EnzymesPub Date : 2025-01-01Epub Date: 2025-07-16DOI: 10.1016/bs.enz.2025.05.003
Alane Beatriz Vermelho, Felipe Raposo P Mansoldo, Veronica Silva Cardoso, Kamila Marques Sette, Claudiu T Supuran, Igor Almeida Rodrigues
{"title":"Trypanosoma cruzi and Leishmania spp. CAs.","authors":"Alane Beatriz Vermelho, Felipe Raposo P Mansoldo, Veronica Silva Cardoso, Kamila Marques Sette, Claudiu T Supuran, Igor Almeida Rodrigues","doi":"10.1016/bs.enz.2025.05.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.003","url":null,"abstract":"<p><p>Neglected tropical diseases (NTDs) such as Chagas disease and leishmaniasis represent significant public health challenges due to limited therapeutic options and the emergence of drug-resistant parasites. This chapter explores the potential of carbonic anhydrases (CAs) as novel drug targets in Trypanosoma cruzi and Leishmania spp., two etiologic agents of these diseases. The α-class CA in T. cruzi (TcCA) and the β-class CA in Leishmania donovani chagasi (LdcCA) have been functionally characterized and play essential roles in parasite metabolism, pH regulation, and survival. Several inhibitors, such as sulfonamides, thiols, hydroxamates, and benzoxaboroles, demonstrate potent enzymatic inhibition with promising selectivity over human isoforms. Advances in drug formulation, including nanoemulsions, have enhanced the bioavailability and efficacy of certain compounds. The chapter also discusses structure-activity relationships (SAR), challenges in translating in vitro potency to in vivo efficacy, and the strategic advantages of targeting parasite-specific CAs in combination therapies. These findings support CAs as viable and selective targets for innovative anti-parasitic drug development.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"129-182"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-25DOI: 10.1016/bs.enz.2024.06.001
Francesco Melfi, Simone Carradori, Arianna Granese, Amar Osmanović, Cristina Campestre
{"title":"Drug design of tyrosinase inhibitors.","authors":"Francesco Melfi, Simone Carradori, Arianna Granese, Amar Osmanović, Cristina Campestre","doi":"10.1016/bs.enz.2024.06.001","DOIUrl":"10.1016/bs.enz.2024.06.001","url":null,"abstract":"<p><p>This copper-containing enzyme catalyzes the rate-limiting step for the melanin skin pigment bioproduction. Tyrosinase inhibitors can be exploited as skin whitening agents and food preservatives, opening new scenarios in food, cosmetics, agriculture and medicine. Despite the availability of natural inhibitors (hydroquinone, α-arbutin, kojic acid, retinoids, azelaic acid, resveratrol, caftaric acid, valonea tannin, chrysosplenetin and phenylethyl resorcinol), several synthetic compounds were proposed to overcome side effects and to improve the efficacy of natural agents. This chapter will gather the recent advances about synthetic tyrosinase inhibitors from the MedChem perspective, providing new suggestions for the scaffold-based design of innovative compounds.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"56 ","pages":"111-134"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-07-03DOI: 10.1016/bs.enz.2024.05.006
Claudiu T Supuran
{"title":"Challenges for developing bacterial CA inhibitors as novel antibiotics.","authors":"Claudiu T Supuran","doi":"10.1016/bs.enz.2024.05.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.006","url":null,"abstract":"<p><p>Acetazolamide, methazolamide, ethoxzolamide and dorzolamide, classical sulfonamide carbonic anhydrase (CA) inhibitors (CAIs) designed for targeting human enzymes, were also shown to effectively inhibit bacterial CAs and were proposed for repurposing as antibacterial agents against several infective agents. CAs belonging to the α-, β- and/or γ-classes from pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, vacomycin resistant enterococci (VRE), Vibrio cholerae, Mycobacterium tuberculosis, Pseudomonas aeruginosa and other bacteria were considered as drug targets for which several classes of potent inhibitors have been developed. Treatment of some of these pathogens with various classes of such CAIs led to an impairment of the bacterial growth, reduced virulence and for drug resistant bacteria, a resensitization to clinically used antibiotics. Here I will discuss the strategies and challenges for obtaining CAIs with enhanced selectivity for inhibiting bacterial versus human enzymes, which may constitute an important weapon for addressing the drug resistance to β-lactams and other clinically used antibiotics.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"383-411"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-07-20DOI: 10.1016/bs.enz.2024.06.007
