EnzymesPub Date : 2025-01-01Epub Date: 2025-07-30DOI: 10.1016/bs.enz.2025.05.005
Claudiu T Supuran
{"title":"Challenges for developing selective fungal/protozoal carbonic anhydrase inhibitors as anti-infectives.","authors":"Claudiu T Supuran","doi":"10.1016/bs.enz.2025.05.005","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.005","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs, EC 4.2.1.1) were characterized in several fungi (Cryptococcus neoformans, Candida albicans and C. glabrata, Saccharomyces cerevisiae, Malassezia globosa, M. restricta and M. pachydermatis, Sordaria macrospora, Aspergillus fumigatus and A. oryzae) and protozoans (Trypanosoma cruzi, Leishmania donovani chagasi, Plasmodium falciparum, Entamoeba histolytica, Trichomonas vaginalis, Toxoplasma gondii) being also shown that they are present in Acanthamoeba castellanii. These enzymes belong to various genetic families (α- and β-CAs for fungi, α-, β-, γ- and η-classes for protozoans), showed significant CO<sub>2</sub> hydrase activity and a vast number of inhibitors were detected belonging to the inorganic anions, sulfonamides, phenols, mono-/dithiocarbamates, boronic acids, benzoxaboroles, or coumarins. However, few of them showed anti-infective properties in vivo or ex vivo, due to the limited number of such studies. Promising results were however obtained with sulfonamides showing antimalarial, anti-Malassezia spp., anti-T. cruzi and anti-leishmanial action against various strains of these pathogens, sometimes resistant to clinically used drugs. The main challenges for obtaining effective antifungals/antiprotozoan agents based on CA inhibitors are: (i) the complex life cycles of most of these pathogens, which frequently have different stages, hosts and diverse gene expression and metabolic patterns; (ii) lack of detailed structural data for many such enzymes; (iii) lack of focused drug design campaigns for the specific enzymes found in these pathogens, and (iv) lack of simple, inexpensive in vivo models for their testing. Future work in the field that should address these limitations might lead to relevant developments for obtaining novel anti-infectives.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"229-250"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253198","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 : 2025-01-01Epub Date: 2025-08-19DOI: 10.1016/bs.enz.2025.07.006
Seppo Parkkila
{"title":"Entamoeba histolytica carbonic anhydrase.","authors":"Seppo Parkkila","doi":"10.1016/bs.enz.2025.07.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.07.006","url":null,"abstract":"<p><p>Amoebiasis, caused by Entamoeba histolytica, remains a major public health issue, particularly in developing countries with poor sanitation. It is also a significant challenge among those who travel to endemic areas, causing, in many cases, so-called traveler diarrhea. Approximately 10 percent of the global population is estimated to be affected by this parasitic infection. The primary route of transmission is the consumption of food or water contaminated with E. histolytica cysts. While most infected individuals may remain asymptomatic, some develop severe complications, including hemorrhagic colitis, liver abscesses, and, in extreme cases, colonic perforation. It has been estimated that amoebiasis is responsible for nearly 100,000 deaths annually. Standard treatment for amoebic colitis involves a combination of luminal agents (such as paromomycin, diloxanide furoate, and diiodohydroxyquin) and tissue amoebicides (including metronidazole and tinidazole). Although these treatments are effective, new therapeutic options to improve patient outcomes are needed. One promising avenue for drug discovery is the β-carbonic anhydrase enzyme (EhiCA) of E. histolytica, which has emerged as a potential target for novel antiamoebic therapies. EhiCA was recently produced as a recombinant protein and has been used in kinetic and inhibition studies with various sulfonamides and anions, with promising results.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"219-228"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253221","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 : 2025-01-01Epub Date: 2025-07-16DOI: 10.1016/bs.enz.2025.07.002
Seppo Parkkila
{"title":"Trichomonas vaginalis carbonic anhydrase.","authors":"Seppo Parkkila","doi":"10.1016/bs.enz.2025.07.002","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.07.002","url":null,"abstract":"<p><p>Trichomoniasis is the most common sexually transmitted infection. It is caused by the parasite Trichomonas vaginalis. Nitroimidazoles, particularly metronidazole and tinidazole, have been the main treatment options for decades. They still remain the standard treatment, and resistance to them is relatively rare. However, cases of resistance do occur, and the side effects can be significant. This highlights the urgent need for new drugs with different mechanisms of action. Promisingly, several innovative leads have emerged. Interesting drug targets in T. vaginalis include two β-carbonic anhydrases, which have been recently described. These enzymes have been characterized in terms of their structural and kinetic properties, and potential inhibitors have been identified. This new knowledge on β-carbonic anhydrases offers hope for the development of novel antitrichomonal agents to effectively combat this parasitic disease in the future.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"207-218"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252905","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 : 2025-01-01Epub Date: 2025-07-19DOI: 10.1016/bs.enz.2025.07.001
Anna Di Fiore, Martina Buonanno, Davide Esposito, Katia D'Ambrosio, Emma Langella, Giuseppina De Simone, Vincenzo Alterio, Simona Maria Monti
