Sandbox Reserved 1601
From Proteopedia
(Difference between revisions)
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== Overview == | == Overview == | ||
| - | Article One <ref name="Wang">PMID:28882140</ref> | + | Article One <ref name="Wang">PMID:28882140</ref> <ref name="Wang"/> |
| - | Article Two <ref name="Baradaran">PMID:29995857</ref> | + | Article Two <ref name="Baradaran">PMID:29995857</ref> <ref name="Badaran"/> |
| - | Article Three <ref name="Woods">PMID:31869674</ref> | + | Article Three <ref name="Woods">PMID:31869674</ref> <ref name="Woods"/> |
| - | Article Four <ref name="Giorgi">PMID:30143745</ref> | + | Article Four <ref name="Giorgi">PMID:30143745</ref> <ref name="Giorgi"/> |
| - | Article Five <ref name="Fan">PMID:29995856</ref> | + | Article Five <ref name="Fan">PMID:29995856</ref> <ref name="Fan"/> |
== Structure == | == Structure == | ||
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== Regulation/Inhibition == | == Regulation/Inhibition == | ||
| - | The most well-known and commonly used inhibitor of calcium uptake into the mitochondria is ruthenium red (RuRed). RuRed effectively inhibits calcium uptake without affecting mitochondrial respiration or calcium efflux. Additionally, it has been shown to mitigate tissue damage due to IRI and slow cancer cell migration. The issue with RuRed is that its purification has always been a challenging matter.<ref name="Woods" /> Interestingly enough, this led to even more developments in the search for an inhibitor. Many scientists had observed that impure RuRed actually had greater inhibition than pure RuRed. One of the common minor impurities of RuRed, Ru360, was found to be the active component of the RuRed mixtures, meaning it responsible for calcium inhibition. Ru360 is now commercially available and has been widely used for the study of calcium-dependent cellular processes and as a therapeutic agent. Very little is known about its mechanism of inhibtion, but studies show that it interacts with the DXXE motif of the loop connecting the TM1 and TM2 helices.<ref name="Woods" /> | + | The most well-known and commonly used inhibitor of calcium uptake into the mitochondria is ruthenium red (RuRed). RuRed effectively inhibits calcium uptake without affecting mitochondrial respiration or calcium efflux. Additionally, it has been shown to mitigate tissue damage due to IRI and slow cancer cell migration. The issue with RuRed is that its purification has always been a challenging matter.<ref name="Woods"/> Interestingly enough, this led to even more developments in the search for an inhibitor. Many scientists had observed that impure RuRed actually had greater inhibition than pure RuRed. One of the common minor impurities of RuRed, Ru360, was found to be the active component of the RuRed mixtures, meaning it responsible for calcium inhibition. Ru360 is now commercially available and has been widely used for the study of calcium-dependent cellular processes and as a therapeutic agent. Very little is known about its mechanism of inhibtion, but studies show that it interacts with the DXXE motif of the loop connecting the TM1 and TM2 helices.<ref name="Woods" /> |
Ru360 was a very successful inhibitor, but it showed low cell permeability. So, a new inhibitor called Ru265 was developed which could be easily synthesized and didn't need chromatographic purification. Ru265 had all of the benefits of Ru360, with with twice the cell permeability. Additionally, the same mutations didn't seem to affect it. Mutations of D261 and S259 in human MCU reduced inhibitory effect of Ru360, but not Ru265. Additionally, there were other mutations that affected Ru265, but not Ru360.<ref name="Woods" /> This shows how much more research is needed before a mechanism is understood for any inhibitor of the MCU. | Ru360 was a very successful inhibitor, but it showed low cell permeability. So, a new inhibitor called Ru265 was developed which could be easily synthesized and didn't need chromatographic purification. Ru265 had all of the benefits of Ru360, with with twice the cell permeability. Additionally, the same mutations didn't seem to affect it. Mutations of D261 and S259 in human MCU reduced inhibitory effect of Ru360, but not Ru265. Additionally, there were other mutations that affected Ru265, but not Ru360.<ref name="Woods" /> This shows how much more research is needed before a mechanism is understood for any inhibitor of the MCU. | ||
Revision as of 20:49, 17 April 2020
| This Sandbox is Reserved from Jan 13 through September 1, 2020 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1598 through Sandbox Reserved 1627. |
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Mitochondrial Calcium Uniporter (MCU) (Heumann Test Page)
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References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
- ↑ 3.0 3.1 Wang CH, Wei YH. Role of mitochondrial dysfunction and dysregulation of Ca(2+) homeostasis in the pathophysiology of insulin resistance and type 2 diabetes. J Biomed Sci. 2017 Sep 7;24(1):70. doi: 10.1186/s12929-017-0375-3. PMID:28882140 doi:http://dx.doi.org/10.1186/s12929-017-0375-3
- ↑ Baradaran R, Wang C, Siliciano AF, Long SB. Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. Nature. 2018 Jul 11. pii: 10.1038/s41586-018-0331-8. doi:, 10.1038/s41586-018-0331-8. PMID:29995857 doi:http://dx.doi.org/10.1038/s41586-018-0331-8
- ↑ Cite error: Invalid
<ref>tag; no text was provided for refs namedBadaran - ↑ 6.0 6.1 6.2 6.3 6.4 Woods JJ, Wilson JJ. Inhibitors of the mitochondrial calcium uniporter for the treatment of disease. Curr Opin Chem Biol. 2019 Dec 20;55:9-18. doi: 10.1016/j.cbpa.2019.11.006. PMID:31869674 doi:http://dx.doi.org/10.1016/j.cbpa.2019.11.006
- ↑ 7.0 7.1 Giorgi C, Marchi S, Pinton P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol. 2018 Nov;19(11):713-730. doi: 10.1038/s41580-018-0052-8. PMID:30143745 doi:http://dx.doi.org/10.1038/s41580-018-0052-8
- ↑ 8.0 8.1 Fan C, Fan M, Orlando BJ, Fastman NM, Zhang J, Xu Y, Chambers MG, Xu X, Perry K, Liao M, Feng L. X-ray and cryo-EM structures of the mitochondrial calcium uniporter. Nature. 2018 Jul 11. pii: 10.1038/s41586-018-0330-9. doi:, 10.1038/s41586-018-0330-9. PMID:29995856 doi:http://dx.doi.org/10.1038/s41586-018-0330-9