Fabrizio Carta
{"title":"Non-sulfonamide bacterial CA inhibitors.","authors":"Fabrizio Carta","doi":"10.1016/bs.enz.2024.06.007","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.06.007","url":null,"abstract":"<p><p>Non-sulfonamide chemical moieties able to inhibit the bacterial (b) expressed Carbonic Anhydrases (CAs; EC 4.2.1.1) constitute an important alternative to the prototypic modulators discussed in Chapter 6, as give access to large and variegate chemical classes, also of the natural origin. This contribution reports the main classes of compounds profiled in vitro on the bCAs and thus may be worth developing for the validation process of this class of enzymes.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"193-212"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-06DOI: 10.1016/bs.enz.2024.05.007
Reygan E Braga, Fares Z Najar, Chelsea L Murphy, Marianna A Patrauchan
{"title":"Carbonic anhydrases in bacterial pathogens.","authors":"Reygan E Braga, Fares Z Najar, Chelsea L Murphy, Marianna A Patrauchan","doi":"10.1016/bs.enz.2024.05.007","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.007","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) catalyze the reversable hydration of carbon dioxide to bicarbonate placing them into the core of the biochemical carbon cycle. Due to the fundamental importance of their function, they evolved independently into eight classes, three of which have been recently discovered. Most research on CAs has focused on their representatives in eukaryotic organisms, while prokaryotic CAs received significantly less attention. Nevertheless, prokaryotic CAs play a key role in the fundamental ability of the biosphere to acquire CO<sub>2</sub> for photosynthesis and to decompose the organic matter back to CO<sub>2</sub>. They also contribute to a broad spectrum of processes in pathogenic bacteria, enhancing their ability to survive in a host and, therefore, present a promising target for developing antimicrobials. This review focuses on the distribution of CAs among bacterial pathogens and their importance in bacterial virulence and host-pathogen interactions.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"313-342"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-25DOI: 10.1016/bs.enz.2024.06.002
Aslınur Doğan, Suleyman Akocak
{"title":"Natural products as tyrosinase inhibitors.","authors":"Aslınur Doğan, Suleyman Akocak","doi":"10.1016/bs.enz.2024.06.002","DOIUrl":"10.1016/bs.enz.2024.06.002","url":null,"abstract":"<p><p>Tyrosinase is a crucial copper-containing enzyme involved in the production of melanin. Melasma, age spots, and freckles are examples of hyperpigmentation diseases caused by excess production of melanin. Inhibiting tyrosinase activity is a crucial method for treating these disorders along with various applications such as cosmetics, food technology, and medicine. Natural products have proven a rich source of tyrosinase inhibitors, with several molecules from plant, marine, and microbial sources showing potential inhibitory action. This chapter provides a complete overview of natural compounds that have been found as tyrosinase inhibitors, with emphasis on their structures, modes of action, and prospective applications.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"56 ","pages":"85-109"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-08-06DOI: 10.1016/bs.enz.2024.05.012
Jenny Parkkinen, Ratul Bhowmik, Martti Tolvanen, Fabrizio Carta, Claudiu T Supuran, Seppo Parkkila, Ashok Aspatwar
{"title":"Mycobacterial β-carbonic anhydrases: Molecular biology, role in the pathogenesis of tuberculosis and inhibition studies.","authors":"Jenny Parkkinen, Ratul Bhowmik, Martti Tolvanen, Fabrizio Carta, Claudiu T Supuran, Seppo Parkkila, Ashok Aspatwar","doi":"10.1016/bs.enz.2024.05.012","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.012","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three β-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the β-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of β-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of β-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the β-CAs of Mtb are indeed druggable targets.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"343-381"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-06-08DOI: 10.1016/bs.enz.2024.05.013
Bianca Laura Bernardoni, Concettina La Motta, Simone Carradori, Ilaria D'Agostino
