The catalytic mechanism of mammalian carbonic anhydrases

Lindskog, Sven; Silverman, David N.

doi:10.1007/978-3-0348-8446-4_10

Cited by 65 publications

(58 citation statements)

References 105 publications

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“…3). 2,7,[10][11][12] The active form of the enzyme is the basic one, with hydroxide bound to Zn(II) (Fig. 3A).…”

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

“…3A). 12 This strong nucleophile attacks the CO 2 molecule bound in a hydrophobic pocket in its neighbourhood (the elusive substrate-binding site comprises residues (Fig. 3B), leading to the formation of bicarbonate coordinated to Zn(II) (Fig.…”

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

“…12 In the catalytically very active isozymes, such as CA II, CA IV, CA V, CA VII, and CA IX, the process is assisted by a histidine residue placed at the entrance of the active site (His 64), as well as by a cluster of histidines, which protrudes from the rim of the active site to the surface of the enzyme, assuring thus a very efficient proton transfer process. 10 This also explains why CA II is one of the most active enzymes known (with a k cat / K m ¼ 1.5 Â 10 8 M À1 sec À1 ), approaching the limit of diffusion control, [7][8][9][10][11][12] and also has important consequences for the design of inhibitors with clinical applications.…”

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

“…These derivatives (11)(12)(13)(14)(15) generally showed very good in vitro CA inhibitory properties against isozyme hCA II, and some of them also showed modest, but interesting IOP lowering properties when administered topically in normotensive or glaucomatous rabbits, but many of them (mainly the benzofuran-and indole-2-sulfonamide derivatives) were still potent allergens, and were ineffective in humans. 33 Less allergenic effects showed the benzo[b]thiophene-2-sulfonamide 11, 32 and the thienothiophene-2-sulfonamides 14, 15, 34 but these latter derivatives showed a strong binding to the ocular pigment, in addition to a modest reactivity towards glutathione, which were considered not really desirable properties for a future drug.…”

Section: B the ''Ring'' Approachmentioning

confidence: 99%

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Carbonic anhydrase inhibitors

Supuran

Scozzafava

Casini

2002

Medicinal Research Reviews

1,402

839

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“…3). 2,7,[10][11][12] The active form of the enzyme is the basic one, with hydroxide bound to Zn(II) (Fig. 3A).…”

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

Section: C a T A L Y T I C A N D I N H I B I T I O N M E C H A N I mentioning

confidence: 99%

Section: B the ''Ring'' Approachmentioning

confidence: 99%

See 2 more Smart Citations

Carbonic anhydrase inhibitors

Supuran

Scozzafava

Casini

2002

Medicinal Research Reviews

1,402

839

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show abstract

“…The first step of catalysis (1) is initiated by nucleophilic attack on the carbon of CO 2 by the metal-bound hydroxide (EM 2+ -OH À ) to yield bicarbonate (HCO 3 À ), which is subsequently displaced by a water molecule (Lindskog, 1997;Lindskog & Silverman, 2000). The second step (2) is the removal of a proton from the now metal-bound water (EM 2+ -H 2 O) via an ordered water network and a residue acting as a weak base (B), which is typically a His at the opening of the active site, thus regenerating EM 2+ -OH À (Lindskog & Silverman, 2000;Fisher et al, 2007).…”

Section: Issn 1399-0047mentioning

confidence: 99%

Structural and biophysical characterization of the α-carbonic anhydrase from the gammaproteobacteriumThiomicrospira crunogenaXCL-2: insights into engineering thermostable enzymes for CO₂sequestration

Díaz-Torres

Mahon

Boone

et al. 2015

Acta Cryst D Biol Crystallogr

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Biocatalytic CO 2 sequestration to reduce greenhouse-gas emissions from industrial processes is an active area of research. Carbonic anhydrases (CAs) are attractive enzymes for this process. However, the most active CAs display limited thermal and pH stability, making them less than ideal. As a result, there is an ongoing effort to engineer and/or find a thermostable CA to fulfill these needs. Here, the kinetic and thermal characterization is presented of an -CA recently discovered in the mesophilic hydrothermal vent-isolate extremophile Thiomicrospira crunogena XCL-2 (TcruCA), which has a significantly higher thermostability compared with human CA II (melting temperature of 71.9 C versus 59.5 C, respectively) but with a tenfold decrease in the catalytic efficiency. The X-ray crystallographic structure of the dimeric TcruCA shows that it has a highly conserved yet compact structure compared with other -CAs. In addition, TcruCA contains an intramolecular disulfide bond that stabilizes the enzyme. These features are thought to contribute significantly to the thermostability and pH stability of the enzyme and may be exploited to engineer -CAs for applications in industrial CO 2 sequestration.

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Carbonic Anhydrases (α‐Class)

Duda

McKenna

2004

Handbook of Metalloproteins

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Carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the hydration of carbon dioxide and the dehydration of bicarbonate: , a process that has physiological importance in respiration, acid–base homeostasis, photosynthesis, and biosynthetic pathways. The α‐class of CA (and the CA domains in more complex isoforms) is monomeric with a molecular weight of approximately 30 kDa. At present, 14 isoforms of the α‐class are known with varying tissue distributions and catalytic activity. The catalytic turnover number of CAs varies from the maximal rate of 10 6 s −1 for isozyme II to 10 3 s −1 for isozyme III. The central structural motif of the α‐CAs can be described as a 10‐stranded twisted β‐sheet, which is flanked by seven α‐helices. The active‐site cavity consists of a single zinc ion tetrahedrally coordinated by three histidine residues (His94, 96, and 119) and a bound water molecule. In most of the α‐CAs, the resultant proton formed by the dehydration reaction of bicarbonate is transferred to bulk solution through the formation of a proton wire, mediated by residue His64, that lies at the mouth of the active site. Known inhibitors of CAs have been shown to bind to the metal ion and displace the zinc‐bound water, whereas activators have been shown to bind at the entrance of the active site and mimic the characteristics of the proton‐shuttling residue His64.

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The catalytic mechanism of mammalian carbonic anhydrases

Cited by 65 publications

References 105 publications

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors

Structural and biophysical characterization of the α-carbonic anhydrase from the gammaproteobacteriumThiomicrospira crunogenaXCL-2: insights into engineering thermostable enzymes for CO₂sequestration

Carbonic Anhydrases (α‐Class)

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The catalytic mechanism of mammalian carbonic anhydrases

Cited by 65 publications

References 105 publications

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors

Structural and biophysical characterization of the α-carbonic anhydrase from the gammaproteobacteriumThiomicrospira crunogenaXCL-2: insights into engineering thermostable enzymes for CO2sequestration

Carbonic Anhydrases (α‐Class)

Contact Info

Product

Resources

About

Structural and biophysical characterization of the α-carbonic anhydrase from the gammaproteobacteriumThiomicrospira crunogenaXCL-2: insights into engineering thermostable enzymes for CO₂sequestration