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Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview.
Fernandes, HS, Teixeira, CSS, Sousa, SF, Cerqueira, NMFSA
Molecules (Basel, Switzerland). 2019;(13)
Abstract
Nature has tailored a wide range of metalloenzymes that play a vast array of functions in all living organisms and from which their survival and evolution depends on. These enzymes catalyze some of the most important biological processes in nature, such as photosynthesis, respiration, water oxidation, molecular oxygen reduction, and nitrogen fixation. They are also among the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions of temperature, pH, and pressure. In the absence of these enzymes, these reactions would proceed very slowly, if at all, suggesting that these enzymes made the way for the emergence of life as we know today. In this review, the structure and catalytic mechanism of a selection of diverse metalloenzymes that are involved in the production of highly reactive and unstable species, such as hydroxide anions, hydrides, radical species, and superoxide molecules are analyzed. The formation of such reaction intermediates is very difficult to occur under biological conditions and only a rationalized selection of a particular metal ion, coordinated to a very specific group of ligands, and immersed in specific proteins allows these reactions to proceed. Interestingly, different metal coordination spheres can be used to produce the same reactive and unstable species, although through a different chemistry. A selection of hand-picked examples of different metalloenzymes illustrating this diversity is provided and the participation of different metal ions in similar reactions (but involving different mechanism) is discussed.
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2.
Enzyme mimetic activities of spinel substituted nanoferrites (MFe2O4): A review of synthesis, mechanism and potential applications.
Chaibakhsh, N, Moradi-Shoeili, Z
Materials science & engineering. C, Materials for biological applications. 2019;:1424-1447
Abstract
Recently, the intrinsic enzyme-like activities of some nanoscale materials known as "nanozymes" have become a growing area of interest. Nanosized spinel substituted ferrites (SFs) with general formula of MFe2O4, where M represents a transition metal, are among a group of magnetic nanomaterials attracting researchers' enormous attention because of their excellent catalytic performance, biomedical applications and capability for environmental remediation. Due to their unique nanoscale physical-chemical properties, they have been used to mimic the catalytic activity of natural enzymes such as peroxidases, oxidases and catalases. In addition, various nanocomposite materials based on SFs have been introduced as novel artificial enzymes. This review mainly highlights the synthetic approaches for newly developed SF-nanozymes and also the structural/experimental factors that are effective on the kinetics and catalytic mechanisms of enzyme-like reactions. SF-nanozymes have been found potentially capable of being applied in various fields such as enzyme-free immunoassays and biosensors for colorimetric detection of biological molecules. Therefore, the application of SF nanoparticles, as efficient enzyme mimetics have been detailed discussed.
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3.
Enzymes in Metabolic Anticancer Therapy.
Maggi, M, Scotti, C
Advances in experimental medicine and biology. 2019;:173-199
Abstract
Cancer treatment has greatly improved over the last 50 years, but it remains challenging in several cases. Useful therapeutic targets are normally unique peculiarities of cancer cells that distinguish them from normal cells and that can be tackled with appropriate drugs. It is now known that cell metabolism is rewired during tumorigenesis and metastasis as a consequence of oncogene activation and oncosuppressors inactivation, leading to a new cellular homeostasis typically directed towards anabolism. Because of these modifications, cells can become strongly or absolutely dependent on specific substrates, like sugars, lipids or amino acids. Cancer addictions are a relevant target for therapy, as removal of an essential substrate can lead to their selective cell-cycle arrest or even to cell death, leaving normal cells untouched. Enzymes can act as powerful agents in this respect, as demonstrated by asparaginase, which has been included in the treatment of Acute Lymphoblastic Leukemia for half a century. In this review, a short outline of cancer addictions will be provided, focusing on the main cancer amino acid dependencies described so far. Therapeutic enzymes which have been already experimented at the clinical level will be discussed, along with novel potential candidates that we propose as new promising molecules. The intrinsic limitations of their present molecular forms, along with molecular engineering solutions to explore, will also be presented.
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4.
Enzymatic Reactions Involving Ketyls: From a Chemical Curiosity to a General Biochemical Mechanism.
Buckel, W
Biochemistry. 2019;(52):5221-5233
Abstract
Ketyls are radical anions with nucleophilic properties. Ketyls obtained by enzymatic one-electron reduction of thioesters were proposed as intermediates for the dehydration of (R)-2-hydroxyacyl-CoA to (E)-2-enoyl-CoA. This concept was extended to the Birch-like reduction of benzoyl-CoA to 1,5-cyclohexadienecarboxyl-CoA. Nature uses two methods to achieve the therefore required low reduction potentials of less than -600 mV, either by an ATP-driven electron transfer similar to that catalyzed by the iron protein of nitrogenase or by electron bifurcation. Ketyls formed by thiyl radical-initiated oxidation of alcohols followed by deprotonation are involved in coenzyme B12-independent diol dehydratases, other glycyl radical enzymes mediating key reactions in the degradations of choline, taurine, and 4-hydroxyproline, and all three classes of ribonucleotide reductases. A special case is the dehydration of 4-hydroxybutyryl-CoA to crotonyl-CoA, which most likely proceeds via an oxidation to an allylic ketyl but requires neither a strong reductant nor an external radical generator.
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5.
