-
Journal of the American Chemical Society Aug 2023With the growing popularity of serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) in chemical protein synthesis, facile and general approaches for...
With the growing popularity of serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) in chemical protein synthesis, facile and general approaches for the preparation of peptide salicylaldehyde (SAL) esters are urgently needed, especially those viable for obtaining expressed protein SAL esters. Herein, we report the access of SAL ester surrogates from peptide hydrazides (obtained either synthetically or recombinantly) via nitrite oxidation and phenolysis by 3-(1,3-dithian-2-yl)-4-hydroxybenzoic acid (SAL(-COOH)). The resulting peptide SAL(-COOH) esters can be activated to afford the reactive peptide SAL(-COOH) esters for subsequent STL/CPL. While being operationally simple for both synthetic peptides and expressed proteins, the current strategy facilitates convergent protein synthesis and combined application of STL with NCL. The generality of the strategy is showcased by the N-terminal ubiquitination of the growth arrest and DNA damage-inducible protein (Gadd45a), the efficient synthesis of ubiquitin-like protein 5 (UBL-5) via a combined N-to-C NCL-STL strategy, and the C-to-N semisynthesis of a myoglobin (Mb) variant.
Topics: Protein C; Peptides; Proteins; Cysteine; Serine; Threonine; Esters
PubMed: 37470345
DOI: 10.1021/jacs.3c05190 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Nanomaterials with biomimetic catalytic abilities have attracted significant attention. However, the stereoselectivity of natural enzymes determined by their unique...
Nanomaterials with biomimetic catalytic abilities have attracted significant attention. However, the stereoselectivity of natural enzymes determined by their unique configurations is difficult to imitate. In this work, a kind of chiral CuCoS-CuS nanoflowers (L/D-Pen-NFs) is developed, using porous CuCoS nanoparticles (NPs) as stamens, CuS sheets as petals, and chiral penicillamine as surface stabilizers. Compared to the natural laccase enzyme, L/D-Pen-NFs exhibit significant advantages in catalytic efficiency, stability against harsh environments, recyclability, and convenience in construction. Most importantly, they display high enantioselectivity toward chiral neurotransmitters, which is proved by L- and D-Pen-NFs' different catalytic efficiencies toward chiral enantiomers. L-Pen-NFs are more efficient in catalyzing the oxidation of L-epinephrine and L-dopamine compared with D-Pen-NFs. However, their catalytic efficiency in oxidizing L-norepinephrine and L-DOPA is lower than that of D-Pen-NFs. The reason for the difference in catalytic efficiency is the distinct binding affinities between CuCoS-CuS nano-enantiomers and chiral molecules. This work can spur the development of chiral nanostructures with biomimetic functions.
Topics: Catalysis; Copper; Stereoisomerism; Nanostructures; Biomimetics; Oxidation-Reduction; Laccase
PubMed: 38196019
DOI: 10.1002/smll.202311275 -
International Journal of Molecular... Apr 2024Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body... (Review)
Review
Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
Topics: Humans; Hepatolenticular Degeneration; Copper; Iron; Ferroptosis; Reactive Oxygen Species; Liver; Animals
PubMed: 38731973
DOI: 10.3390/ijms25094753 -
Mediterranean Journal of Rheumatology Mar 2024Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating...
INTRODUCTION
Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating agent, is used in high doses in the treatment of Wilson disease leading to a variety of cutaneous reactions, including hyper-sensitivity reactions, pseudoxanthoma elasticum, elastosis perforans serpiginosa, anetoderma, and cutis laxa (CL). We present a rare case of localised CL induced by penicillamine for Wilson disease, in the absence of elastosis perforans serpiginosa.
CASE DESCRIPTION
A 41-year-old male with Wilson disease treated with long-term high-dose penicillamine was referred to us for a basal cell carcinoma on the scalp. On physical examination, diffusely flaccid and redundant skin on the right side of the neck were observed. Histopathology revealed findings consistent with CL.
CONCLUSION
Long-term treatment with penicillamine for Wilson disease may induce localized CL, possibly by direct inhibition of cross-linkage of collagen fibres.
PubMed: 38736957
DOI: 10.31138/mjr.280223.pil -
Cureus May 2024Wilson's disease (WD), or "hepato-lenticular degeneration," is a rare genetic disorder of autosomal recessive inheritance causing toxic tissue accumulation of copper,...
