carbonic anhydrases
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Carbonic anhydrases (CAs) are physiologically important enzymes that catalyze a reversible conversion of carbon dioxide to bicarbonate and participate in ion transport and pH control. Two human isoenzymes, CA IX and CA XII, are overexpressed in cancer and contribute to tumor physiology. Particularly CA IX is confined to only few normal tissues but is ectopically induced in many tumor types mainly due to its strong transcriptional activation by hypoxia accomplished via HIF-1 transcription factor. Therefore, CA IX can serve as a surrogate marker of hypoxia and a prognostic indicator. CA IX appears implicated in cell adhesion and in balance of pH disturbances caused by tumor metabolism. Both tumor-related expression pattern and functional involvement in tumor progression make it a suitable target for anticancer treatment. Here we summarize a current knowledge on CA IX and CA XII, and discuss possibilities of their exploitation for cancer detection, diagnostics, and therapy.
- MeSH
- financování organizované MeSH
- karboanhydrasy metabolismus MeSH
- lidé MeSH
- nádory enzymologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Patogenní kvasinky rodu Candida představují nejrozšířenější příčinu mykotických onemocnění. Tyto druhy jsou úspěšnými patogeny díky tomu, že jsou schopné se rozmnožovat v nejrůznějších místech jako je například kůže, gastrointestinální trakt, krev nebo vaginální sliz- nice a také díky schopnosti adheze na abiotické povrchy. Jednou z klíčových strategií přežití těchto patogenů je jejich schopnost poliferovat v různých koncentracích oxidu uhličitého (CO2). K zvládnutí takového rozdílu používají kvasinky rodu Candida karbanické anhydrasy (CA) kódované homologem genu NCE103, které katalyzují reverzibilní hydrataci CO2 na bikarbonát. CA jsou postradatelné během infekce krevního řečiště, ale jsou nezbytné pro přežití kvasinek na kůži nebo na abiotických površích. Kvasinkové CA jsou strukturně odlišné od lidských a představují tak vhodný cíl pro vývoj profylaktických látek.
Pathogenic yeasts of the genus Candida represent the most prevalent cause of mycotic diseases worldwide. These species are successful pathogens due to their ability to proliferate under a wide variety of conditions, colonizing host niches as diverse as skin, blood, or vagina and also to adhere to abiotic surfaces. One of the key survival strategies of fungal pathogens is the ability to proliferate in different carbon dioxide (CO2) concentrations. To cope with such difference, Candida possesses carbonic anhydrase (CA), encoded by NCE103 gene, which catalyzes reversible hydratation of CO2 into bicarbonate. This enzyme is dispensable during the bloodstream infection, but it is essential for survival of the fungus on skin or abiotic surfaces. Fungal CAs are structurally unrelated to human CAs, which makes them an ideal target for prophylactic intervention.
- Klíčová slova
- NCE103,
- MeSH
- antifungální látky farmakologie klasifikace MeSH
- Candida enzymologie genetika patogenita MeSH
- fungální léková rezistence účinky léků MeSH
- houby enzymologie MeSH
- kandidóza invazivní patologie terapie MeSH
- kandidóza etiologie farmakoterapie klasifikace patologie MeSH
- karboanhydrasy * genetika chemie klasifikace účinky léků MeSH
- kvasinky * enzymologie klasifikace patogenita MeSH
- oxid uhličitý MeSH
- Publikační typ
- práce podpořená grantem MeSH
Autoři ve sledovaném souboru 6 dětí s dlouhotrvajícím glaukomovým onemocněním zjišťovali možnost použití lokálně aplikovaného inhibitoru karboanhydrázy, 2% dorzolamid hydrochloridu ve formě očních kapek TRUSOPT (fh-ma Merck a spol.). V předběžné studii hodnotí účinnost léku u glaukomu dětského oka plně kladně, předchozí nezbytná léčba perorálním acetazolamidem mohla být u všech nemocných bez nepříznivé odezvy vysazena. Nesetkali se s nežádoucími účinky léku, ani s projevy intolerance, pro které by museli zavedenou léčbu TRUSOPTEM přerušit. v dostupné literatuře jde zatím o první sdělení o léčbě TRUSOPTEM u dětského glaukomu.
rhe authors investigated in a group of six children with glaucoma persisting for I long time the possibility to use locally applied carbonic anhydrase inhibitor, 2% dorsolamide hydrochloride in the form of eye drops (TRUSOPT, Merck Co.). In the submitted preliminary study they evaluate the effectiveness of the drug in glaucoma in children very favourably, previous essential treatment with oral acetazolamide could be discontinued in all patients without a deleterious effect. The authors did not encounter any undesirable effects of the drug nor manifestations of intolerance calling for discontinuation of TRUSOPT treatment. This is so far the fírst communication on TRUSOPT treatment of child glaucoma in the available literature.
