completely inhibited the binding, suggesting that Hymeglusin binds to a Cys residue of HMG-CoA synthase. Recombinant hamster HMG-CoA synthase labeled with [(3)H]Hymeglusin was digested with V8 protease, and the [(3)H]peptide was purified by high performance liquid chromatography (HPLC). The sequence of the peptide was Ser-Gly-Asn-Thr-Asp-Ile-Glu-Gly-Ile-Asp-Thr-Thr-Asn-Ala-[(3)H]hymeglusyl Cys-Tyr-Gly-Gly-Thr-Ala-Ala-Val-Phe-Asn-Ala-Val-Asn-, which corresponds to the active site sequence (from Ser 115 to Asn 141) of hamster HMG-CoA synthase. These findings showed that Hymeglusin inhibits hamster cytosolic HMG-CoA synthase by covalently modifying the active Cys 129 residue of the enzyme.

Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by Hymeglusin

Biochemistry 2012 Jun 12;51(23):4713-22.PMID:22510038DOI:10.1021/bi300037k.

Hymeglusin (1233A, F244, L-659-699) is established as a specific β-lactone inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition results from formation of a thioester adduct to the active site cysteine. In contrast, the effects of Hymeglusin on bacterial HMG-CoA synthase, mvaS, have been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. After removal of the inhibitor from culture media, a growth curve inflection point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon Hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than that measured for human HMGCS. Hydroxylamine cleaves the thioester adduct; substantial enzyme activity is restored at a rate that is 8-fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme-inhibitor thioester adduct stability and solvent accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 Å) reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica juncea) HMGCS binds Hymeglusin in a more solvent-exposed cavity.