{"title":"Saccharomyces cerevesiae, Candida spp. and Cryptococcus neoformans β-CAs.","authors":"Anna Di Fiore, Martina Buonanno, Davide Esposito, Katia D'Ambrosio, Emma Langella, Giuseppina De Simone, Vincenzo Alterio, Simona Maria Monti","doi":"10.1016/bs.enz.2025.07.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.07.001","url":null,"abstract":"<p><p>Carbonic anhydrases are ubiquitous metalloenzymes which catalyze the CO<sub>2</sub> hydration to bicarbonate and proton. β-Carbonic Anhydrases from fungi, such as Saccharomyces cerevisiae, Candida spp. and Cryptococcus neoformans, have been widely investigated as potential targets for antifungal therapies. In this chapter, we provide a comprehensive overview on their properties highlighting their role as CO₂-sensing enzymes. We survey functional, biochemical, structural, and kinetic features, summarize inhibition and activation studies, and review in vitro experiments. Taken together, these data underscore fungal β‑carbonic anhydrases as promising potential targets for the development of new antifungal strategies.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"33-64"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252992","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 : 2025-01-01Epub Date: 2025-06-27DOI: 10.1016/bs.enz.2025.05.002
Claudiu T Supuran, Clemente Capasso
{"title":"Plasmodium falciparum η-carbonic anhydrase.","authors":"Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2025.05.002","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.002","url":null,"abstract":"<p><p>Malaria parasites belonging to the genus Plasmodium encode for a carbonic anhydrase (CA, EC 4.2.1.1) originally considered to belong to the α-class, which has been investigated starting with 2004 as a potential antimalarial target, considering the observation that CA levels in red blood cells infected with these parasites are much higher compared to those of uninfected cells. In plasmodia, CA is involved in metabolic pathways leading to the biosynthesis of pyrimidines, which are scarcely present in the blood of infected hosts, making this enzyme crucial for the life cycle of the parasite in many intraerythrocytic stages of its development. It has been then shown in 2014 that P. falciparum CA (PfCA) belongs in fact to a new CA genetic class, the η-CA, characterized by a particular zinc ion coordination within the active site, with two histidine and a glutamine as protein ligands. A short, truncated and longer PfCA forms have been cloned and characterized in detail, being shown that they act as efficient catalysts for the hydration of CO<sub>2</sub> to bicarbonate and protons, but neither of them were crystallized for the moment, and their 3D structure is not known. PfCA inhibition with anions, sulfonamides, phenols and coumarins has been investigated too, with many low nanomolar in vitro inhibitors being detected. Only for acetazolamide and an ureido-substituted benzenesulfonamide it has been demonstrated a potent growth inhibition of the pathogen in P. falciparum infected red blood cells. Although these results are encouraging but rather preliminary, η-CAs from malaria-producing protozoans and presumably other organisms encoding them, may be considered as innovative drug targets for obtaining anti-infectives with new mechanisms of action but these enzymes should be investigated in more details in order to better understand their structure and physiological/pathological roles.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"113-127"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252015","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 : 2025-01-01Epub Date: 2025-07-08DOI: 10.1016/bs.enz.2025.05.004
Clemente Capasso, Claudiu T Supuran
{"title":"Toxoplasma gondii, babesia, and other protozoan carbonic anhydrases.","authors":"Clemente Capasso, Claudiu T Supuran","doi":"10.1016/bs.enz.2025.05.004","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.004","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) play an essential role in the physiology and survival of protozoan parasites. This study explores the biological functions, molecular features, and therapeutic potential of protozoan CAs, focusing on the α, β, and η classes. Emphasis is placed on the structural and functional divergences between protozoan and mammalian CAs, underscoring the opportunities for selective drug targeting. Key protozoan pathogens, including Toxoplasma gondii, Trypanosoma cruzi, Leishmania spp., Trichomonas vaginalis, Entamoeba histolytica and Plasmodium falciparum, are examined with respect to their CA classes, which are evaluated for their roles in parasite metabolism and as candidates for therapeutic intervention. The potential of CA inhibitors as novel antiparasitic agents was critically assessed. By integrating established findings with emerging data, this analysis offers a comprehensive framework for the strategic exploitation of protozoan CAs for the development of next generation antiparasitic therapies.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"183-206"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252927","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 : 2025-01-01Epub Date: 2025-07-08DOI: 10.1016/bs.enz.2025.04.002
Niccolò Paoletti, Claudiu T Supuran, Clemente Capasso