- Klíčová slova
- TRUSOPT (MERCK CO.),
- MeSH
- dítě MeSH
- glaukom farmakoterapie chirurgie MeSH
- inhibitory karboanhydras aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.
- MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- izoenzymy antagonisté a inhibitory metabolismus MeSH
- karboanhydrasy metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- enzymy MeSH
- histamin MeSH
- lidé MeSH
- techniky in vitro MeSH
- žaludeční sliznice enzymologie účinky léků MeSH
- Check Tag
- lidé MeSH
- MeSH
- antigeny nádorové MeSH
- karboanhydrasa I MeSH
- karboanhydrasy * MeSH
- lidé MeSH
- nádory * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
Isoquinolinesulfonamides inhibit human carbonic anhydrases (hCAs) and display selectivity toward therapeutically relevant isozymes. The crystal structure of hCA II in complex with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamide revealed unusual inhibitor binding. Structural analyses allowed for discerning the fine details of the inhibitor binding mode to the active site, thus providing clues for the future design of even more selective inhibitors for druggable isoforms such as the cancer associated hCA IX and neuronal hCA VII.
- MeSH
- inhibitory karboanhydras chemie metabolismus farmakologie MeSH
- isochinoliny chemie metabolismus farmakologie MeSH
- izoenzymy antagonisté a inhibitory chemie metabolismus MeSH
- karboanhydrasa II antagonisté a inhibitory chemie metabolismus MeSH
- konformace proteinů MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- substrátová specifita MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The pathogenic yeast Candida albicans can proliferate in environments with different carbon dioxide concentrations thanks to the carbonic anhydrase CaNce103p, which accelerates spontaneous conversion of carbon dioxide to bicarbonate and vice versa. Without functional CaNce103p, C. albicans cannot survive in atmospheric air. CaNce103p falls into the β-carbonic anhydrase class, along with its ortholog ScNce103p from Saccharomyces cerevisiae. The crystal structure of CaNce103p is of interest because this enzyme is a potential target for surface disinfectants. RESULTS: Recombinant CaNce103p was prepared in E. coli, and its crystal structure was determined at 2.2 Å resolution. CaNce103p forms a homotetramer organized as a dimer of dimers, in which the dimerization and tetramerization surfaces are perpendicular. Although the physiological role of CaNce103p is similar to that of ScNce103p from baker's yeast, on the structural level it more closely resembles carbonic anhydrase from the saprophytic fungus Sordaria macrospora, which is also tetrameric. Dimerization is mediated by two helices in the N-terminal domain of the subunits. The N-terminus of CaNce103p is flexible, and crystals were obtained only upon truncation of the first 29 amino acids. Analysis of CaNce103p variants truncated by 29, 48 and 61 amino acids showed that residues 30-48 are essential for dimerization. Each subunit contains a zinc atom in the active site and displays features characteristic of type I β-carbonic anhydrases. Zinc is tetrahedrally coordinated by one histidine residue, two cysteine residues and a molecule of β-mercaptoethanol originating from the crystallization buffer. The active sites are accessible via substrate tunnels, which are slightly longer and narrower than those observed in other fungal carbonic anhydrases. CONCLUSIONS: CaNce103p is a β-class homotetrameric metalloenzyme composed of two homodimers. Its structure closely resembles those of other β-type carbonic anhydrases, in particular CAS1 from Sordaria macrospora. The main differences occur in the N-terminal part and the substrate tunnel. Detailed knowledge of the CaNce103p structure and the properties of the substrate tunnel in particular will facilitate design of selective inhibitors of this enzyme.
- MeSH
- Candida albicans enzymologie MeSH
- karboanhydrasy chemie MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- kvarterní struktura proteinů MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- sekvence aminokyselin MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
