Generation of Reactive Oxygen Species by Photosensitizers and their Modes of Action on Proteins

2019 ◽  
Vol 25 (40) ◽  
pp. 5528-5539 ◽  
Author(s):  
Itzhak Bilkis ◽  
Israel Silman ◽  
Lev Weiner
Keyword(s):  
Singlet Oxygen ◽  
State Of The Art ◽  
Molten Globule ◽  
Peptide Hormone ◽  
Amino Acid Residues ◽  
Malignant Cells ◽  
Gnrh Receptors ◽  
Membrane Interfaces ◽  
Partially Unfolded ◽  
Specific Peptide

In this review, we first survey the mechanisms underlying the chemical modification of amino acid residues in proteins by singlet oxygen elicited by photosensitizers. Singlet oxygen has the capacity to cause widespread chemical damage to cellular proteins. Its use in photodynamic therapy of tumors thus requires the development of methodologies for specific addressing of the photosensitizer to malignant cells while sparing normal tissue. We describe three targeting paradigms for achieving this objective. The first involves the use of a photosensitizer with a high affinity for its target protein; in this case, the photosensitizer is methylene blue for acetylcholinesterase. The second paradigm involves the use of the hydrophobic photosensitizer hypericin, which has the capacity to interact selectively with partially unfolded forms of proteins, including nascent species in rapidly dividing or virus-infected and cancer cells, acting preferentially at membrane interfaces. In this case, partially unfolded molten globule species of acetylcholinesterase serve as the model system. In the third paradigm, the photodynamic approach takes advantage of a general approach in ‘state-of-the-art’ chemotherapy, by coupling the photosensitizer emodin to a specific peptide hormone, GnRH, which recognizes malignant cells via specific GnRH receptors on their surface.

scholarly journals Conserved Amino Acid Residues that Are Important for Ligand Binding in the Type I Gonadotropin-Releasing Hormone (GnRH) Receptor Are Required for High Potency of GnRH II at the Type II GnRH Receptor

2007 ◽  
Vol 21 (1) ◽  
pp. 281-292 ◽  
Author(s):  
Sipho Mamputha ◽  
Zhi-liang Lu ◽  
Roger W. Roeske ◽  
Robert P. Millar ◽  
Arieh A. Katz ◽  
...  
Keyword(s):  
Inositol Phosphate ◽  
Gnrh Receptor ◽  
Type I ◽  
Type Ii ◽  
Amino Acid Residues ◽  
Binding Assays ◽  
Antagonist Activity ◽  
Conserved Residues ◽  
Gnrh Receptors ◽  
Mutant Receptors

Abstract GnRH I regulates reproduction. A second form, designated GnRH II, selectively binds type II GnRH receptors. Amino acids of the type I GnRH receptor required for binding of GnRH I (Asp2.61(98), Asn2.65(102), and Lys3.32(121)) are conserved in the type II GnRH receptor, but their roles in receptor function are unknown. We have delineated their functions using mutagenesis, signaling and binding assays, immunoblotting, and computational modeling. Mutating Asp2.61(97) to Glu or Ala, Asn2.65(101) to Ala, or Lys3.32(120) to Gln decreased potency of GnRH II-stimulated inositol phosphate production. Consistent with proposed roles in ligand recognition, mutations eliminated measurable binding of GnRH II, whereas expression of mutant receptors was not decreased. In detailed analysis of how these residues affect ligand-dependent signaling, [Trp2]-GnRH I showed lesser decreases in potency than GnRH I at the Asp2.61(97)Glu mutant. In contrast, [Trp2]-GnRH II showed the same loss of potency as GnRH II at this mutant. This suggests that Asp2.61(97) contributes to recognition of His2 of GnRH I, but not of GnRH II. GnRH II showed a large decrease in potency at the Asn2.65(101)Ala mutant compared with analogs lacking the C⋕O group of Gly10NH2. This suggests that Asn2.65(101) recognizes Gly10NH2 of GnRH II. GnRH agonists showed large decreases in potency at the Lys3.32(120)Gln mutant, but antagonist activity was unaffected. This suggests that Lys3.32(120) recognizes agonists, but not antagonists, as in the type I receptor. These data indicate that roles of conserved residues are similar, but not identical, in the type I and II GnRH receptors.

scholarly journals Suppression of the pro-apoptotic function of cytochrome c by singlet oxygen via a haem redox state-independent mechanism

2005 ◽  
Vol 392 (2) ◽  
pp. 399-406 ◽  
Author(s):  
Daisuke Suto ◽  
Kazuaki Sato ◽  
Yoshihiro Ohba ◽  
Tetsuhiko Yoshimura ◽  
Junichi Fujii
Keyword(s):  
Cytochrome C ◽  
Singlet Oxygen ◽  
Protein Modification ◽  
Redox State ◽  
Amino Acid Residues ◽  
Apoptotic Pathway ◽  
Oxidative Protein Modification ◽  
A Cell ◽  
Cyt C ◽  
Caspase Cascade

