Enzymes最新文献

{"title":"Carbonic anhydrase-related proteins VIII, X, and XI: Evolutionary divergence and emerging biological roles.","authors":"Ashok Aspatwar, Seppo Parkkila","doi":"10.1016/bs.enz.2026.05.004","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.05.004","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) constitute a large family of zinc metalloenzymes best known for catalyzing the reversible hydration of carbon dioxide. Within this family, three isoforms-carbonic anhydrase-related proteins (CARPs) VIII, X, and XI-are unusual because they lack catalytic activity due to substitutions in three histidine residues required for coordination of the catalytic Zn²⁺ ion. Despite the absence of enzymatic activity, these proteins are evolutionarily conserved and show distinct expression patterns, particularly in the central nervous system and reproductive tissues, suggesting biological functions beyond catalysis. Among the CARPs, CA VIII is the best characterized and has been associated with cerebellar development and motor coordination. Mutations in the CA8 gene are associated with neurological disorders, including cerebellar ataxia. In contrast, the functions of CA X and CA XI remain less well defined, although available evidence suggests their involvement in neuronal signaling and related regulatory processes. Previous reviews have summarized the current knowledge on CARPs. In this chapter, we provide an updated overview of their evolutionary divergence, expression patterns, molecular interactions, and biological roles. Particular attention is given to insights from genetic studies and model organisms. Despite increasing interest, several aspects of CARP biology remain incompletely understood, and further studies are required to clarify their physiological and pathological significance.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"177-194"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563318","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}

{"title":"Challenges and opportunities in the drug design and pharmacological applications of MMP inhibitors.","authors":"Claudiu T Supuran, Antoine Dufour","doi":"10.1016/bs.enz.2026.03.005","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.03.005","url":null,"abstract":"<p><p>The 23 members of the matrix metalloproteinase (MMP) family are involved in a multitude of physiological processes, such as cell migration, invasion, cell signaling, immune response, fibrosis, extracellular matrix remodeling, tissue homeostasis, but also in a broad range of diseases, among which cancer, inflammation (sepsis, arthritis, asthma, chronic obstructive pulmonary disorder), periodontitis, etc. Their biochemical characterization, expression patterns, role as targets, offtargets or antitargets in many physiologic or pathologic conditions made relevant progress over the last decades. MMP inhibitors (MMPIs) belonging to a variety of classes (hydrozamates, carboxylates, thiols, phosphonates, etc.) are well known. The first/second generations such derivatives, all zinc binders, have been investigated in clinical trials as anticancer agents in the late '90s, with poor results, probably due to their metabolic instability, toxicity and lack of selectivity for the target isoform(s). Recent developments in the field saw the design of highly selective inhibitors for several MMPs, belonging to the modified tetracyclines class, as well as mechanism based, suicide inhibitors belonging to the substituted thiiranes class, exosite and allosteric inhibitors which spare the zinc ion from the enzyme active site. Two compounds are in clinical use for the management of periodontitis (doxycycline, at submicrobial dosages) and abametapir for the treatment of lice infestation. Clinical trials in various types of cancer, in different inflammatory conditions, and microbial infections (tuberculosis) with some of the new generation MMPIs are ongoing, and the expected results will demonstrate their efficacy, probably in combination therapy with other drugs. More selective new inhibitors, better planned clinical trials and a better understanding of the biology/pharmacology of these enzymes may lead to other breakthroughs in the field.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"317-338"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026282","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}

{"title":"MMPs in oral diseases.","authors":"Krista Juurikka, Tuula Salo, Pirjo Åström","doi":"10.1016/bs.enz.2026.07.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.07.001","url":null,"abstract":"<p><p>MMPs are essential for the physiological tissue turnover within the oral cavity and maxillofacial structures but their dysregulation may lead to pathogenic, tissue-destructive oral diseases. Within oral tissues, matrix metalloproteinases (MMPs) are produced by a variety of cells, including fibroblasts, keratinocytes, epithelial cells, immune cells, osteoclasts, osteoblasts, and odontoblasts. Activation of MMPs in periodontal tissues degrades extracellular matrix components which may lead to periodontal attachment loss and alveolar bone destruction. Various MMPs serve as putative biomarkers in dental diseases, and their levels can be easily measured from oral fluids. In addition to their role in periodontal manifestations, MMPs are associated with caries, pulpal inflammation, oral potentially malignant disorders and cancers. MMP inhibitors and chairside test measuring active MMP8 have demonstrated potential clinical usability in adjunctive periodontal therapy and diagnostics. In the next chapters, we discuss the importance and function of MMPs and their use as biomarkers in oral diseases.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"169-208"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026286","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}

