Structure and Inhibition of the CO2-Sensing Carbonic Anhydrase Can2 from the Pathogenic Fungus Cryptococcus neoformans

Schlicker, Christine; Hall, Rebecca; Vullo, Daniela; Middelhaufe, Sabine; Gertz, M.; Supuran, Claudiu T.; Mühlschlegel, Fritz A.; Steegborn, Clemens

doi:10.1016/j.jmb.2008.11.037

Cited by 185 publications

(187 citation statements)

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“…2,[4][5][6][7][8][9][10][11] In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that they have potential as anticonvulsant, antiobesity, anticancer, and antiinfective drugs. 2,[4][5][6][7][8][9][10][11] Many of the mammalian CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited or activated to treat a wide range of disorders. 2,4 However a critical barrier to the design of CAIs as therapeutic agents is related to the high number of isoforms in humans, their rather diffuse localization in many tissues/organs, and the lack of isozyme selectivity of the presently available inhibitors of the sulfonamide/sulfamate type.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

et al. 2009

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Coumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.

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Section: Introductionmentioning

confidence: 99%

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

et al. 2009

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“…Mitochondrial deacetylases, for example, contribute to physiological and pathological processes (3,65,66) and are considered attractive therapeutic targets for metabolic and aging-related diseases (67). Modulation of PDEs by using small molecules is even better established and PDEs are widely used as drug targets (27,31).…”

Section: Discussionmentioning

confidence: 99%

“…cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger.…”

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confidence: 99%

“…Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3,4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8,9). cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger.…”

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A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

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Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMPdegrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1, 2). Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3, 4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8, 9).cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13). Unique from transmembrane adenylyl cyclases, sAC is activated by bicarbonate (14), and it appears to act as a metabolic sensor (15), whose mitochondrial form(s) seems to modulate PKA-mediated regulation of respiration (8) and apoptosis (16).The opponents of the cyclic nucleotide-forming cyclases are cyclic nucleotide monophosphate (cNMP)-degrading phosphodiesterases (PDEs). Mammalian cells contain a varying subset of members of the classical PDE family, which comprises 11 PDE gene families (PDE1-11) (17, 18) and non-generic PDEs such as the protein human Prune (19,20). The isoforms of the generic PDEs comprise homologous catalytic domains, fused to varying regulatory domains, making them sensitive to a variety of signals s...

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“…neoformans Can2 revealed that the enzyme carries a unique N-terminal extension that can interact with the active site entrance of the dimer, so the N-terminus was hypothesized to be an internal regulator or an interaction site for a different protein (Schlicker et al, 2009). Deletion analysis of the CA-encoding genes in C. neoformans and C. albicans revealed that CAN2 and NCE103 are essential for survival under ambient air, but dispensable for in vivo proliferation and virulence at the high CO 2 levels found in the host (Bahn et al, 2005;Klengel et al, 2005).…”

Section: Cas Of the Fungal Pathogens Candida Albicans And Cryptococcumentioning

confidence: 99%

Carbonic anhydrases in fungi

2010

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Carbonic anhydrases (CAs) are metalloenzymes that catalyse the interconversion of carbon dioxide and bicarbonate with high efficiency. This reaction is fundamental to biological processes such as respiration, photosynthesis, pH homeostasis, CO2 transport and electrolyte secretion. CAs are distributed among all three domains of life, and are currently divided into five evolutionarily unrelated classes (α, β, γ, δ and ζ). Fungal CAs have only recently been identified and characterized in detail. While Saccharomyces cerevisiae and Candida albicans each have only one β-CA, multiple copies of β-CA- and α-CA-encoding genes are found in other fungi. Recent work demonstrates that CAs play an important role in the CO2-sensing system of fungal pathogens and in the regulation of sexual development. This review focuses on CA functions in S. cerevisiae, the fungal pathogens C. albicans and Cryptococcus neoformans, and the filamentous ascomycete Sordaria macrospora.

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Structure and Inhibition of the CO2-Sensing Carbonic Anhydrase Can2 from the Pathogenic Fungus Cryptococcus neoformans

Cited by 185 publications

References 47 publications

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Carbonic anhydrases in fungi

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