Stimuli for apoptotic signalling typically induce release of cyt c (cytochrome c) from mitochondria. Cyt c then initiates the formation of the apoptosome, comprising Apaf-1 (apoptotic protease-activating factor 1), caspase-9 and other cofactors. The issue of whether the redox state of the haem in cyt c affects the initiation of the apoptotic pathway is currently a subject of debate. In a cell-free reconstitution system, we found that only oxidized cyt c was capable of activating the caspase cascade. Oxidized cyt c was reduced by the physiological reductants cysteine and glutathione, after which it was unable to activate the caspase cascade. It is thus likely that cyt c with oxidized haem is in a conformation capable of interaction with Apaf-1 and forming apoptosomes. When either oxidized or reduced cyt c was treated with submillimolar concentrations of endoperoxide, which affected less than 3% of the redox state of haem, the ability of the oxidized cyt c to activate the caspase cascade was abolished. Higher amounts of singlet oxygen were required to affect the optical spectral change of haem, suggesting that the suppressed pro-apoptotic function of oxidized cyt c is a mechanism that is separate from the redox state of haem. Oxidative protein modification of cyt c by singlet oxygen was evident, on the basis of elevated contents of carbonyl compounds. Our data suggest that singlet oxygen eliminates the pro-apoptotic ability of oxidized cyt c not via the reduction of haem, but via the modification of amino acid residues that are required for apoptosome formation.

scholarly journals Corticotropin-releasing hormone physiology

2006 ◽  
Vol 155 (suppl_1) ◽  
pp. S71-S76 ◽  
Author(s):  
Joseph A Majzoub
Keyword(s):  
Immune Function ◽  
Peptide Hormone ◽  
Amino Acid Residues ◽  
Corticotropin Releasing Hormone ◽  
Camp Response Element ◽  
Releasing Hormone ◽  
Surface Receptors ◽  
Glucose Levels ◽  
Metabolic Functions ◽  
Organ Systems

Corticotropin-releasing hormone (CRH), also known as corticotropin-releasing factor, is a highly conserved peptide hormone comprising 41 amino acid residues. Its name derives from its role in the anterior pituitary, where it mediates the release of corticotropin (ACTH) leading to the release of adrenocortical steroids. CRH is the major hypothalamic activator of the hypothalamic–pituitary–adrenal (HPA) axis. Major functions of the HPA include: (i) influencing fetal development of major organ systems including lung, liver, and gut, (ii) metabolic functions, including the maintenance of normal blood glucose levels during the fasting state via glycogenolysis and gluconeogenesis, (iii) modulation of immune function, and (iv) maintenance of cardiovascular tone. In addition, CRH, acting both directly and via the HPA, has a role in regulating several neuroendocrine functions including behavior, food intake, reproduction, growth, immune function, and autonomic function. CRH has been localized to the paraventricular nucleus (PVN) of the hypothalamus, which projects to the median eminence and other hypothalamic and midbrain targets. The CRH gene is composed of two exons. The CRH promoter contains a cAMP-response element, and the intron contains a restrictive element-1/neuron restrictive silencing element (RE-1/NRSE) sequence. Recently, a family of CRH-related peptides, termed the urocortins, has been identified. These peptides probably play a role in integrating multiple aspects of the stress-response, although their functions are largely unknown. Both CRH and the urocortins interact with two transmembrane G-protein-coupled cell surface receptors, CRH-R1, and CRH-R2, which differ in their patterns of tissue distribution. In addition, the binding affinities for CRH and the urocortins to the two receptors differ considerably, and may contribute to the different actions of these peptides.

scholarly journals The specificity of combination between ristocetins and peptides related to bacterial cell wall mucopeptide precursors

1971 ◽  
Vol 124 (5) ◽  
pp. 845-852 ◽  
Author(s):  
M. Nieto ◽  
H. R. Perkins
Keyword(s):  
Cell Wall ◽  
Amino Acid ◽  
Bacterial Cell ◽  
Bacterial Cell Wall ◽  
Optical Rotatory Dispersion ◽  
Amino Acid Residues ◽  
Peptide Molecule ◽  
Micro Organisms ◽  
Specific Peptide ◽  
Absorption Characteristics

The affinity of ristocetin B for analogues of the C-terminal tripeptide sequence of bacterial cell wall mucopeptide precursors resembles that of vancomycin. Complex-formation requires a d-configuration in the two amino acid residues of the C-terminal dipeptide, an l-configuration is preferred in the preceding amino acid residue and positive charges on the peptide molecule decrease its affinity. The specificity of ristocetin B, however, differs from that of vancomycin in the requirements for the size of the side chains on the C-terminal dipeptide. These differences may explain the observed differences in antibiotic behaviour of vancomycin and ristocetin with particular micro-organisms. The optical rotatory dispersion and u.v.-absorption characteristics of the ristocetins are very different from those of vancomycin but nearly identical with those of ristomycin A. Aglycones prepared from ristomycin A were antibiotically active and also combined with a specific peptide.

