Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

Wang, Yanling K.; Chen, Wei; Blair, Derek; Pu, Mingming; Xu, Yuntao; Miller, Scott J.; Redfield, Alfred G.; Chiles, Thomas C.; Roberts, Mary F.

doi:10.1021/ja710348r

Cited by 30 publications

(44 citation statements)

References 43 publications

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“…In contrast, the dioctanoylphosphoinositides showed significantly larger linewidths in the presence of PTEN. The D-diC 8 PI and L-3,5-dideoxy-diC 8 PI, which bind to the active site (13,14), exhibited a 25-30 Hz increase in linewidth under the experimental conditions used. diC 7 PC also exhibited a large increase in linewidth (28 Ϯ 4 Hz for 1 mM of the phospholipid), consistent with occupation of the AHS and part of the active site as suggested by the kinetics.…”

Section: Table 1 Relative Activities Of Arg-47 Mutants Compared To Wimentioning

confidence: 93%

“…followed a previously published protocol with minor modifications (13,14) that are summarized below. The plasmid was transformed into Escherichia coli BL21-CodonPlus (DE3)-RIL cells from Stratagene, and the cells were grown at 37°C until the A 600 reached 0.8.…”

Section: Methodsmentioning

confidence: 99%

“…Enzyme Kinetics-The PTEN phosphatase assay for release of inorganic phosphate has been described previously (14). Generally, the assays were carried out at 37°C in 50 mM Tris, pH 8.0, with 2 mM EDTA, 10 mM DTT, and substrates.…”

Section: Methodsmentioning

confidence: 99%

“…Mutants of Arg-47 showed much lower activity compared with the wild type protein regardless of the identity of the mutated amino acid, indicating the importance of this particular residue for substrate binding and/or catalysis (13). The interactions of the ␤2-␣1 loop could facilitate the binding of several 3-deoxy-PI derivatives that inhibit enzyme activity (14). Detergent molecules, such as Triton X-100, were shown to reduce the kinetic inhibition caused by the deoxy-PI molecules and hence were proposed to bind in this hydrophobic pocket termed the "adjacent hydrophobic site" (AHS).…”

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confidence: 99%

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Phospholipid-binding Sites of Phosphatase and Tensin Homolog (PTEN)

Yang

Stec

Redfield

et al. 2015

Journal of Biological Chemistry

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Background: PTEN activity is enhanced by PI(4,5)P 2 via either an allosteric or interfacial effect. Results:31 P field cycling NMR with spin-labeled PTEN detects a PI(4,5)P 2 -binding site near but not in the active site. Conclusion: A model for PTEN identifies Lys-13 and Arg-47 as part of the PI(4,5)P 2 site. Significance: Occupation of the PI(4,5)P 2 -binding site on PTEN stabilizes productive interfacial binding.

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Section: Table 1 Relative Activities Of Arg-47 Mutants Compared To Wimentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Phospholipid-binding Sites of Phosphatase and Tensin Homolog (PTEN)

Yang

Stec

Redfield

et al. 2015

Journal of Biological Chemistry

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“…1A) (6,7). This work enabled access to a wide variety of myo-inositol phosphates (8), phosphatidyl-myo-inositol phosphates (9)(10)(11), and related analogs, as well as facilitating studies of their biochemistry (12)(13)(14)(15).…”

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confidence: 99%

Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: Enantioselective synthesis of d - myo -inositol-6-phosphate

Jordan

Kayser-Bricker

Miller

2010

Proc. Natl. Acad. Sci. U.S.A.