{"title":"Sordaria macrospora carbonic anhydrases.","authors":"Niccolò Paoletti, Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2025.04.002","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.04.002","url":null,"abstract":"<p><p>Sordaria macrospora, a coprophylous fungus used for the last three decades as a model organism for studying fruiting body development of fungi, encodes for four carbonic anhydrases (CAs, EC 4.2.1.1), CAS1-CAS4. CAS1-CAS3 are β-CAs and were investigated in detail in the last years, whereas CAS4, an α-class enzyme, was less investigated. All of them are crucial for the fungus, as the mutant lacking the genes encoding for these four enzymes showed a drastically reduced vegetative growth rate compared to the wild type organism. CAS4 is a secreted protein, CAS2 is mitochondrial, whereas CAS1 and CAS3 are cytosolic enzymes. The catalytic activity of CAS1-CAS3 for the CO<sub>2</sub> hydration reaction showed that all of them possess a significant activity, with CAS3 being the most effective catalyst. The X-ray crystal structures of CAS1 and CAS2 were also obtained, showing that the two enzymes are tetramers (dimers of dimers) with an open active site in the case of CAS1 and a closed one for CAS2, similar to other plant/fungal/bacterial β-CAs studied so far. Detailed anion and sulfonamide inhibition studies were reported for all three β-Cas, which led to the identification of several effective inhibitors. Potential biotechnological applications of these enzymes for carbon (CO<sub>2</sub>) capture are also discussed.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"91-111"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252961","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 : 2025-01-01Epub Date: 2025-07-19DOI: 10.1016/bs.enz.2025.07.003
Katia D'Ambrosio, Anna Di Fiore, Vincenzo Alterio, Martina Buonanno, Vincenzo Massimiliano Vivenzio, Simona Maria Monti, Giuseppina De Simone, Emma Langella
{"title":"Fungal α-carbonic anhydrases.","authors":"Katia D'Ambrosio, Anna Di Fiore, Vincenzo Alterio, Martina Buonanno, Vincenzo Massimiliano Vivenzio, Simona Maria Monti, Giuseppina De Simone, Emma Langella","doi":"10.1016/bs.enz.2025.07.003","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.07.003","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) are widely distributed in the fungal kingdom and play crucial roles for their growth, development, virulence, and survival. Known fungal CAs belong either to the α- or the β-classes, with the α-class encoded only in filamentous ascomycetes. Here we report the main findings relative to α-CAs characterized so far from different fungi, namely Aspergillus oryzae, Sordaria macrospora and Paracoccidioides. Structural, functional and biochemical data will be discussed underlying the necessity of more research efforts to gain a comprehensive understanding of fungal α-CAs.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"21-32"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253215","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 : 2025-01-01Epub Date: 2025-07-16DOI: 10.1016/bs.enz.2025.04.001
Silvia Selleri, Andrea Angeli
{"title":"Malassezia spp. carbonic anhydrases.","authors":"Silvia Selleri, Andrea Angeli","doi":"10.1016/bs.enz.2025.04.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.04.001","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) are essential metalloenzymes that catalyse the reversible conversion of CO₂ to bicarbonate, playing a crucial role in pH regulation, CO₂ sensing, and metabolic homeostasis. In Malassezia species, β-class CAs have emerged as promising drug targets for antifungal and dermatological applications, particularly in conditions such as dandruff and seborrheic dermatitis. Among the studied Malassezia species, the carbonic anhydrases from M. globosa (MgCA), M. restricta (MreCA) and M. pachydermatis (MpaCA) have been extensively characterized, demonstrating significant functional differences in both inhibition and activation mechanisms. This chapter explores the inhibition of Malassezia CAs using diverse classes of inhibitors, including sulfonamides, boronic acids, phenols, dithiocarbamates, and benzoxaboroles. Many of these compounds exhibit selective inhibition of fungal CAs over human isoforms, underscoring their potential as novel antifungal agents. Additionally, activation studies have revealed that both MgCA and MreCA can be modulated by biogenic amines and amino acids, with MreCA displaying markedly higher sensitivity, particularly to catecholamines like L-adrenaline, suggesting a potential link between stress responses and fungal virulence. The differential inhibition and activation profiles of Malassezia β-CAs provide valuable insights into fungal physiology, enzyme regulation, and potential therapeutic interventions. These findings establish a strong foundation for the rational design of selective inhibitors and activators that could serve as next-generation antifungal agents.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"65-89"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252026","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 : 2025-01-01Epub Date: 2025-06-27DOI: 10.1016/bs.enz.2025.05.001
Claudiu T Supuran, Clemente Capasso
{"title":"Overview on fungal and protozoan carbonic anhydrases.","authors":"Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2025.05.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2025.05.001","url":null,"abstract":"<p><p>An overview of carbonic anhydrases (CAs) in fungi and protozoa is provided, emphasizing their evolutionary significance, functional diversity, and implications for human health. CAs are metalloenzymes that catalyze the reversible hydration of carbon dioxide, playing crucial roles in cellular homeostasis, pH regulation, and metabolic adaptation. In fungi, α- and β-class CAs are predominant, facilitating growth and virulence, particularly in pathogenic species such as Candida spp., Cryptococcus neoformans and many others. Protozoa exhibit a broader range of CA classes, including the recently identified η-class in Plasmodium falciparum, which is vital for the survival of the parasite and presents a significant potential as a drug target. The evolutionary trajectories of CAs reflect adaptations to diverse ecological niches, with gene duplication leading to functional diversification. Understanding the biochemical properties and regulatory mechanisms of CAs in these organisms can lead to innovative therapeutic strategies against fungal and protozoan infections, highlighting their potential as drug and diagnostic targets.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"57 ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252054","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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