Abstract
Analyses of sequences and structures of the cyclosporine A (CsA)-binding proteins (cyclophilins) and the immunosuppressive macrolide FK506-binding proteins (FKBPs) have revealed that they exhibit peculiar spatial distributions of charges, their overall hydrophobicity indexes vary within a considerable level whereas their points isoelectric (pIs) are contained from 4 to 11. These two families of peptidylprolyl cis/trans isomerases (PPIases) have several distinct functional attributes such as: (1) high affinity binding to some pharmacologically-useful hydrophobic macrocyclic drugs; (2) diversified binding epitopes to proteins that may induce transient manifolds with altered flexibility and functional fitness; and (3) electrostatic interactions between positively charged segments of PPIases and negatively charged intracellular entities that support their spatial integration. These three attributes enhance binding of PPIase/pharmacophore complexes to diverse intracellular entities, some of which perturb signalization pathways causing immunosuppression and other system-altering phenomena in humans.
Highlights
About forty years ago, two different types of macrocyclic molecules were isolated and shown to possess immunosuppressive activities, such as the cyclic peptide containing non-standard amino acid residues (AAs) cyclosporine A (CsA) and its homologues [1], and two polyketides having L-pipecolic acid ring, namely immunosuppressive macrolide FK506 [2] and rapamycin [3,4]
All those compounds have been found in soil samples coming from three different regions of Earth, namely CsA and its derivatives were purified from the ascomycete fungus Tolypocladium inflatum found in a soil sample from Norway [1], FK506 was isolated from a bacterial culture of Streptomyces tsukubaensis found in a soil sample from Japan [2] whereas rapamycin was recuperated from a filament-forming bacterium, Streptomyces hygroscopicus found in a soil sample of Rapa Nui (Easter Island) [3,4], respectively
(Figure 2) [29,62] or FKBP12a/FK506 [63], and the X-ray structure of the rapamycin-binding domain (RBD) of mTOR bound to FKBP12a/rapamycin [28] revealed the following intermolecular interaction networks: (1) the (CnA–CnB)/(hFKBP12a–FK506; 1TCO.pdb) [63] ternary complex is stabilized by 105 interactions between CnA/CnB and FK506, 175 interactions between hFKBP12a and FK506, and 210 interactions between CnA/CnB and hFKBP12a; (2) the hFKBP12a/rapamycin complex bound to the RBD of mTOR (4FAP.pdb) [28] is stabilized by 177 inter-molecular interactions between rapamycin and hFKBP12a in addition to 106 and 77 interactions between rapamycin–RBD and hFKBP12a–RBD, respectively
Summary
About forty years ago, two different types of macrocyclic molecules were isolated and shown to possess immunosuppressive activities, such as the cyclic peptide containing non-standard amino acid residues (AAs) cyclosporine A (CsA) and its homologues [1], and two polyketides having L-pipecolic acid ring, namely immunosuppressive macrolide FK506 [2] and rapamycin [3,4]. It has been shown that either the in [7,19]) bind to FK506 or rapamycin and their structural analogues [23] It has been shownofthat following two complexes, namely. FKBP12/rapamycin binds to serine-threonine kinase mTORthe and it hinders kinase activity site [27,28], which causes anergy of cells. The cyclophilin (CyPA)/CsA complex hinders access to phosphatase activity site The cyclophilin A (CyPA)/CsA complex hinders access to phosphatase activity as (shown bound as phosphate ion in ion lightin light red spheres). It would imply that under physiologic conditions, conditions, of some immunophilins could by notthebeimmunosuppressive fully inhibited by the PPIase activityPPIase of someactivity immunophilins could not be fully inhibited drugs drugs or their non‐immunosuppressive analogues Forthat example, it has been orimmunosuppressive their non-immunosuppressive analogues. Useful moleculesimmunosuppression (pharmacophores) may influence other signalization networks than the well-described scenario for CsA-, FK506-, or rapamycin-induced immunosuppression [24,25,26,27,28]
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