Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

Asymmetric enamine catalysis.

https://www.cell.com/trends/immunology/pdf/0167-5699(92)90111-J.pdf

The mechanism of action of cyclosporin A and FK506

FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline rotamase. Saccharomyces cerevisiae cells treated with rapamycin irreversibly arrested in the G1 phase of the cell cycle. An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1, were viable and fully resistant to rapamycin and (ii) FK506 antagonized rapamycin toxicity in vivo. Mutations that conferred rapamycin resistance altered conserved residues in FKBP that are critical for drug binding. Two genes other than FPR1, named TOR1 and TOR2, that participate in rapamycin toxicity were identified. Nonallelic noncomplementation between FPR1, TOR1, and TOR2 alleles suggests that the products of these genes may interact as subunits of a protein complex. Such a complex may mediate nuclear entry of signals required for progression through the cell cycle.

https://science.sciencemag.org/content/sci/253/5022/905.full.pdf

Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast.

/pdf/regulation-of-translation-initiation-by-frap-mtor-495vylnz0t.pdf

Regulation of translation initiation by FRAP/mTOR

THE structurally novel macrolide FK506 (refs 1,2) has recently been demonstrated to have potent immunosuppressive activity3–7 at concentrations several hundredfold lower than cyclosporin A (CsA). Cyclosporin A, a cyclic peptide, has found widespread clinical use in the prevention of graft rejection following bone marrow and organ transplantation8. The mechanisms of immunosuppression mediated by FK506 and CsA appear to be remarkably similar, suggesting that these unrelated structures act on a common receptor or on similar molecular targets, perhaps the CsA receptor, cyclophilin9–11, which has recently been shown by Fischer etal.12 and Takahashi etal.13 to have cis–trans peptidyl-prolyl isomerase activity. We have prepared an FK506 affinity matrix and purified a binding protein for FK506 from bovine thymus and from human spleen. This FK506-binding protein (FKBP) has a relative molecular mass (Mr) of ∼14,000(14K), a pi of 8.8–8.9, and does not cross-react with antisera against cyclophilin. The first 40 N-terminal residues of the bovine and 16 residues of the human FKBP were determined; the 16-residue fragments are identical to each other and unrelated to any known sequences. This protein catalyses the cis–trans isomerization of the proline amide in a tetrapeptide substrate and FK506 inhibits the action of this new isomerase. The FKBP and cyclophilin appear to be members of an emerging class of novel proteins that regulate T cell activation and other metabolic processes, perhaps by the recognition (and possibly the isomerization) of proline-containing epitopes in target proteins.

A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.

L'epoxydation asymetrique de Sharpless a ete etudiee avec trois substrats achiraux, elle donne des epoxyalcools dont la purete enantiomere augmente avec le degre d'achevement de la reaction

Reactions that proceed with a combination of enantiotopic group and diastereotopic face selectivity can deliver products with very high enantiomeric excess: experimental support of a mathematical model

Ozonolytic cleavage of cycloalkenes to terminally differentiated products

4-Phenyl-2,4,6-triazatetra~yclo[6.3.2.0~~~.0~~~] trideca- 10,12-diene-3,5dione was prepared by the reported procedure.’ Spectral parameters are as follows: I3C NMR (CDCI,, 30 “C, 25.2 MHz, CHC1, assigned as 76.91 ppm) 6 73.750 (Cl/C5), 40.957 (C2/C4/C6/C8), 127.532 (C6/C9), 131.516, 127.752 (ipso/para C), 128.830, 125.435 (meta/para C), 148.573 (C=O); ’H NMR (CDzCIz, XL 200 MHz, 30 OC, tetramethylsilane) 6 7.49 (Ph), 4.92 (t, J = 7.7 Hz, Hl/H5), 4.35 (major coupling t, J = 7.7 Hz, H2/H4/H6/H8), 6.08 (major coupling t, J = 7.7 Hz, H6/H9). At -10 OC the peak at 6 4.35 begins to broaden, at -70 OC it is totally flat, and below this the solute precipitates. Crystal Structure Data. Intensity data were collected at 293 K and at 153 K on a Nicolet P3 four-circle computer-controlled diffractometer, using graphite-monochromated X-radiation (Cu Ka, h = 1.5418 8, for 293 K and Mo Ka, h = 0.71069 A for 153 K). The crystals are monoclinic, space group P2,/c. The structure was solved by using the (19) Not all exchange processes that occur in solution are observed in the solid state. Miller, R. D.; Yannoni, C. S. J. Am. Chem. Soc. 1980, 102, 7396-7397. Macho, V.; Miller, R. D.; Yannoni, C. S. Ibid. 1983, 105, 3735-3737. Lyerla, J. R.; Yannoni, C. S.; Fyfe, C. A. Ace. Chem. Res. 1982, 15, 208-216. For a semibullvalene that is fluctional in the crystalline state, see ref 4a and lle.

Dynamic behavior of dicobalt hexacarbonyl propargyl cations and their reactions with chiral nucleophiles

The gramicidin A transmembrane channel is believed to consist of two head-to-head beta helices. Computer-generated models were used to formulate the structure of new single-chain channel molecules based on the gramicidin motif. The chemical synthesis of two tartaric acid-gramicidin A hybrids and single-channel analyses of their conducting properties are reported. These studies illustrate the rational design and synthesis of long-lived channels with tunable conductance properties and provide support for current molecular models of the natural (dimeric) gramicidin channel.

https://science.sciencemag.org/content/sci/244/4906/813.full.pdf

Stuart L. Schreiber

Papers

A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase.

Reactions that proceed with a combination of enantiotopic group and diastereotopic face selectivity can deliver products with very high enantiomeric excess: experimental support of a mathematical model

Ozonolytic cleavage of cycloalkenes to terminally differentiated products

Dynamic behavior of dicobalt hexacarbonyl propargyl cations and their reactions with chiral nucleophiles

Transmembrane channels based on tartaric acid-gramicidin A hybrids.