Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pylori

Nishimori, Isao; Vullo, Daniela; Minakuchi, Tomoko; Morimoto, Kaori; Onishi, Saburo; Scozzafava, Andrea; Supuran, Claudiu T.

doi:10.1016/j.bmcl.2006.01.044

Cited by 46 publications

(31 citation statements)

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“…Other uses being explored include treatment of osteoporosis and as a diagnostic tool in magnetic resonance imaging (MRI) and photon emission tomography (PET) (25). Furthermore, other R-class CA isozymes that may be therapeutically targeted by CA inhibitors are found in the prokaryotic mammalian pathogens Neisseria gonorrheae, (28)(29)(30) Helicobacter pylori (31)(32)(33), and the eukaryotic malarial parasite Plasmodium falciparum (34)(35)(36). Known R-CA inhibitors include various anions, imidazole, phenol, hydroxyurea, carboxylates, organic phosphates and phosphonates, and various sulfonamide compounds (R-C-SO 2 NH 2 ) (4,11,25).…”

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confidence: 99%

Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study

et al. 2008

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This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791. Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S- (2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect.

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confidence: 99%

Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study

et al. 2008

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“…This pathogenic bacterium lives in the highly acidic environment of the stomach (pH = 2-3). Its genome encodes three CAs: one α-, one β-, and one γ-CA, respectively [66][67][68][69][70]. The α-CA was shown to possess a periplasmic localization, the β-CA has been found in the cytoplasm, whereas no information is available on the expression/localization of the H. pylori γ-CA.…”

Section: Helicobacter Pylorimentioning

confidence: 99%

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

Capasso

Supuran

2017

CTMC

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Background: Clinically used antibiotics act through one of these four mechanisms: cell wall biosynthesis inhibition, inhibition of protein biosynthesis, interference with DNA and RNA synthesis and the folate pathway. Objective:The metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) widespread in microorganisms and present as three genetically distinct families may be considered for the design of antiinfective agents with a different mechanism of action compared to the clinically used antibiotics. CAs are crucial for the life cycle of the pathogen, interfering with pH regulation and biosynthetic processes in which CO 2 or bicarbonate are substrates. CA inhibition was shown to lead to debilitation or growth defects of several pathogenic bacteria. Method:CAs catalyzes the interconversion between carbon dioxide to bicarbonate, leading to the formation of protons, and thus affecting pH homeostasis. Several classes of CA inhibitors (CAIs) are known to date, among which the metal complexing anions, the unsubstituted sulfonamides, the dithiocarbamates, etc., which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere.Results: Effective inhibitors for many bacterial CAs belonging to the α-, β-, and γ-CA classes were detected, some of which inhibited bacterial growth in vivo. Few of the inhibitors investigated so far were also selective for the bacterial over the human CA isoforms, which may pose problems for their wide clinical applications. Conclusion:Structure-based drug design campaigns might lead to the achievement of the desired selectivity/potency for preferentially inhibiting bacterial but not the host CAs.

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“…The two enzymes possess a significant CO 2 hydrase activity, as determined by several groups, which is probably due to their crucial physiological roles for the bacterium 37,[38][39][40][41][42][43][44] . HpaCA is composed of 247 amino acid residues and shows 27-36% similarity with other a-class bacterial CAs, including Klebsiella pneumonia, Neisseria gonorrhoeae, Enterococcus faecalis, Anabaena PCC7120 and Synechococcus PCC7942 37,38,45 .…”

Section: Treatment Of Gastric and Duodenal Ulcers By Ca Inhibitorsmentioning

confidence: 99%

“…The catalytic activity of recombinant, purified HpaCA and HpbCA for the physiologic reaction (CO 2 hydration), in comparison with that of several a-CAs of human origin, such as hCA I-III (cytosolic isozymes), hCA VA and VB (mitochondrial isoforms) and hCA XII and XIV (transmembrane isozymes), are shown in Table 3. It may be observed that HpaCA and HpbCA are catalytically efficient CAs, possessing a high enzymatic activity (the b-class enzyme is 3.2 times more active than the a-CA from this bacterium) [38][39][40][41] . Furthermore, this activity is almost identical (as k cat /K m value) to that of hCA I, whereas the K m value of the bacterial enzyme is closer to that of hCA II than that of hCA I.…”

Section: Treatment Of Gastric and Duodenal Ulcers By Ca Inhibitorsmentioning

confidence: 99%

“…In fact, HpbCA is a medium-efficiency CA, possessing a catalytic activity higher than that of hCA III, hCA VA, hCA XII and hCA XIV among others. Only hCA VB and especially hCA II, one of the best catalysts known in nature, show a better activity than HpbCA [38][39][40][41] . Also, it may be observed that the activity of all these enzymes is inhibited by the CA inhibitor (CAI) par excellence, the sulfonamide drug, acetazolamide AAZ [53][54][55][56][57] , which may explain why Ulcosilvanil showed a range of severe side effects, due to inhibition of CA isoforms in other organs than the stomach, or better to say, due to hCAs and not Hpa/bCA inhibition (Table 3).…”

Section: Treatment Of Gastric and Duodenal Ulcers By Ca Inhibitorsmentioning

confidence: 99%

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The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015)

Buzás¹,

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pylori

Cited by 46 publications

References 51 publications

Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study

Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study

Inhibition of Bacterial Carbonic Anhydrases as a Novel Approach to Escape Drug Resistance

The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015)

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