{"title":"Helicobacter pylori CAs inhibition.","authors":"Bianca Laura Bernardoni, Concettina La Motta, Simone Carradori, Ilaria D'Agostino","doi":"10.1016/bs.enz.2024.05.013","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.013","url":null,"abstract":"<p><p>Infections from Helicobacter pylori (Hp) are endangering Public Health safety worldwide, due to the associated high risk of developing severe diseases, such as peptic ulcer, gastric cancer, diabetes, and cardiovascular diseases. Current therapies are becoming less effective due to the rise of (multi)drug-resistant phenotypes and an urgent need for new antibacterial agents with innovative mechanisms of action is pressing. Among the most promising pharmacological targets, Carbonic Anhydrases (EC: 4.2.1.1) from Hp, namely HpαCA and HpβCA, emerged for their high druggability and crucial role in the survival of the pathogen in the host. Thereby, in the last decades, the two isoenzymes were isolated and characterized offering the opportunity to profile their kinetics and test different series of inhibitors.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"213-241"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-08-16DOI: 10.1016/bs.enz.2024.05.009
Marta Ferraroni
{"title":"Bacterial β-carbonic anhydrases.","authors":"Marta Ferraroni","doi":"10.1016/bs.enz.2024.05.009","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.009","url":null,"abstract":"<p><p>β-Carbonic anhydrases (β-CA; EC 4.2.1.1) are widespread zinc metalloenzymes which catalyze the interconversion of carbon dioxide and bicarbonate. They have been isolated in many pathogenic and non-pathogenic bacteria where they are involved in multiple roles, often related to their growth and survival. β-CAs are structurally distant from the CAs of other classes. In the active site, located at the interface of a fundamental dimer, the zinc ion is coordinated to two cysteines and one histidine. β-CAs have been divided in two subgroups depending on the nature of the fourth ligand on the zinc ion: class I have a zinc open configuration with a hydroxide ion completing the metal coordination, which is the catalytically active species in the mechanism proposed for the β-CAs similar to the well-known of α-CAs, while in class II an Asp residue substitute the hydroxide. This latter active site configuration has been showed to be typical of an inactive form at pH below 8. An Asp-Arg dyad is thought to play a key role in the pH-induced catalytic switch regulating the opening and closing of the active site in class II β-CAs, by displacing the zinc-bound solvent molecule. An allosteric site well-suited for bicarbonate stabilizes the inactive form. This bicarbonate binding site is composed by a triad of well conserved residues, strictly connected to the coordination state of the zinc ion. Moreover, the escort site is a promiscuous site for a variety of ligands, including bicarbonate, at the dimer interface, which may be the route for bicarbonate to the allosteric site.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"55 ","pages":"65-91"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EnzymesPub Date : 2024-01-01Epub Date: 2024-05-24DOI: 10.1016/bs.enz.2024.05.001
Samaneh Zolghadri, Ali Akbar Saboury
{"title":"Catalytic mechanism of tyrosinases.","authors":"Samaneh Zolghadri, Ali Akbar Saboury","doi":"10.1016/bs.enz.2024.05.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2024.05.001","url":null,"abstract":"<p><p>Tyrosinases (TYR) play a key role in melanin biosynthesis by catalyzing two reactions: monophenolase and diphenolase activities. Despite low amino acid sequence homology, TYRs from various organisms (from bacteria to humans) have similar active site architectures and catalytic mechanisms. The active site of the TYRs contains two copper ions coordinated by histidine (His) residues. The catalytic mechanism of TYRs involves electron transfer between copper sites, leading to the hydroxylation of monophenolic compounds to diphenols and the subsequent oxidation of these to corresponding dopaquinones. Although extensive studies have been conducted on the structure, catalytic mechanism, and enzymatic capabilities of TYRs, some mechanistic aspects are still debated. This chapter will delve into the structure of the active site, catalytic function, and inhibition mechanism of TYRs. The goal is to improve our understanding of the molecular mechanisms underlying TYR activity. This knowledge can help in developing new strategies to modulate TYR function and potentially treat diseases linked to melanin dysregulation.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"56 ","pages":"31-54"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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