Current Medicinal Chemistry - Volume 24, Issue 3, 2017

Aromatic amino acid, cysteine sulfinic acid, glutamate and histidine decarboxylases, belonging to group II of pyridoxal 5'-phosphate-dependent enzymes, catalyze the synthesis of dopamine/serotonin, hypotaurine, γ-aminobutyric acid and histamine, respectively. Considering that these reaction products are all essential bioactive molecules, group II decarboxylases have been long studied from an evolutionary, biochemical and pharmacological standpoint. Despite the fact that they all belong to a common fold-type, during evolution each decarboxylase has evolved unique structural elements responsible for its substrate specificity. Combining a literature update with bioinformatic analyses, this review focuses on some structural determinants shared by these enzymes revealing their intrinsic substrate specificity and highlighting the importance of some residues/regions for catalytic competence. In particular, two key structural features emerge: 1) a mobile catalytic loop, and 2) an open-to-close conformation accompanying the apo-holo transition. Drawing attention on these elements is crucial in correlating subtle structural modifications to functional properties for the understanding, at a molecular level of a pathological condition. This is corroborated by the increasingly important role played by these decarboxylases in several different pathological states (autoimmune diseases, type I diabetes, Parkinson's disease, aromatic amino acid decarboxylase deficiency, Tourette's syndrome and cholangiocarcinoma).

Background: Pregnancy specific β1-glycoproteins (PSGs) have long been recognized as trophoblast quality and embryo viability markers. However, biological roles of PSGs remain obscure, and structure/function relationships to other feto-placental proteins as well as implications for drug design have not been reviewed. This review summarizes and discusses advances in 45-year studies of PSGs with focus on the latest achievements and the challenges for future investigations. Methods: Literature search was performed to review the majority of recent PSG studies with emphasis on usage of high-throughput integrated proteomic profiling technologies, systems biology and bioinformatics approaches that enhance novel biomarker and drug target discovery as well as protein structure/activity analysis. Results: Clinical significance and screening performance improved when PSG measurements were combined with those of other placenta-derived proteins: hCG, hPL, PAPP-A, and proMBP. Nevertheless, analysis of protein co-expression and co-localization data and the involvement of PSGs in protein interaction networks are being introduced to discover novel, specific and high-sensitive, gestational/cancer biomarkers. Despite biological roles of PSGs are not fully understood, there are evidences of that they exhibit immunomodulatory, antiinflammatory and proangiogenic effects. Investigation of structure/function relationships showed that PSGs may function in cooperative/coordinated manner with numerous regulatory proteins including alpha-fetoprotein and transforming growth factors-β; this is provided by the presence of conserved short linear motifs (SLiMs) such as RGD, PXXP and AFP14-20-like (YXCX) ones. Conclusion: PSG-derived peptides may be used as a rationale to design novel drugs that mimic SLiMs involved in protein-protein interactions to inhibit domain-motif binding and to block cell signaling, and/or exert immunomodulatory, anti-inflammatory and proangiogenic effects.

Graphene-based nanomaterials have drawn abundant interest in various fields such as biomedicine in recent years. Thanks to the ultra-high surface area of single-layered graphene, higher molecular loading is obtained. In addition, easy modifications were acquired because of its ample oxygen-content functional groups. Owing to its excellent physical- chemical properties, graphene-based nanomaterials have been widely explored as novel nanovectors for disease theranostics. In this article, we gave a comprehensive review of graphenebased nanomaterials, including introduction about different members of graphene family nanomaterials (GFNs), various modifications, toxicity and biomedical applications of graphene- based derivatives. More attentions were given to phototherapy in this paper. The mechanisms of photothermal and photodynamic therapy were also offered. Finally, the prospects and challenges of the graphene-based nanomaterials were discussed in this review.

Infectious urinary stones make a serious medical problem concerning up to 20% of population. Additionally, recurrence after treatment reaches 50%. The formation of infectious urinary stones is connected with urinary tract infection with various bacteria. These are mainly the bacteria from Proteus species which have been isolated in 70% of bacteriainduced urinary stone cases. These microorganisms produce urease - a bacterial enzyme which plays a principal role in the crystallization process and is one of the main virulence parameters of these bacteria. The most common solid components of infectious urinary stones are the crystals of struvite and amorphous carbonate apatite. The formation of this kind of stones involves two main processes. The first one is the nucleation process of solid phases and the second is the aggregation of the precipitated phases, both crystalline and amorphous. In recent years, both these processes have been deeply investigated. In particular, different active compounds have been reported as potentially novel therapeutic agents to prevent or inhibit the formation of infectious urinary stones. In addition, there is rich scientific evidence regarding the chemical mechanisms of inhibitory effect of these active compounds. In recent years, specific interior and exterior structure of struvite and its porous nature have also been reported. In this article, we summarize and discuss recent development in this field of research. The paper concludes with future goals and challenges.

Background: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group. Objective: Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies. Conclusion: The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.