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| Used to treat urea cycle disorders Sodium phenylbutyrate helps remove ammonia from the body. -Phenyl-butyrate (PB)4 is an aromatic fatty acid that is converted in vivo to phenylacetate (PA) by β-oxidation in liver and kidney mitochondria. -In human body, phenylbutyrate is oxidized to phenylacetate, which is in turn conjugated with glutamine and eliminated in urine as phenylacetylglutamine, thereby mediating elimination of waste nitrogen -Phenylbutyrate is one of the first drugs encountered in cancer therapy as a histone deacetylase inhibitor (HDACI) (relatively weak compared to vorinostat (SAHA), romidepsin, etc.). -Butyric acid is one of the short-chain fatty acids produced by the gut microbiota through the fermentation of dietary fiber. Butyrate is primarily recognized for its beneficial effects in the colon and is tightly linked to gut health. -Phenylbutyrate is a derivative of butyrate that has been chemically modified by the addition of a phenyl group. This structural change increases its lipophilicity (fat solubility) and alters its metabolic fate and biological activity. This allows it to be used as a systemic drug, in contrast to the locally produced butyrate in the gut, which is rapidly metabolized by colonocytes Pathways: -Histone deacetylase (HDAC) inhibitor -ER stress inhibitor (at least in normal cell) -Can act as a chemical chaperone, helping to reduce ER stress by facilitating proper protein folding. -Modulation of NF-κB Signaling -Changes in pathways such as PI3K/Akt/mTOR and MAPK. -Some preclinical investigations have reported that treatment with phenylbutyrate leads to mitochondrial dysfunction and endoplasmic reticulum (ER) stress, both of which can result in an increase of ROS within cancer cells. Note: Sodium butyrate (NaBu) vs Sodium phenylbutyrate -Sodium butyrate is primarily a research tool with limited clinical application, whereas phenylbutyrate is used clinically -Phenylbutyrate typically exhibits improved pharmacokinetics and is more amenable to systemic use compared to sodium butyrate. -Both compounds act as HDAC inhibitors, phenylbutyrate additionally modulates ER stress and mitochondrial function, leading to potentially greater ROS production in certain cancer cells. https://www.purepba.com/shop/
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| Type: enzyme |
| PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells. -C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A -PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells. -inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis. -PK exists in four isoforms: PKM1, PKM2, PKR, and PKL -PKM2 plays a role in the regulation of glucose metabolism in diabetes. -PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy. – Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP. – The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms. – Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation. – Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions. – Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers. – High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage. PKM2 in carcinogenesis and oncotherapy Inhibitors of PKM2: -Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established Full List of PKM2 inhibitors from Database -key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells. Tumor pyruvate kinase M2 modulators Flavonoids effect on PKM2 Compounds name IC50/AC50uM Effect Flavonols 1. Fisetin 0.90uM Inhibition 2. Rutin 7.80uM Inhibition 3. Galangin 8.27uM Inhibition 4. Quercetin 9.24uM Inhibition 5. Kaempferol 9.88uM Inhibition 6. Morin hydrate 37.20uM Inhibition 7. Myricetin 0.51uM Activation 8. Quercetin 3-b- D-glucoside 1.34uM Activation 9. Quercetin 3-D -galactoside 27-107uM Ineffective Flavanons 10. Neoeriocitrin 0.65uM Inhibition 11. Neohesperidin 14.20uM Inhibition 12. Naringin 16.60uM Inhibition 13. Hesperidin 17.30uM Inhibition 14. Hesperitin 29.10uM Inhibition 15. Naringenin 70.80uM Activation Flavanonols 16. (-)-Catechin gallateuM 0.85 Inhibition 17. (±)-Taxifolin 1.16uM Inhibition 18. (-)-Epicatechin 1.33uM Inhibition 19. (+)-Gallocatechin 4-16uM Ineffective Phenolic acids 20. Ferulic 11.4uM Inhibition 21. Syringic and 13.8uM Inhibition 22. Caffeic acid 36.3uM Inhibition 23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition 24. Gallic acid 332.6uM Inhibition 25. Shikimic acid 990uM Inhibition 26. p-Coumaric acid 22.2uM Activation 27. Sinapinic acids 26.2uM Activation 28. Vanillic 607.9uM Activation |
| 2429- | PB, | Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data |
| - | in-vitro, | Colon, | NA |
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