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Pyridoxal 5′‐phosphate (PLP), the catalytically active form of vitamin B6, acts as a cofactor in many metabolic processes. In humans, PLP is produced in the reactions catalysed by pyridox(am)ine 5′‐phosphate oxidase (PNPO) and pyridoxal kinase (PDXK). Both PNPO and PDXK are involved in cancer progression of many tumours. The silencing of PNPO and PDXK encoding genes determines a strong reduction in tumour size and neoplastic cell invasiveness in models of acute myeloid leukaemia (in the case of PDXK) and ovarian and breast cancer (in the case of PNPO). In the present work, we demonstrate that pyridoxilidenerhodanine 5′‐phosphate (PLP‐R), a PLP analogue that has been tested by other authors on malignant cell lines reporting a reduction in proliferation, inhibits PNPO in vitro following a mixed competitive and allosteric mechanism. We also show that the unphosphorylated precursor of this inhibitor (PL‐R), which has more favourable pharmacokinetic properties according to our predictions, is phosphorylated by PDXK and therefore transformed into PLP‐R. On this ground, we propose the prototype of a novel prodrug‐drug system as a useful starting point for the development of new, potential, antineoplastic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Sorcin is a protein that helps cells handle calcium. It is often found in high amounts in cancer cells, especially those that are resistant to treatment. Sorcin plays a key role in cancer growth and spread by helping cancer cells avoid the toxic effects of chemotherapy drugs, acting on multiple cellular mechanisms. This review will explore sorcin's structure and function, its role in cancer, and how we might be able to target it for new treatments. SOluble Resistance-related Calcium-binding proteIN (sorcin) earned its name due to its co-amplification with ABCB1 in multidrug-resistant cells. Initially thought to be an accidental consequence of this co-amplification, recent research indicates that sorcin plays a more active role as an oncoprotein, significantly impacting multidrug resistance (MDR). Sorcin is a highly expressed calcium-binding protein, often overproduced in human tumors and multidrug-resistant cancers, and is a promising novel MDR marker. In tumors, sorcin levels inversely correlate with both patient response to chemotherapy and overall prognosis. Multidrug-resistant cell lines consistently exhibit higher sorcin expression compared to their parental counterparts. Furthermore, sorcin overexpression via gene transfection enhances drug resistance to various chemotherapeutic drugs across numerous cancer lines. Conversely, silencing sorcin expression reverses drug resistance in many cell lines. Sorcin participates in several mechanisms of MDR, including drug efflux, drug sequestering, cell death inhibition, gene amplification, epithelial-to-mesenchymal transition, angiogenesis, and metastasis. The present review focuses on the structure and function of sorcin, on sorcin's role in cancer and drug resistance, and on the approaches aimed at targeting sorcin. [ABSTRACT FROM AUTHOR]

The capability to obtain essential nutrients in hostile environments is a critical skill for pathogens. Under zinc‐deficient conditions, Pseudomonas aeruginosa expresses a pool of metal homeostasis control systems that is complex compared with other Gram‐negative bacteria and has only been partially characterized. Here, the structure and zinc‐binding properties of the protein PA4063, the first component of the PA4063–PA4066 operon, are described. PA4063 has no homologs in other organisms and is characterized by the presence of two histidine‐rich sequences. ITC titration detected two zinc‐binding sites with micromolar affinity. Crystallographic characterization, performed both with and without zinc, revealed an α/β‐sandwich structure that can be classified as a noncanonical ferredoxin‐like fold since it differs in size and topology. The histidine‐rich stretches located at the N‐terminus and between β3 and β4 are disordered in the apo structure, but a few residues become structured in the presence of zinc, contributing to coordination in one of the two sites. The ability to bind two zinc ions at relatively low affinity, the absence of catalytic cavities and the presence of two histidine‐rich loops are properties and structural features which suggest that PA4063 might play a role as a periplasmic zinc chaperone or as a concentration sensor useful for optimizing the response of the pathogen to zinc deficiency. [ABSTRACT FROM AUTHOR]

Pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B 6 , acts as a cofactor in many metabolic processes. In humans, PLP is produced in the reactions catalysed by pyridox(am)ine 5'-phosphate oxidase (PNPO) and pyridoxal kinase (PDXK). Both PNPO and PDXK are involved in cancer progression of many tumours. The silencing of PNPO and PDXK encoding genes determines a strong reduction in tumour size and neoplastic cell invasiveness in models of acute myeloid leukaemia (in the case of PDXK) and ovarian and breast cancer (in the case of PNPO). In the present work, we demonstrate that pyridoxilidenerhodanine 5'-phosphate (PLP-R), a PLP analogue that has been tested by other authors on malignant cell lines reporting a reduction in proliferation, inhibits PNPO in vitro following a mixed competitive and allosteric mechanism. We also show that the unphosphorylated precursor of this inhibitor (PL-R), which has more favourable pharmacokinetic properties according to our predictions, is phosphorylated by PDXK and therefore transformed into PLP-R. On this ground, we propose the prototype of a novel prodrug-drug system as a useful starting point for the development of new, potential, antineoplastic agents., (© 2024 Federation of European Biochemical Societies.)

Giardia duodenalis is a cosmopolitan zoonotic protozoan parasite causing giardiasis, one of the most common diarrhoeal diseases in human and animals. Beyond its public health relevance, Giardia represents a valuable and fascinating model microorganism. The deep-branching phylogenetic position of Giardia, its simple life cycle and its minimalistic genomic and cellular organization provide a unique opportunity to define basal and "ancestral" eukaryotic functions. The eukaryotic 14-3-3 protein family represents a distinct example of phosphoserine/phosphothreonine-binding proteins. The extended network of protein-protein interactions established by 14-3-3 proteins place them at the crossroad of multiple signalling pathways that regulate physiological and pathological cellular processes. Despite the remarkable insight on 14-3-3 protein in different organisms, from yeast to humans, so far little attention was given to the study of this protein in protozoan parasites. However, in the last years, research efforts have provided evidences on unique properties of the single 14-3-3 protein of Giardia and on its association in key aspects of Giardia life cycle. In the first part of this chapter, a general overview of the features commonly shared among 14-3-3 proteins in different organisms (i.e. structure, target recognition, mode of action and regulatory mechanisms) is included. The second part focus on the current knowledge on the biochemistry and biology of the Giardia 14-3-3 protein and on the possibility to use this protein as target to propose new strategies for developing innovative antigiardial therapy., (© 2019 Elsevier Ltd All rights reserved.)

The trypanosomatid-induced diseases are considered as neglected, because the countries where they kill people are not important markets for western big pharmaceutical companies. However, recently some effort has been made to translate the use of already known drugs to neglected infectious disease. Although many metals are essential to life, many disorders affecting metal homeostasis and bioavailability are responsible for several human diseases. Metals can be toxic even at very low concentrations and semimetals are classified as toxic and dangerous for the environment. However, metal- and metalloid-based therapeutic drugs have existed for centuries. Some of them, as antimony and arsenic compounds, are still the first line drugs used for the treatment of leishmaniasis and trypanosomiases in developing countries. Other metal complexes (as those of Ag, Pt, Pd and Au), already present in the market for cancer therapies or to cure bacterial infection or for anti-inflammatory treatments, have been proposed also against the vector-borne infections caused by trypanosomatids. The use of novel approaches based on nanotechnologies, allowing selective targeting, may represent a promising strategy to decrease the toxicity of these drugs.