{"title":"Tissue inhibitors of metalloproteinases (TIMPs).","authors":"Niccolò Paoletti, Antoine Dufour, Claudiu T Supuran","doi":"10.1016/bs.enz.2026.05.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.05.001","url":null,"abstract":"<p><p>The extracellular matrix (ECM) is a dynamic structural network essential for cellular organization, continuously remodeled by proteases such as matrix metalloproteinases (MMPs). Under physiological conditions, these proteases are strictly controlled through gene transcription, zymogen activation, and endogenous tissue inhibitors of metalloproteinases (TIMPs). TIMPs are vital endogenous inhibitors that tightly regulate various metalloproteinases, including MMPs, ADAMs (a disintegrin and metalloproteinase), and ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) to maintain healthy tissue homeostasis. Disrupting this balance between metalloproteases and TIMPs triggers uncontrolled ECM turnover, changes in immune responses, activation of cell surface receptors that can drive pathological conditions such as fibrosis, cancer, autoimmune diseases, arthritis, cardiovascular diseases and many others. Since their initial discovery, four human TIMPs have been identified, each demonstrating unique biological roles and tissue distributions. TIMPs represent an evolutionarily ancient protein lineage found across bacteria, invertebrates, and vertebrates. Despite their critical role in maintaining human health, there is still a significant gap in our understanding of exactly how their dysregulation drives disease progression.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"135-168"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026477","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}

{"title":"Carbonic anhydrase IX and XII.","authors":"Katia D'Ambrosio, Emma Langella, Simona Maria Monti, Giuseppina De Simone, Anna Di Fiore","doi":"10.1016/bs.enz.2026.06.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.06.001","url":null,"abstract":"<p><p>The membrane-associated carbonic anhydrases (CAs) IX and XII have emerged as critical players in cancer biology due to their significant expression in various malignancies. The two enzymes differ in catalytic efficiency, with CA IX acting as a highly efficient catalyst while CA XII possesses moderate catalytic activity, and although both form a dimer, their resulting structural arrangement is diverse. Regarding their regulatory mechanisms, CA IX expression is primarily driven by the hypoxia-inducible factor 1 pathway in hypoxic microenvironments, whereas CA XII exhibits a more complex, context-dependent expression profile modulated by both hypoxia and estrogen receptor signaling. Both enzymes contribute to adaptation of tumor cells to acidic microenvironments and promote cancer progression. Considering this evidence, CA IX and CA XII represent attractive targets for modern oncology. This chapter comprehensively reviews their functional and structural properties and explores the most recent progresses in targeted intervention strategies highlighting the most promising approaches. Notably, while these enzymes exist as orthologs in other vertebrates, the scope of this chapter is restricted to human CA IX and CA XII, reflecting the overwhelming predominance of studies on the human isoforms in current literature.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"195-242"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563236","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}

{"title":"Carbonic anhydrases I and II.","authors":"Claudiu T Supuran, Clemente Capasso","doi":"10.1016/bs.enz.2026.06.005","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.06.005","url":null,"abstract":"<p><p>Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO₂/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"29-67"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563286","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}

{"title":"Role of MMPs in neutrophil biology.","authors":"Jennifer Vandooren","doi":"10.1016/bs.enz.2026.06.004","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.06.004","url":null,"abstract":"<p><p>Neutrophils are central effectors of the innate immune system, providing rapid responses to harmful stimuli and contributing to both host defense and resolution of inflammation. Among their effector mechanisms is the production and secretion of matrix metalloproteinases (MMPs), particularly MMP-8, MMP-9, and MMP-25. This chapter examines the roles of neutrophil-derived MMPs across neutrophil biology, from their development and maturation in the bone marrow to their functional activities in peripheral tissues. We discuss how these proteases regulate immune responses, tissue remodeling and inflammatory resolution. In addition, we explore the involvement of neutrophil MMPs in a range of pathological conditions, including cardiovascular disease, pulmonary disease, infection, trauma, and cancer. Collectively, these insights highlight the dual roles of neutrophil MMPs in host protection and disease progression.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"243-279"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026412","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}

