Total synthesis of D-myo-inositole 3,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate

Falck, John R.; Abdali, Abdelkrim

doi:10.1016/s0960-894x(01)81261-0

Cited by 17 publications

(5 citation statements)

References 22 publications

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“…Substituting cysteine for arginine 28 (R28C) in the PH domain of Btk, a natural mutation that causes X-linked immunodeficiency in mice, significantly affects the binding of PtdIns-3,4,5-P 3 and inositol 1,3,4,5-P 4 . In vivo, overexpression of the Class I A PI 3-K enzyme p110* (a constitutively active form of PI 3-K) or Class I B PI 3-K ␥ was shown to enhance Btk autophosphorylation and Src family kinase-mediated tyrosine phosphorylation of Btk (69,70).…”

Section: Pi-345-pmentioning

confidence: 99%

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

Rameh

Cantley

1999

Journal of Biological Chemistry

917

681

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Phosphoinositide 3-kinases 1 are a subfamily of lipid kinases that catalyze the addition of a phosphate molecule specifically to the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinositides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes (Fig. 1). Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4-and 5-positions (PtdIns-4,5-P 2 ). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. To date, nine members of the PI 3-K family have been isolated from mammalian cells. They are grouped, as suggested by Domin and Waterfield (1), into three classes according to the molecules that they preferentially utilize as substrates. Four different lipid products can be generated by the different PI 3-K members: the singly phosphorylated form PtdIns-3-P; the doubly phosphorylated forms PtdIns-3,4-P 2 and PtdIns-3,5-P 2 ; and finally the triply phosphorylated form PtdIns-3,4,5-P 3 (Fig. 1).PI 3-K was first described as a PI kinase activity associated with the viral oncoproteins, v-Src, v-Ros, and polyomavirus middle T. Mutational studies of these oncoproteins more than 10 years ago indicated a critical role for the associated PI kinase in cell transformation (reviewed by Ref. 2).Recent advances in the field have been achieved by the development of new techniques to probe for the direct targets of PI 3-K lipid products. The chemical synthesis of short chain fatty acid versions of these lipids (3-5) has been a crucial step in determining the specificity of lipid-binding proteins. Additionally, new cloning strategies have been developed to isolate new lipid-binding proteins (6). Here we will review the most recent advances in our understanding of the role of PI 3-K in cell function by dissecting the contribution of each of its lipid products. PtdIns-3-PRegulation-PtdIns-3-P is constitutively present in both mammalian and yeast cells (7,8). It can be produced in vitro via phosphorylation of PtdIns by Class I, II, or III PI 3-Ks (Fig. 1). However, the majority of PtdIns-3-P in mammalian cells is probably produced by Class III PI 3-K (9). The mammalian Class III enzyme is highly related to the yeast Vps34 gene product (10) and, like the yeast enzyme, is specific for PtdIns and will not phosphorylate PtdIns-4-P or PtdIns-4,5-P 2 (11).Targets-PtdIns-3-P was recently shown to specifically interact with a 70-residue protein module called the FYVE finger domain. This domain is a special type of RING zinc finger that is characterized by two zinc-binding sites and a highly conserved stretch of basic residues surrounding the third zinc-coordinating cysteine. Liposomes containing PtdIns-3-P were shown to associate with several FYVE domains (15)(16)(17). Other phosphoinositides bound poorly ...

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Section: Pi-345-pmentioning

confidence: 99%

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

Rameh

Cantley

1999

Journal of Biological Chemistry

917

681

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“…Unfortunately, one of the very precursors that caused the misinterpretation mentioned above was used for the previously reported synthesis of Ins(1,5,6)P 3 ( 9b ) . A different approach was exploited for the total synthesis of Ins(3,4,5)P 3 ( 9a ), but no value for the optical activity was quoted. We therefore set out to synthesize both optical antipodes, employing the partially purified InsP 5 /InsP 4 -phosphohydrolase as an enzymatic tool.…”

Section: Resultsmentioning

confidence: 99%

“…Then 400 mL of diethyl ether was added, and the solution was filtered. The residue was washed with diethyl ether (3 × 100 mL), and the combined organic phase was evaporated to yield 4a as a colorless solid (2.57 [23], 81 [100], 68 [4], 55 [27], 54 [45], 42 [5]. Anal.…”