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Despite the ubiquitous use of phosphoramidite chemistry in the synthesis of biophosphates, catalytic asymmetric phosphoramidite transfer remains largely unexplored for phosphate ester synthesis. We have discovered that a tetrazole-functionalized peptide, in the presence of 10-Å molecular sieves, functions as an enantioselective catalyst for phosphite transfer. This chemistry in turn has been used as the key step in a streamlined synthesis of myo-inositol-6-phosphate. Mechanistic insights implicate phosphate as a directing group for a highly selective kinetic resolution of a protected inositol monophosphate. This work represents a distinct and efficient method for the selective catalytic phosphorylation of natural products.kinetic resolution | organocatalysis T he inositol phosphates and their phosphoinositide relatives are hubs for an extraordinary amount of biochemistry, and there appears to be no wane in the pace of discovery in this field (1-3). Many early efforts have focused on the biochemistry of the inositol lipids, whereas the last decade has seen a revival of interest in the myriad of inositol phosphates and polyphosphates not associated with the lipid bilayer (1). Total syntheses of these compounds and their analogs have played a critical role in enabling high-precision studies of their biochemistry (4). Historically, the strategy for synthesis in this area has been dominated by protecting group manipulations and classical resolution (5). Our laboratory endeavored to take a step forward in 2001, introducing a class of catalysts that rely on catalytic enantioselective transfer of P(V) reagents ( Fig. 1A) (6, 7). This work enabled access to a wide variety of myo-inositol phosphates (8), phosphatidyl-myo-inositol phosphates (9-11), and related analogs, as well as facilitating studies of their biochemistry (12-15).Although catalytic enantioselective P(V) chemistry continues to prove useful, we have observed limitations. First, the nearly exclusive requirement of phenyl substituents on the chlorophosphate P(V) reagent necessitates additional protecting group manipulations in many syntheses (8-11) due to reagent stability and the incompatibility of phenyl phosphate hydrolysis conditions with synthetic schemes. Despite their utility in concert with peptide-based catalysts, chlorophosphates are generally regarded as less reactive and less versatile reagents compared to their phosphorous(III) analogues. In fact, these realities were an impetus for the development of P(III) reagents for complex phosphate and polynucleotide synthesis (16). Second, from the standpoint of asymmetric, catalytic syntheses of phosphoinositides, the P(V) methodology has thus far failed to effectively differentiate the respective 4-or 6-positions of myo-inositol (Fig. 1B) (17), even though it is highly selective for differentiation of the enantiotopic 1-and 3-positions of the myo-inositol ring.We speculate that this discrepancy in 4∕6 vs 1∕3 desymmetrization is due to local structure of the reacting hydroxyl groups (Fig. 2). Whereas the...

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The Barton‐McCombie Reaction

2012

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Deoxygenations of alcohols, i.e., processes that replace a hydroxyl group with hydrogen at a saturated carbon, find applications in both total synthesis and the systematic modifications of natural products. They may also be employed to introduce deuterium or tritium in a site‐specific manner. Reductive methods that involve ionic or highly polarized reagents or intermediates can be limited in their applicability: for example, competing reaction pathways including cationic rearrangements and anionic eliminations may be encountered in sterically hindered systems with substrates bearing heteroatoms close to the center undergoing reduction. As evidenced by developments over the last few decades, methods that involve the generation and direct quenching via hydrogen atom abstraction of the derived, carbon‐centered radical typically show the greatest tolerance for the presence of other functional groups and for variations in both the steric acid and the electronic environment in the vicinity of the center undergoing deoxygenation. Derivatization of the hydroxyl is a prerequisite, the determinant factors for efficient formation of the deoxygenated product lies in the ability of the combination of the substrate and reagents to induce homolysis of the C‐O bond coupled with the induction of homolysis to rapidly reduce a free radical by hydrogen donation, thereby propagating an efficient chain process. A high‐yielding way to realize this sequence was first described by Barton McCombie using the free‐radical chain reaction of O ‐thioacyl derivatives of secondary alcohols with tri‐ n ‐butylstannane. This chapter provides a detailed description and comparison of the combinations of substrates and reagents that will bring about these processes and provides a summary and evaluation of alternative deoxygenation methods. Mechanistic and stereochemical issues set out the scope and limitations of these processes with respect to both the thioacylation and reduction steps and exemplify some applications to both total synthesis and the modification of natural products.

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Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

Cited by 30 publications

References 43 publications

Phospholipid-binding Sites of Phosphatase and Tensin Homolog (PTEN)

Phospholipid-binding Sites of Phosphatase and Tensin Homolog (PTEN)

Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: Enantioselective synthesis of d - myo -inositol-6-phosphate

The Barton‐McCombie Reaction

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