{"title":"Carbonic anhydrase XIII.","authors":"Alessandro Bonardi","doi":"10.1016/bs.enz.2026.05.005","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.05.005","url":null,"abstract":"<p><p>Carbonic anhydrase XIII (CA XIII) is a recently identified member of the α-carbonic anhydrase family and a cytosolic enzyme with conserved structural and catalytic features. Since its discovery in 2004, its gene organization, protein structure, catalytic mechanism, and inhibition profile have been extensively characterized. CA XIII exhibits moderate catalytic activity compared to other cytosolic isozymes, with differences in proton transfer dynamics accounting for its distinct efficiency. The enzyme is widely expressed in human tissues, particularly in epithelial and reproductive systems, suggesting roles in pH regulation, bicarbonate metabolism, and tissue homeostasis. Despite this, its physiological function remains incompletely defined. Emerging evidence links CA XIII to pathological processes, including its downregulation in colorectal cancer and tumor-suppressive effects in breast cancer models. In contrast, studies in acute myeloid leukemia indicate a context-dependent role in cell proliferation and drug response. Associations with inflammatory conditions, aging, and cognition further suggest broader biological relevance. Pharmacologically, CA XIII is sensitive to sulfonamide inhibitors and activators, making it a relevant target for isozyme-selective drug design. However, the lack of in vivo models remains a major limitation, highlighting the need for integrative future studies.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"243-270"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563312","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}

{"title":"Matrix metalloproteinase-13 selective inhibitors.","authors":"Simone Giovannuzzi, Claudiu T Supuran","doi":"10.1016/bs.enz.2026.03.001","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.03.001","url":null,"abstract":"<p><p>Matrix metalloproteinase-13 (MMP13) is the primary protease responsible for the irreversible degradation of type II collagen in the extracellular matrix (ECM), playing a pivotal role in the pathogenesis of osteoarthritis (OA), rheumatoid arthritis (RA), and various malignant cancers. While early clinical efforts with broad-spectrum zinc-chelating inhibitors were abandoned due to dose-limiting musculoskeletal syndrome (MSS), recent research has focused on achieving high isoform selectivity by targeting unique structural features such as the deep S1' specificity pocket and the MMP13-specific S1'' side pocket. This chapter reviews a wide set of advanced inhibitor scaffolds, including selective sulfonamide hydroxamates, hydantoins such as AZD6605, and non-zinc-binding templates like quinazoline-2-carboxamides and pyrimidine-dicarboxamides. Furthermore, we discuss innovative strategies such as the use of allosteric inhibitors, exosite-binding agents targeting the hemopexin domain, and selectively deuterated molecules (e.g., AQU-019) to improve metabolic stability. Finally, the chapter highlights the clinical potential of neutralizing antibodies (e.g., 14D10), targeted polypharmacology for dual MMP10/13 inhibition, and the development of selective PET radiotracers for non-invasive monitoring of disease progression and atherosclerotic plaque instability.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"60 ","pages":"101-134"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026355","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}

{"title":"Carbonic anhydrases IV and XV.","authors":"Seppo Parkkila","doi":"10.1016/bs.enz.2026.05.006","DOIUrl":"https://doi.org/10.1016/bs.enz.2026.05.006","url":null,"abstract":"<p><p>Carbonic anhydrases (CAs) IV and XV are glycosylphosphatidylinositol (GPI)-anchored membrane-associated enzymes involved in the regulation of pH and ion homeostasis. This review summarizes current knowledge on their structure, post-translational modifications, tissue distribution, physiological roles, and inhibition profiles. CA IV is widely expressed across multiple tissues, including kidney, lung, brain, and reproductive organs, where it participates in ion transport processes and forms functional and physical interactions with ion transporters. In contrast, CA XV displays a highly restricted expression pattern, primarily localized to specific nephron segments in the kidney, and is absent in humans. Comparative analyses highlight both shared structural features and distinct functional specializations between these isozymes. In addition, CA IV has been implicated in human disease, particularly retinitis pigmentosa, whereas CA XV remains less explored due to its limited clinical relevance. Understanding these enzymes provides insight into membrane-associated CA biology and their potential as pharmacological targets.</p>","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":"59 ","pages":"85-103"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563234","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}