Section: Methodsmentioning

confidence: 99%

Enzyme-Assisted Total Synthesis of the Optical Antipodes d-myo-Inositol 3,4,5-Trisphosphate and d-myo-Inositol 1,5,6-Trisphosphate: Aspects of Their Structure−Activity Relationship to Biologically Active Inositol Phosphates

et al. 1999

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Unambiguous total syntheses of both optical antipodes of the enantiomeric pair D-myo-inositol 3,4,5-trisphosphate (Ins(3,4,5)P3) and D-myo-inositol 1,5,6-trisphosphate (Ins(1,5,6)P3) are described. The ring system characteristic of myo-inositol was constructed de novo from p-benzoquinone. X-ray data for the enzymatically resolved (1S,2R,3R,4S)-1,4-diacetoxy-2,3-dibromocyclohex-5-ene enabled the unequivocal assignment of the absolute configuration. Subsequent transformations under stereocontrolled conditions led to enantiopure C2-symmetrical 1,4-(di-O-benzyldiphospho)conduritol B derivatives. Their synthetic potential was exploited to prepare Ins(3,4,5,6)P4 and Ins(1,4,5,6)P4 in three steps. With a recently identified and partially purified InsP5/InsP4 phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P3 and Ins(1,5,6)P3, on a preparative scale. An HPLC system employed for both purification of the inositol phosphates and analytical runs ensured that the products were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the complexation properties of Ins(3,4,5)P3/Ins(1,5,6)P3 resemble those of Ins(1,2,3)P3, a compound with antioxidant potential. The set of inositol phosphates synthesized was used to clarify structural motifs important for molecular recognition by p42(IP4), a high-affinity Ins(1,3,4,5)P4/PtdIns(3,4,5)P3-specific binding protein from pig cerebellum.

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“…Earlier syntheses of a number of phosphatidylinositol polyphosphates have been reported, and these synthetic compounds have been employed to verify specific biological roles for these ligands. Falck and co-workers described the synthesis of the sn -1,2-distearoyl analogue of PtdInsP 3 using (−)-quinic acid as the chiral starting material for the construction of d - myo -inositol skeleton. − Gou and Chen have completed an analogous synthesis from enzymatically-resolved 1- d -dicyclohexylidene- myo -inositol, while Bruzik and Kubiak started from the camphor ketal of myo -inositol , …”

Section: Resultsmentioning

confidence: 99%

“…Falck and co-workers described the synthesis of the sn-1,2-distearoyl analogue of PtdInsP 3 using (-)-quinic acid as the chiral starting material for the construction of D-myo-inositol skeleton. [42][43][44] Gou and Chen have completed an analogous synthesis from enzymatically-resolved 1-D-dicyclohexylidene-myoinositol, 45 while Bruzik and Kubiak started from the camphor ketal of myo-inositol. 46 Watanabe et al reported concise routes to the racemic form of PtdIns(3,4,5)P 3 and recently the optically pure form from the enzymatically resolved 1-D-1,2-cyclohexylidene-myo-inositol.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Photoactivatable 1,2-O-Diacyl-sn-glycerol Derivatives of 1-l-Phosphatidyl-d-myo-inositol 4,5-Bisphosphate (PtdInsP₂) and 3,4,5-Trisphosphate (PtdInsP₃)

1996

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Photoactivatable analogues of 1-L-phosphatidyl-D-myo-inositol 4,5-bisphosphate (PtdIns(4,5)P(2) or PtdInsP(2)) and the corresponding 3,4,5-trisphosphate (PtdIns(3,4,5)P(3) or PtdInsP(3)) were prepared from the two chiral precursors, methyl alpha-D-glucopyranoside and 1,2-isopropylidene-sn-glycerol. Two key synthetic transformations included the Ferrier rearrangement reaction to construct the optically-pure inositol skeleton and the sequential acylation of the primary and secondary hydroxyl groups on the glycerol derivatives. The sn-1-O-(6-aminohexanoyl) PtdInsP(2) and PtdInsP(3) derivatives were further modified to contain benzophenone photophores in unlabeled and high specific activity tritium-labeled forms.

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Total synthesis of D-myo-inositole 3,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate

Cited by 17 publications

References 22 publications

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

Enzyme-Assisted Total Synthesis of the Optical Antipodes d-myo-Inositol 3,4,5-Trisphosphate and d-myo-Inositol 1,5,6-Trisphosphate: Aspects of Their Structure−Activity Relationship to Biologically Active Inositol Phosphates

Synthesis of Photoactivatable 1,2-O-Diacyl-sn-glycerol Derivatives of 1-l-Phosphatidyl-d-myo-inositol 4,5-Bisphosphate (PtdInsP₂) and 3,4,5-Trisphosphate (PtdInsP₃)

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Total synthesis of D-myo-inositole 3,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate

Cited by 17 publications

References 22 publications

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function

Enzyme-Assisted Total Synthesis of the Optical Antipodes d-myo-Inositol 3,4,5-Trisphosphate and d-myo-Inositol 1,5,6-Trisphosphate: Aspects of Their Structure−Activity Relationship to Biologically Active Inositol Phosphates

Synthesis of Photoactivatable 1,2-O-Diacyl-sn-glycerol Derivatives of 1-l-Phosphatidyl-d-myo-inositol 4,5-Bisphosphate (PtdInsP2) and 3,4,5-Trisphosphate (PtdInsP3)

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Synthesis of Photoactivatable 1,2-O-Diacyl-sn-glycerol Derivatives of 1-l-Phosphatidyl-d-myo-inositol 4,5-Bisphosphate (PtdInsP₂) and 3,4,5-Trisphosphate (PtdInsP₃)