Photochemical Induction of Enzymatic Activity of a Carbocyclic Analog of Coenzyme B12: A Contribution to the Elucidation of the Mechanism of Action of Coenzyme B12

1976 ◽  
Vol 15 (3) ◽  
pp. 170-171 ◽  
Author(s):  
G. N. Schrauzer ◽  
R. Nathan Katz ◽  
J. H. Grate ◽  
T. M. Vickrey
Keyword(s):  
Enzymatic Activity ◽  
Mechanism Of Action ◽  
Coenzyme B12

scholarly journals Studies on the Mechanism of Action of Coenzyme B12

1972 ◽  
Vol 247 (13) ◽  
pp. 4197-4207
Author(s):  
Thomas H. Finlay ◽  
Jay Valinsky ◽  
Kazuyoshi Sato ◽  
Robert H. Abeles
Keyword(s):  
Mechanism Of Action ◽  
Coenzyme B12

scholarly journals Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches

2019 ◽  
Vol 20 (7) ◽  
pp. 1616 ◽  
Author(s):  
Wenbo Li ◽  
Zheng Sun
Keyword(s):  
Clinical Trials ◽  
Enzymatic Activity ◽  
Histone Deacetylase ◽  
Mechanism Of Action ◽  
Histone Deacetylase Inhibitors ◽  
Catalytic Domain ◽  
Hdac Inhibitors ◽  
Mechanistic Studies ◽  
Low Toxicity ◽  
Strict Specificity

Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing catalytic domain of the histone deacetylase (HDACs) and they repress the deacetylase enzymatic activity. The broad therapeutic effect of HDIs with seemingly low toxicity is somewhat puzzling when considering that most HDIs lack strict specificity toward any individual HDAC and, even if they do, each individual HDAC has diverse functions under different physiology scenarios. Here, we review recent mechanistic studies using omics approaches, including epigenomics, transcriptomics, proteomics, metabolomics, and chemoproteomics, methods. These omics studies provide non-biased insights into the mechanism of action for HDIs.

A Novel Non-Competitive Chemical Proteasome Inhibitor Displays Preclinical Activity in Myeloma and Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1711-1711
Author(s):  
Xiaoming Li ◽  
Tabitha E Wood ◽  
Remco Sprangers ◽  
Xinliang Mao ◽  
Xiaoming Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Enzymatic Activity ◽  
Mouse Models ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Leukemia Cells ◽  
Tumor Cell Lines

Abstract The proteasome is an enzymatic complex that rids cells of excess and misfolded proteins and possesses chymotrypin, trypsin, and caspase-like enzymatic activity. To date, all of the proteasome inhibitors approved for clinical use or in clinical trials inhibit the complex competitively by binding the active sites of the enzymes. Here, we report a novel chemical proteasome inhibitor that binds the alpha subunits of the 20S proteasome and inhibits the complex non-competitively through a dual copper-dependent and independent mechanism. In a screen of a focused chemical library for novel proteasome inhibitors, we identified 5-amino-8-hydroxyquinoline (5AHQ). When added to myeloma or leukemia intact cells or cell extracts, 5AHQ inhibited the enzymatic activity of the proteasome at low micromolar concentrations. In order to obtain further insight into the mechanism of action of 5AHQ, we carried out a kinetic analysis of inhibition of the enzymatic activity of purified T. Acidophilium proteasome. By Lineweaver-Burk plot analysis, 5AHQ inhibited the proteasome non-competitively. Next, we investigated the binding of 5AHQ to the proteasome. By NMR analysis, 5AHQ bound the half-proteasome complex comprised of a pair of α-rings, α7-α7, and clear spectral changes were observed that localized to residues Ile159, Val113, Val87, Val82, Leu112, Val89, Val134, Val24 and Leu136 inside the antechamber. In contrast, the competitive inhibitor MG132 that binds the proteolytic chamber did not produce any changes in spectra of α7-α7, as expected. 5AHQ bound copper in a 2:1 stoichiometry with a logβ′ value of 9.09, and the addition of copper to 5AHQ enhanced 5AHQ-mediated inhibition of the proteasome. However, binding intracellular copper was not sufficient to explain the effects of 5AHQ on the proteasome as analogues of 5AHQ that did not bind copper continued to inhibit the proteasome, copper-binding molecules not structurally related to 5AHQ did not affect the proteasome, and 5AHQ inhibited isolated proteasomes in buffers devoid of copper and other heavy metals. Given the effects of 5AHQ on the proteasome, we examined the effects of this molecule on the viability of leukemia and myeloma cell lines. Leukemia, myeloma and solid tumor cell lines were treated with increasing concentrations of 5AHQ for 72 hours and cell viability was measured by the MTS assay. 5AHQ induced cell death in 9/9 myeloma, 6/10 leukemia, and 3/10 solid tumor cell lines with an LD50 ≤5 uM. Cell death was confirmed by Annexin V staining. Consistent with its mechanism of action as a proteasome inhibitor, the ability of 5AHQ to induce cell death matched its ability to inhibit the proteasome. In addition, 5AHQ-mediated cell death was associated with inhibition of the NF-kappaB signalling pathway. As 5AHQ induced cell death in malignant cells, we evaluated the effects of oral 5AHQ in 3 mouse models of leukemia. Sublethally irradiated NOD-SCID mice were injected subcutaneously with OCI-AML2 or K562 human leukemia cells or intraperitoneally with MDAY-D2 murine leukemia cells. After tumor implantation, mice were treated with 5AHQ (50 mg/kg/day) or buffer control by oral gavage. Oral 5AHQ decreased tumor weight and volume in all 3 mouse models compared to control without causing weight loss or gross organ toxicity. In summary, we have identified a new strategy for inhibition of the proteasome and a lead for a new therapeutic agent for the treatment of hematologic malignancies.

The mechanism of action of coenzyme B12

Vitamin B12 ◽  
1979 ◽  
pp. 575-586
Author(s):  
D. Dolphin ◽  
A. R. Banks ◽  
W. R. Cullen ◽  
A. R. Cutler ◽  
R. B. Silverman
Keyword(s):  
Mechanism Of Action ◽  
Coenzyme B12
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