scholarly journals Pursuing Orally Bioavailable Hepcidin Analogues via Cyclic N-Methylated Mini-Hepcidins

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 164
Author(s):  
Daniela Goncalves Monteiro ◽  
Johannes W. A. van Dijk ◽  
Randy Aliyanto ◽  
Eileen Fung ◽  
Elizabeta Nemeth ◽  
...  
Keyword(s):  
Amino Acid ◽  
Oral Bioavailability ◽  
Iron Absorption ◽  
Peptide Hormone ◽  
Proteolytic Degradation ◽  
Amino Acid Residues ◽  
Lysosomal Degradation ◽  
Tissue Iron ◽  
Orally Bioavailable ◽  
The Stability

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut and export of iron from storage to ultimately decrease systemic iron levels. The key interaction motif in hepcidin has been localised to the highly conserved N-terminal region, comprising the first nine amino acid residues, and has led to the development of mini-hepcidin analogs that induce ferroportin internalisation and have improved drug-like properties. In this work, we have investigated the use of head-to-tail cyclisation and N-methylation of mini-hepcidin as a strategy to increase oral bioavailability by reducing proteolytic degradation and enhancing membrane permeability. We found that backbone cyclisation and N-methylation was well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues often surpassing their linear counterparts in potency. Both macrocyclisation and backbone N-methylation were found to improve the stability of the mini-hepcidins, however, there was no effect on membrane-permeabilizing activity.

scholarly journals The transmembrane autophagy cargo receptors ATI1 and ATI2 interact with ATG8 through intrinsically disordered regions with distinct biophysical properties

2019 ◽  
Vol 476 (3) ◽  
pp. 449-465 ◽  
Author(s):  
Ida Marie Zobbe Sjøgaard ◽  
Simon Bressendorff ◽  
Andreas Prestel ◽  
Swathi Kausika ◽  
Emilie Oksbjerg ◽  
...  
Keyword(s):  
Molten Globule ◽  
Resonance Spectroscopy ◽  
Amino Acid Residues ◽  
In Planta ◽  
Interacting Protein ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Specific Proteins ◽  
Sizable Fraction ◽  
Disordered Regions

Abstract Selective autophagy has emerged as an important mechanism by which eukaryotic cells control the abundance of specific proteins. This mechanism relies on cargo recruitment to autophagosomes by receptors that bind to both the ubiquitin-like AUTOPHAGY8 (ATG8) protein through ATG8-interacting motifs (AIMs) and to the cargo to be degraded. In plants, two autophagy cargo receptors, ATG8-interacting protein 1 (ATI1) and 2 (ATI2), were identified early on, but their molecular properties remain poorly understood. Here, we show that ATI1 and ATI2 are transmembrane proteins with long N-terminal intrinsically disordered regions (IDRs). The N-terminal IDRs contain the functional AIMs, and we use nuclear magnetic resonance spectroscopy to directly observe the disorder-order transition of the AIM upon ATG8 binding. Our analyses also show that the IDRs of ATI1 and ATI2 are not equivalent, because ATI2 has properties of a fully disordered polypeptide, while ATI1 has properties more consistent with a collapsed pre-molten globule-like conformation, possibly as a consequence of a higher content of π-orbital-containing amino acid residues. Finally, we show that a sizable fraction of ATI2, but not ATI1, is phosphorylated in planta.

scholarly journals Distinct modes of action of IAPP oligomers on membranes

2021 ◽  
Author(s):  
Aliasghar Sepehri ◽  
Binod Nepal ◽  
Themis Lazaridis
Keyword(s):  
Water Channel ◽  
Peptide Hormone ◽  
Β Cells ◽  
Islet Amyloid ◽  
Amyloid Aggregates ◽  
Membrane Modeling ◽  
Helix Orientation ◽  
Partially Unfolded

Islet Amyloid Polypeptide (IAPP, also known as amylin) is a peptide hormone which is co-secreted with insulin by pancreatic β-cells and forms amyloid aggregates in type II diabetes. Various lines of evidence indicate that oligomers of this peptide may induce toxicity by disrupting or forming pores in cell membranes but the structures of these pores are unknown. Here we create models of pores for both helical and β-structured peptides using implicit membrane modeling and test their stability using multimicrosecond all-atom simulations. We find that the helical peptides behave similarly to antimicrobial peptides; they remain stably inserted in a highly tilted or partially unfolded configuration creating a narrow water channel. Parallel helix orientation creates a somewhat larger pore. An octameric β barrel of parallel β-hairpins is highly stable in the membrane, whereas the corresponding barrel made of antiparallel hairpins is not. We propose that certain experiments probe the helical pore state while others probe the β-structured pore state; this provides a possible explanation for lack of correlation that is sometimes observed between in vivo toxicity and in vitro liposome permeabilization experiments.

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