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.
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.
Adelt
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Institute für Biochemie und Organische Chemie, Bergische Universität Wuppertal, Gaussstrasse 20, 42097 Wuppertal.
Plettenburg
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Stricker
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Reiser
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Altenbach
H J
HJ
Vogel
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D017766:Acid Anhydride Hydrolases / Q000737:chemistry*; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D004023:Dictyostelium / Q000201:enzymology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007295:Inositol Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; C118500:inositol 3,4,5-trisphosphate; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; C118875:inositol-1,5,6-triphosphate; D017766:Acid Anhydride Hydrolases; C116368:diphosphoinositol polyphosphate phosphohydrolase