Structural and mechanistic insight from antiviral and antiparasitic enzyme drug targets for tropical infectious diseases.
de Godoy, AS, Sachetto Fernandes, R, Campos Aguiar, AC, Vieira Bueno, R, de Moraes Roso Mesquita, NC, Carvalho Guido, RV, Oliva, G
Current opinion in structural biology. 2019;:65-72
Abstract
With almost half of the world population living at risk, tropical infectious diseases cause millions of deaths every year in developing countries. Considering the lack of economic prospects for investment in this field, approaches aiming the rational design of compounds, such as structure-based drug discovery (SBDD), fragment screening, target-based drug discovery, and drug repurposing are of special interest. Herein, we focused in the advances on the field of SBDD targeting arboviruses such as dengue, yellow fever, zika and chikungunya enzymes of the RNA replication complex (RC) and enzymes involved in a variety of pathways essential to ensure parasitic survival in the host, for malaria, Chagas e leishmaniasis diseases. We also highlighted successful examples such as promising new inhibitors and molecules already in preclinical/clinical phase tests, major gaps in the field and perspectives for the future of drug design for tropical diseases.
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6.
New metal cofactors and recent metallocofactor insights.
Hausinger, RP
Current opinion in structural biology. 2019;:1-8
Abstract
A vast array of metal cofactors are associated with the active sites of metalloenzymes. This Opinion describes the most recently discovered metal cofactor, a nickel-pincer nucleotide (NPN) coenzyme that is covalently tethered to lactate racemase from Lactobacillus plantarum. The enzymatic function of the NPN cofactor and its pathway for biosynthesis are reviewed. Furthermore, insights are summarized from recent advances involving other selected organometallic and inorganic-cluster cofactors including the lanthanide-pyrroloquinoline quinone found in certain alcohol dehydrogenases, tungsten-pyranopterins or molybdenum-pyranopterins in chosen enzymes, the iron-guanylylpyridinol cofactor of [Fe] hydrogenase, the nickel-tetrapyrrole coenzyme F430 of methyl coenzyme M reductase, the vanadium-iron cofactor of nitrogenase, redox-dependent rearrangements of the nickel-iron-sulfur C-cluster in carbon monoxide dehydrogenase, and light-dependent changes in the multi-manganese cluster of the oxygen-evolving complex.
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7.
Screening and development of enzymes for determination and transformation of amino acids.
Asano, Y
Bioscience, biotechnology, and biochemistry. 2019;(8):1402-1416
Abstract
The high stereo- and substrate specificities of enzymes have been utilized for micro-determination of amino acids. Here, I review the discovery of l-Phe dehydrogenase and its practical use in the diagnosis of phenylketonuria in more than 5,400,000 neonates over two decades in Japan. Screening and uses of other selective enzymes for micro-determination of amino acids have also been discussed. In addition, novel enzymatic assays with the systematic use of known enzymes, including assays based on a pyrophosphate detection system using pyrophosphate dikinase for a variety of l-amino acids with amino-acyl-tRNA synthetase have been reviewed. Finally, I review the substrate specificities of a few amino acid-metabolizing enzymes that have been altered, using protein engineering techniques, mainly for production of useful chemicals, thus enabling the wider use of natural enzymes.
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8.
Sulfur-dependent microbial lifestyles: deceptively flexible roles for biochemically versatile enzymes.
Crane, EJ
Current opinion in chemical biology. 2019;:139-145
Abstract
A wide group of microbes are able to "make a living" on Earth by basing their energetic metabolism on inorganic sulfur compounds. Because of their range of stable redox states, sulfur and inorganic sulfur compounds can be utilized as either oxidants or reductants in a diverse array of energy-conserving reactions. In this review the major enzymes and basic chemistry of sulfur-based respiration and chemolithotrophy are outlined. The reversibility and versatility of these enzymes, however, means that they can often be used in multiple ways, and several cases are discussed in which enzymes which are considered to be hallmarks of a particular respiratory or lithotrophic process have been found to be used in other, often opposing, metabolic processes. These results emphasize the importance of taking into account the geochemistry, biochemistry and microbiology of an organism and/or environment when trying to interpret the function of a particular sulfur-dependent redox enzyme.
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9.
Amino Acid Degrading Enzymes and their Application in Cancer Therapy.
Pokrovsky, VS, Chepikova, OE, Davydov, DZ, Zamyatnin, AA, Lukashev, AN, Lukasheva, EV
Current medicinal chemistry. 2019;(3):446-464
Abstract
BACKGROUND Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on the development and preclinical and clinical evaluation of amino acid degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, L-lysine α-oxidase. Further research into cancer cell metabolism may therefore define possible targets for controlling tumor growth. OBJECTIVE The purpose of this review was to summarize recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on Lasparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer. METHODS We carried out a structured search among literature regarding to amino acid degrading enzymes. The main aspects of search were in vitro and in vivo studies, clinical trials concerning application of these enzymes in oncology. RESULTS Most published research are on the subject of L-asparaginase properties and it's use for cancer treatment. L-arginine deiminase has shown promising results in a phase II trial in advanced melanoma and hepatocellular carcinoma. Other enzymes, in particular Lmethionine γ-lyase and L-lysine α-oxidase, were effective in vitro and in vivo. CONCLUSION The findings of this review revealed that therapy based on amino acid depletion may have the potential application for cancer treatment but further clinical investigations are required to provide the efficacy and safety of these agents.
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10.
Determining Redox Potentials of the Iron-Sulfur Clusters of the AdoMet Radical Enzyme Superfamily.
Maiocco, SJ, Walker, LM, Elliott, SJ
Methods in enzymology. 2018;:319-339
Abstract
While protein film electrochemistry (PFE) has proven to be an effective tool in the interrogation of redox cofactors and assessing the electrocatalytic activity of many different enzymes, recently it has been proven to be useful for the study of the redox potentials of the cofactors of AdoMet radical enzymes (AREs). In this chapter, we review the challenges and opportunities of examining the redox cofactors of AREs in a high level of detail, particularly for the deconvolution of redox potentials of multiple cofactors. We comment on how to best assess the electroactive nature of any given ARE, and we see that when applied well, PFE allows for not only determining redox potentials, but also determining proton-coupling and ligand-binding phenomena in the ARE superfamily.