Development of inositol-based antagonists for the<scp>d</scp>-myo-inositol 1,4,5-trisphosphate receptor

Keddie, Neil S.; Ye, Yulin; Aslam, Tariq; Luyten, Tomas; Bello, Davide; Garnham, Clive; Bultynck, Geert; Galione, Antony; Conway, Stuart J.

doi:10.1039/c0cc03003a

Cited by 22 publications

(23 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inositol 1,4,5-trisphosphate analogues in which the 5phosphate group was replaced with less-acidic bioisosteres have been synthesized. [239] Thec hiral protected 1,4-bisphosphate 234 (Scheme 31) was prepared by using an ine-step procedure that exposes the 5-hydroxy group for the introduction of ab ioisostere to replace the 5-phosphate.T wo compounds were prepared from the versatile 1,4-bisphosphate intermediate 234:one having amethylphosphonate and one asulfate group at the 5-position. Themethylphosphonate group was incorporated at the 5-position of the inositol ring by using bis [6-(trifluoromethyl)benzotriazol-1-yl]methylphosphonate.H ydrogenolysis in the presence of ac atalyst then removed all the benzyl groups in excellent yield to give 235.T he sulfate group was introduced at the 5-hydroxy position by using sulfur trioxide in pyridine.H ydrogenolysis removed all the benzyl groups to give the 5-modified sulfate product 236.T he 5-carboxylate group was generated by oxidative cleavage of the 5-O-allyl derivative 237 and the remaining benzyl groups were deprotected by hydrogenolysis to give 238.F or the final modified compound, as lightly different intermediate (239 in Scheme 32) was used.…”

Section: Replacement Of the 5-phosphate Group Of Ins(145)p 3 With Bmentioning

confidence: 99%

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

2016

View full text Add to dashboard Cite

show abstract

Section: Replacement Of the 5-phosphate Group Of Ins(145)p 3 With Bmentioning

confidence: 99%

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

2016

View full text Add to dashboard Cite

show abstract

“…Measurements in DT40 and TKO Cells-These experiments were performed as described (30,31 ], we used a Zeiss AxioObserver.Z1 microscope with a Fluor ϫ20/ 0.75 objective, Sutter Lambda DG-4 monochromator and filter sets 21 and 62 (Zeiss) for Fura-2 and mCherry, respectively. Images were recorded with an AxioCamHsM camera in the AxioVision version 4.6 software physiology module.…”

Section: Mag-fluo4mentioning

confidence: 99%

The C Terminus of Bax Inhibitor-1 Forms a Ca2+-permeable Channel Pore

Bultynck

Kiviluoto

Henke

et al. 2012

Journal of Biological Chemistry

Self Cite

102

View full text Add to dashboard Cite

Background: Evolutionary conserved Bax inhibitor-1 (BI-1) protects against ER stress-mediated apoptosis. Results: We identified a Ca 2ϩ -permeable channel pore in the C terminus of BI-1. Critical pore properties are an ␣-helical structure and two aspartate residues conserved among animals, but not among plants and yeast. Conclusion: C-terminal domain of BI-1 harbors a Ca 2ϩ -permeable channel pore. Significance: BI-1 has Ca 2ϩ channel properties likely relevant for its function in ER stress and apoptosis. Bax inhibitor-1 (BI-1) is a multitransmembrane domainspanning endoplasmic reticulum (ER)-located protein that is evolutionarily conserved and protects against apoptosis and ER stress. Furthermore, BI-1 is proposed to modulate ER Ca 2؉homeostasis by acting as a Ca 2؉ -leak channel. Based on experimental determination of the BI-1 topology, we propose that its C terminus forms a Ca 2؉ pore responsible for its Ca 2؉ -leak properties. We utilized a set of C-terminal peptides to screen for Ca 2؉ leak activity in unidirectional 45 Ca 2؉ -flux experiments and identified an ␣-helical 20-amino acid peptide causing Ca 2؉ leak from the ER. The Ca 2؉ leak was independent of endogenous ER Ca 2؉ -release channels or other Ca 2؉ -leak mechanisms, namely translocons and presenilins. The Ca 2؉ -permeating property of the peptide was confirmed in lipid-bilayer experiments. Using mutant peptides, we identified critical residues responsible for the Ca 2؉ -leak properties of this BI-1 peptide, including a series of critical negatively charged aspartate residues. Using peptides corresponding to the equivalent BI-1 domain from various organisms, we found that the Ca 2؉ -leak properties were conserved among animal, but not plant and yeast orthologs. By mutating one of the critical aspartate residues in the proposed Ca 2؉ -channel pore in full-length BI-1, we found that Asp-213 was essential for BI-1-dependent ER Ca 2؉ leak. Thus, we elucidated residues critically important for BI-1-mediated Ca 2؉ leak and its potential channel pore. Remarkably, one of these residues was not conserved among plant and yeast BI-1 orthologs, indicating that the ER Ca2؉ -leak properties of BI-1 are an added function during evolution. leak from the ER (9, 10). BI-1 seems to be strongly evolutionarily conserved and BI-1 orthologs from plants can substitute for mammalian BI-1 in regard to its anti-apoptotic function (11). Besides this, other diverse functions of BI-1 have been described. BI-1 is a negative regulator of the ER-stress sensor (12), it interacts with G-actin and increases actin polymerization (13), enhances cancer metastasis by altering glucose metabolism and by activating a sodium-hydrogen exchanger (14), and it reduces production of reactive oxygen species through direct interaction with NADPH-P450 reductase (15), a member of the microsomal monooxygenase system.Recently, the role of BI-1 in Ca 2ϩ signaling has been further explored. The effect of BI-1 on cell death seems to involve changes in the amount of Ca 2ϩ that is releasable from intrace...

show abstract

“…Inositol 1,4,5-trisphosphate analogues in which the 5-phosphate was replaced with less acidic bioisosteres have been synthesized. [239] The chiral protected 1,4- …”

Section: Replacement Of the 5-phosphate Of Ins(145)p 3 With Bioisosmentioning

confidence: 99%

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

2015

View full text Add to dashboard Cite

Cell signalling via inositol phosphates, eg the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-and scyllo-) and derivatives rarer or thought not to exist in nature. However, recently, neoand D-chiro-inositol hexakisphosphates were revealed in both terrestrial and aquatic ecosystems, highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, e.g. scyllo-inositol (neurodegenerative diseases), and D-chiro-inositol (diabetes). It is timely to consider exploration of roles and applications of "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo-series.

show abstract

Development of inositol-based antagonists for thed-myo-inositol 1,4,5-trisphosphate receptor

Cited by 22 publications

References 22 publications

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

The C Terminus of Bax Inhibitor-1 Forms a Ca2+-permeable Channel Pore

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

Contact Info

Product

Resources

About