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Prolyl Isomerase

The first enzyme to catalyze prolyl isomerization was identified by Fischer and colleagues (1984). This discovery was possible because they developed an ingenious assay for prolyl isomerases based on the conformational specificity of chymotrypsin. This protease cleaves a chro-mogenic reporter group from a tetrapeptide (such as succinyl-Ala-Ala-Pro-Phe-4-nitroanilide) only when the Ala—Pro bond of this peptide is in the trans conformation. In aqueous solution the assay peptide exists as a 90 10 mixture of molecules with the Ala—Pro bond in trans and cis, respectively. Therefore, in the presence of a high concentration of chymotrypsin, 90% of the peptide molecules are cleaved within the dead time of manual mixing. Hydrolysis of the remaining 10% is slow because it is limited in rate by the cis —trans isomerization of the Ala—Pro bond. Acceleration of this reaction serves as a sensitive probe for prolyl isomerase activities. [Pg.256]

Kofron and colleagues (1991 1992) improved this assay. They increased the fraction of the cis isomer (and thus the sensitivity of the assay) from 10% up to 70% by dissolving the assay peptide in an anhydrous mixture of trifluoroethanol and LiCl. Other isomer-specific proteases were introduced to widen the range of peptides available [Pg.256]

A variant of the peptide-based assay avoids the coupling with isomer-specific proteolysis (Janowski et al., 1997). The absorbance at 330 nm of succinyl-Ala-Phe-Pro-Phe-4-nitroanilide decreases slightly when the Phe and the nitroanilide moieties rearrange on the cis —trans isomerization at the Phe-Pro bond of the peptide. Because of the small change in signal, the sensitivity of the assay is limited, but it is the method of choice for assaying prolyl isomerases sensitive to proteases. [Pg.257]

Recently, Kiillertz and Fischer developed a new prolyl isomerase assay for high-troughput screening of up to 20,000 samples per day. This assay employs a disulfide-bonded cis peptide with internally quenched fluorescence. Cis/trans isomerization is initiated by rapid reductive ring opening and followed by the increase in fluorescence (G. Kiillertz and G. Fischer, unpublished). [Pg.257]

There is no common nomenclature for prolyl isomerases. The systematic name peptidylproline cis, trans-isomerase (E.C. 5.2.1.8) is shortened to prolyl isomerase, proline isomerase, PPI, or PPIase. Sometimes the expression rotamase is used. [Pg.257]


FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... [Pg.507]

Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pinl restores the functions of Alzheimer-associated phosphorylated tau protein [see comments]. Nature 1999 399 784-788. [Pg.272]

Loss of function of the prolyl isomerase Pinl by homologous recombination has been reported to lead to the formation of abundant filaments made of hyperphosphorylated mouse tau and neurodegeneration [39]. [Pg.757]

Liou, Y.-C. et al. Role of the prolyl isomerase Pinl in protecting against age-dependent neurodegeneration. Nature 424 556-561,2003. [Pg.759]

PROLYL ISOMERASE PEPTIDYLTRANSFERASE Percent diastereoisomer excess,... [Pg.769]

PROLINE REDUCTASE L-Proline to D-proline interconversion, PROLINE RACEMASE PROLIPOPROTEIN SIGNAL PEPTIDASE PROLYL 3-HYDROXYLASE PROLYL 4-HYDROXYLASE PROLYL ISOMERASE... [Pg.774]

Fluorine in biological mimics Peptidyl prolyl isomerases (PPIases)... [Pg.700]

The preparation of the fluoroolefin amide isosteres is reviewed. The incorporation of the amide isosteres in peptidomimetics and the influence of that isosteric substitution on biological activity on inhibition of peptidyl prolyl isomerases cyclophilin (CyP) and Pini, dipeptidyl peptidase IV/CD26 (DPP IV) and thermolysin is described. In addition, select fiuoroolefination procedures which may have utility in the construction of fluoroolefin amide isosteres are illustrated. [Pg.700]

X.J. Wang, F.A. Etzkorn, Peptidyl-prolyl isomerase inhibitors. Biopolymers 84 (2006) 125-146. [Pg.731]

The potential utility of peptides as therapeutics with clinical applications is limited by its metabolic instability or poor transmembrane mobility. Consequently, the preparation of metabolically stable peptide analogs that can either mimic or block the function of natural peptides or enzymes is an important area of medicinal chemistry research. Synthesis of fluoroolefin amide isosteres, its incorporation in peptidomimetics, and the influence of that isosteric substitution on the inhibition of several enzymes such as peptidyl prolyl isomerases, dipeptidyl peptidase IV, and thermolysin is described. Moreover, protein folding and activity... [Pg.820]

Harding, MW., Galat, A., Uehling, DE., and Schreiber, S.L. (1989) A receptor for the immunosuppressant FK506 is a cis-trans pep-tidyl-prolyl isomerase. Nature 341, 758-760. [Pg.195]

Siekierka, JJ., Hung, SH., Poe, M., Lin, CS., and Sigal, NH. (1989). A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct ftom cyclophilin. Nature 341, 755-757. [Pg.195]

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. [Pg.1191]

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). [Pg.91]


See other pages where Prolyl Isomerase is mentioned: [Pg.125]    [Pg.308]    [Pg.98]    [Pg.6]    [Pg.6]    [Pg.16]    [Pg.27]    [Pg.508]    [Pg.251]    [Pg.753]    [Pg.44]    [Pg.335]    [Pg.576]    [Pg.576]    [Pg.734]    [Pg.769]    [Pg.774]    [Pg.19]    [Pg.703]    [Pg.723]    [Pg.723]    [Pg.734]    [Pg.239]    [Pg.1626]    [Pg.283]    [Pg.321]    [Pg.640]    [Pg.125]    [Pg.287]   
See also in sourсe #XX -- [ Pg.2 , Pg.3 , Pg.4 , Pg.5 , Pg.6 , Pg.7 ]




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Assays, prolyl isomerases

Functions of Prolyl Isomerases

Isomerases peptidyl prolyl cis-trans

Isomerization peptide bonds, prolyl isomerases

Peptidyl Prolyl Isomerases (PPIases)

Peptidyl prolyl cis/trans isomerases (PPIases

Peptidyl prolyl isomerase, protein folding role

Peptidyl prolyl isomerases

Peptidyl prolyl isomerases PPIs)

Prolyl Isomerases as Catalysts of in Vitro Protein Folding

Prolyl Isomerases as Tools in Protein Folding

Prolyl isomerases Immunophilins)

Prolyl isomerases and immunosuppressant drugs

Prolyl isomerases cyclophilins

Prolyl isomerases discovery

Prolyl isomerases isomerization

Prolyl isomerases parvulins

Prolyl isomerases proline-limited steps

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