Development of a Practical Process for the Opening of Macrocyclic Cyclosporin A and Amino Acid Deletion

2014 ◽  
Vol 18 (12) ◽  
pp. 1763-1770 ◽  
Author(s):  
Bernard Riss ◽  
Arnaud Grandeury ◽  
Thorsten Gut ◽  
Manuela Seeger-Weibel ◽  
Christian Zuercher ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cyclosporin A ◽  
Amino Acid Deletion

The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae

1993 ◽  
Vol 13 (8) ◽  
pp. 5010-5019 ◽  
Author(s):  
J Heitman ◽  
A Koller ◽  
J Kunz ◽  
R Henriquez ◽  
A Schmidt ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acids ◽  
Amino Acid ◽  
Cyclosporin A ◽  
Secretory Pathway ◽  
Yeast Cells ◽  
Amino Acid Transporters ◽  
Yeast Saccharomyces Cerevisiae ◽  
Eukaryotic Microorganisms

The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.

Blockade of endothelium-dependent responses in conscious rats by cyclosporin A: effect of L-arginine

1993 ◽  
Vol 264 (3) ◽  
pp. H708-H714 ◽  
Author(s):  
M. J. Gallego ◽  
A. Lopez Farre ◽  
A. Riesco ◽  
M. Monton ◽  
S. M. Grandes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Atrial Natriuretic Peptide ◽  
Endothelial Function ◽  
Cyclosporin A ◽  
Wistar Rats ◽  
Immunosuppressive Drug ◽  
Simultaneous Administration ◽  
Harmful Effects ◽  
Functional Alteration

This study was undertaken to examine the effect of the major immunosuppressive drug, cyclosporin A (CyA), on endothelial function. Conscious Wistar rats, treated with CyA (25 mg.kg-1 x day-1 im for 15 days), developed an inhibition of the endothelium-dependent acetylcholine (ACh)-mediated vasodilation, diuresis, natriuresis, and guanosine 3',5'-cyclic monophosphate excretion. The response to two endothelium-independent agents, i.e., sodium nitroprusside and atrial natriuretic peptide was preserved in similarly treated rats. The toxic effects of CyA were acutely overcome by the administration of the amino acid L-arginine (L-Arg), a source of substrate for nitric oxide. Moreover, the simultaneous administration of L-Arg (200 mg/kg ip for 15 days) significantly prevented the functional effects of CyA toxicity. The present data suggest that, in early stages of CyA toxicity, the predominant functional alteration occurs at the endothelial level. The reversibility of such alteration by L-Arg opens the possibility for further strategies aimed to reduce the harmful effects of CyA.

scholarly journals A Three Amino Acid Deletion in Glycoprotein IIIa Is Responsible for Type I Glanzmann's Thrombasthenia: Importance of Residues Ile325Pro326Gly327 for β3 Integrin Subunit Association

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 669-677 ◽  
Author(s):  
Marie-Christine Morel-Kopp ◽  
Cécile Kaplan ◽  
Valérie Proulle ◽  
Vincent Jallu ◽  
Chantal Melchior ◽  
...  
Keyword(s):  
Amino Acid ◽  
Restriction Site ◽  
Restriction Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Integrin Subunit ◽  
Wild Type ◽  
Amino Acid Deletion ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

Abstract Glanzmann's thrombasthenia (GT) is a recessive autosomal bleeding disorder characterized by abnormal platelet aggregation due to a qualitative or quantitative defect of the glycoprotein (GP) IIb-IIIa complex (integrin αIIbβ3). We describe a new mutation in the GPIIIa gene responsible for type I GT in a consanguineous Algerian family. A discordance between phenotyping and genotyping of the GPIIIa-related HPA-1 platelet alloantigen system in three family members heterozygous for the disease suggested a genetic defect in the GPIIIa gene and a normal GPIIb gene. Sequence analysis of amplified genomic DNA fragments showed a 6-bp deletion in exon 7 of the GPIIIa gene resulting in the amino acid deletion/substitution (Ile325Pro326Gly327 → Met) and creating a new BspHI restriction site. Expression of the mutated integrin β3 subunit cDNA in Chinese hamster ovary cells showed that the cDNA gene was transcribed into a full-length β3 protein with an apparent molecular weight identical to wild-type β3 and accumulated as a single-chain molecule in the cell cytoplasm. The absence of heterodimeric complex formation of the mutant β3 protein with endogeneous αv was shown by immunoprecipitation experiments, intracellular immunofluorescent labeling, and a semiquantitative enzyme-linked immunosorbent assay using the αvβ3 complex-specific monoclonal antibodies LM609 and 23C6. Substitution of the methionine residue by a proline, present at position 326 of wild-type β3, did not restore the ability of the recombinant mutant β3 protein to associate with αv, suggesting that the Ile-Pro-Gly motif is located in a β3 domain important for integrin subunit interaction. The association of a BspHI restriction site with this newly identified mutation has allowed allele-specific restriction analysis of Algerian GT individuals and the identification of two new unrelated type I patients exhibiting the same mutation, suggesting that the described mutation might be significant in this population and that BspHI restriction analysis will provide a useful screening assay for antenatal diagnosis and genetic counselling.

Pfeiffer syndrome type 2 associated with a single amino acid deletion in the PGFR2 gene

2000 ◽  
Vol 58 (1) ◽  
pp. 81-83 ◽  
Author(s):  
Manuela Priolo ◽  
Margherita Lerone ◽  
Maria Baffico ◽  
Maurizia Baldi ◽  
Roberto Ravazzolo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Amino Acid ◽  
Syndrome Type ◽  
Amino Acid Deletion ◽  
Pfeiffer Syndrome
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