Wilson's disease (WD), or "hepato-lenticular degeneration," is a rare genetic disorder of autosomal recessive inheritance causing toxic tissue accumulation of copper, mainly in the liver, brain, and cornea. Its phenotypic and genotypic heterogeneity characterizes it. This study aimed to clarify the clinical features and spectrum of Wilson's disease in children from the eastern region of Morocco and to study the evolutionary profile and survival in this population while discussing and highlighting the various diagnostic and therapeutic difficulties encountered in the management of WD in our context. This retrospective study encompassed 24 children diagnosed with Wilson's disease, selected from the gastroenterology-hepatology and pediatric nutrition units at Mohamed VI University Hospital in Oujda, Morocco, over a span of nine years, from January 2015 to November 2023. Our series results show 14 boys and 10 girls; the median age of discovery was 11 years, with extremes ranging from 18 months to 15 years. The consanguinity was found in 13 patients. Clinically, the edemato-ascitic syndrome was noted in 14 patients with an alteration of the general state; icterus was found in 13 patients; signs of portal hypertension were present in six patients; and neurological signs in seven cases. Skin manifestations occurred in three cases, and arthralgia in three cases. Six children were diagnosed on the occasion of a family screening. Biologically, hepatic cytolysis was found in 20 patients, with signs of hepatocellular failure in 15 cases. Hemolytic anemia was present in nine patients. Ceruloplasminemia was decreased in 21 patients and cupremia in 19 patients. Cupruria was increased in 22 cases. The Kayser-Fleicher ring was found in 10 cases. Abdominal ultrasound showed ascites in 16 patients, hepatomegaly in 1, splenomegaly in two cases, hepatosplenomegaly in five cases, and cirrhosis in two. MRI showed signal abnormalities in 11 patients. Therapeutically, D-penicillamine was initially introduced in 18 patients and zinc acetate in 6 patients. The evolution was favorable for 15 patients still followed up in the department. Three patients died of hepatocellular failure, and two died of hepatic encephalopathy. Four patients were lost to follow-up.
PubMed: 38854322
DOI: 10.7759/cureus.60023 -
Small (Weinheim An Der Bergstrasse,... Dec 2023Despite great advances in understanding the biological behaviors of chiral materials, the effect of chirality-configured nanoparticles on tissue regeneration-related...
Despite great advances in understanding the biological behaviors of chiral materials, the effect of chirality-configured nanoparticles on tissue regeneration-related biological processes remains poorly understood. Herein, the chirality of MoS quantum dots (QDs) is tailored by functionalization with l-/d-penicillamine, and the profound chiral effects of MoS QDs on cellular activities, angiogenesis, and tissue regeneration are thoroughly investigated. Specifically, d-MoS QDs show a positive effect in promoting the growth, proliferation, and migration of human umbilical vein endothelial cells. The expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and fibroblast growth factor (FGF) in d-MoS QDs group is substantially up-regulated, resulting in enhanced tube formation activity. This distinct phenomenon is largely due to the higher internalization efficiency of d-MoS QDs than l-MoS QDs and chirality-dependent nano-bio interactions. In vivo angiogenic assay shows the expression level of angiogenic markers in newly-formed skin tissues of d-MoS QDs group is higher than that in l-MoS QDs group, leading to an accelerated re-epithelialization and improved skin regeneration. The findings of chirality-dependent angiogenesis activity of MoS QDs provide new insights into the biological activity of MoS nanomaterials, which also opens up a new path to the rational design of chiral nanomaterials for tissue regeneration application.
Topics: Humans; Quantum Dots; Molybdenum; Vascular Endothelial Growth Factor A; Human Umbilical Vein Endothelial Cells
PubMed: 37590390
DOI: 10.1002/smll.202304857 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2024Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials....
Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Cu-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of Cu-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, Cu-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of Cu-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. Cu-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. Cu-Dp44mT was more efficient than Cu chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with Cu-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by Cu-Dp44mT.
Topics: Copper; Sulfhydryl Compounds; Oxidation-Reduction; Thiosemicarbazones; Glutathione; Penicillamine; Acetylcysteine
PubMed: 38408264
DOI: 10.1002/chem.202304212 -
Biochemical and Biophysical Research... Jun 2023Oxidative metabolism of rhododendrol (RD), a skin-whitening ingredient, by tyrosinase has caused leukoderma in a certain population of Japanese consumers. Toxic RD...
Oxidative metabolism of rhododendrol (RD), a skin-whitening ingredient, by tyrosinase has caused leukoderma in a certain population of Japanese consumers. Toxic RD metabolites and reactive oxygen species are proposed causes for the melanocyte death. However, the mechanism by which reactive oxygen species are produced during RD metabolism remains elusive. Some phenolic compounds are known to act as suicide substrates for tyrosinase, resulting in release of a copper atom and hydrogen peroxide during its inactivation. We hypothesized that RD may be a suicide substrate for tyrosinase and that the released copper atom may be responsible for the melanocyte death through hydroxyl radical production. In line with this hypothesis, human melanocytes incubated with RD showed an irreversible decrease in tyrosinase activity and underwent cell death. A copper chelator, d-penicillamine, markedly suppressed the RD-dependent cell death without significantly affecting the tyrosinase activity. Peroxide levels in RD-treated cells were not affected by d-penicillamine. Given the unique enzymatic properties of tyrosinase, we conclude that RD acted as a suicide substrate and resulted in release of a copper atom and hydrogen peroxide, which would collectively impair melanocyte viability. These observations further imply that copper chelation may alleviate chemical leukoderma caused by other compounds.
Topics: Humans; Monophenol Monooxygenase; Reactive Oxygen Species; Copper; Penicillamine; Hydrogen Peroxide; Melanocytes; Hypopigmentation; Chelating Agents
PubMed: 37119768
DOI: 10.1016/j.bbrc.2023.04.062 -
Journal of Chromatography. A Aug 2024Developing novel chiral stationary phases (CSPs) with versatility is of great importance in enantiomer separation. This study fabricated a dual-chiral covalent organic...
Developing novel chiral stationary phases (CSPs) with versatility is of great importance in enantiomer separation. This study fabricated a dual-chiral covalent organic framework (PA-CA COF) via successive post-synthetic modifications. The chiral trans-1,2-cyclohexanediamine (CA) and (D)-penicillamine (PA) groups were periodically aligned within nanochannels of the COF, allowing selective recognition of enantiomers through intermolecular interactions. It can be a versatile high-performance liquid chromatography (HPLC) CSP for separating a wide range of enantiomers, including chiral pharmaceutical intermediates and chiral drugs. With separation performance comparable to commercial chiral columns and even greater versatility, the PA-CA COF@SiO column held promise for practical applications. Chiral separation results combined with molecular simulation indicated that the mixed mode of PA and CA resulted in the broad separation capability of PA-CA COF. The introduction of the dual-chiral COFs concept opens up a new avenue for chiral recognition and separation, holding great potential for practical enantiomer separation.
Topics: Stereoisomerism; Chromatography, High Pressure Liquid; Penicillamine; Cyclohexylamines; Silicon Dioxide; Metal-Organic Frameworks
PubMed: 38797135
DOI: 10.1016/j.chroma.2024.465014 -
ACS Applied Materials & Interfaces Jul 2023The self-association of metabolites into well-ordered assemblies at the nanoscale has significant biological and medical implications. The thiol-containing amino acid...
The self-association of metabolites into well-ordered assemblies at the nanoscale has significant biological and medical implications. The thiol-containing amino acid cysteine (CYS) can assemble into amyloid-like nanofibrils, and its oxidized form, the disulfide-bonded cystine (CTE), forms hexagonal crystals as those found in cystinuria due to metabolic disorder. Yet, there have been no attempts to connect these two phenomena, especially the fibril-to-crystal transition. Here, we reveal that these are not separated events, and the CYS-forming amyloid fibrils are mechanistically linked to hexagonal CTE crystals. For the first time, we demonstrated that cysteine fibrils are a prerequisite for forming cystine crystals, as observed experimentally. To further understand this mechanism, we studied the effects of thiol-containing cystinuria drugs (tiopronin, TIO; and d-penicillamine, PEN) and the canonical epigallocatechin gallate (EGCG) amyloid inhibitor on fibril formation by CYS. The thiol-containing drugs do not solely interact with monomeric CYS via disulfide bond formation but can disrupt amyloid formation by targeting CYS oligomers. On the other hand, EGCG forms inhibitor-dominant complexes (more than one EGCG molecule per cysteine unit) to prevent CYS fibril formation. Interestingly, while CYS can be oxidized into CTE, the thiol drugs can reduce CTE back to CYS. We thus suggest that the formation of crystals in cystinuria could be halted at the initial stage by targeting CYS fibril formation as an alternative to solubilizing the water-insoluble hexagonal CTE crystals at a later stage. Taken together, we depicted a complex hierarchical organization in a simple amino acid assembly with implications for therapeutic intervention.
Topics: Humans; Cysteine; Cystine; Cystinuria; Amino Acids; Amyloid; Disulfides
PubMed: 37387421
DOI: 10.1021/acsami.3c03267