Structural insights into novel mechanisms of inhibition of the major β-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus

Kim, Subin; Yeon, Jungyoon; Sung, Jongmin; Kim, Najin; Hong, Semi; Jin, Mi Sun

doi:10.1016/j.jsb.2021.107700

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…The β-CA family is the only CA family known to exhibit allostery, with HCO 3 − acting as both a substrate and an inhibitor in type II members. Binding of the HCO 3 − disrupts the "gatekeeper" Asp-Arg dyad, leading to the Asp-Zn bond that displaces the catalytic H 2 O, leading to inhibition (36,(45)(46)(47). In addition to activating the enzyme, the RuBP binding pocket presented here appears distinct from these previously characterized sites, engaging different residues and sitting further from relative active sites (figs.…”

Section: A Distinct Paradigm For Ca Allosteric Regulationmentioning

confidence: 99%

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

Pulsford,

Outram,

Förster

et al. 2024

Sci. Adv.

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Cyanobacterial CO 2 concentrating mechanisms (CCMs) sequester a globally consequential proportion of carbon into the biosphere. Proteinaceous microcompartments, called carboxysomes, play a critical role in CCM function, housing two enzymes to enhance CO 2 fixation: carbonic anhydrase (CA) and Rubisco. Despite its importance, our current understanding of the carboxysomal CAs found in α-cyanobacteria, CsoSCA, remains limited, particularly regarding the regulation of its activity. Here, we present a structural and biochemical study of CsoSCA from the cyanobacterium Cyanobium sp. PCC7001. Our results show that the Cyanobium CsoSCA is allosterically activated by the Rubisco substrate ribulose-1,5-bisphosphate and forms a hexameric trimer of dimers. Comprehensive phylogenetic and mutational analyses are consistent with this regulation appearing exclusively in cyanobacterial α-carboxysome CAs. These findings clarify the biologically relevant oligomeric state of α-carboxysomal CAs and advance our understanding of the regulation of photosynthesis in this globally dominant lineage.

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Section: A Distinct Paradigm For Ca Allosteric Regulationmentioning

confidence: 99%

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

Pulsford,

Outram,

Förster

et al. 2024

Sci. Adv.

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“…Asp-Arg dyad, leading to Asp-Zn bond that displaces the catalytic H2O, leading to inhibition 40,[49][50][51] . In addition to activating the enzyme, the RuBP binding pocket presented here appears distinct from these previously characterised sites, engaging different residues and sitting further from relative active sites (Fig.…”

Section: A Distinct Paradigm For Carbonic Anhydrase Allosteric Regula...mentioning

confidence: 99%

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

Pulsford

Outram

Förster

et al. 2023

Preprint

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Cyanobacterial CO2concentrating mechanisms (CCMs) sequester a globally significant proportion of carbon into the biosphere. Proteinaceous microcompartments, called carboxysomes, play a critical role in CCM function, housing two enzymes to enhance CO2fixation: carbonic anhydrase (CA) and Rubisco. Despite its importance, our current understanding of the carboxysomal CAs found in α-cyanobacteria, CsoSCA, remains limited, particularly regarding the regulation of its activity. Here, we present the first structural and biochemical study of CsoSCA from the cyanobacterium Cyanobium PCC7001. Our results show that the Cyanobium CsoSCA is allosterically activated by the Rubisco substrate ribulose-1,5-bisphosphate (RuBP), and forms a hexameric trimer of dimers. Comprehensive phylogenetic and mutational analyses are consistent with this regulation appearing exclusively in cyanobacterial α-carboxysome CAs. These findings clarify the biologically relevant oligomeric state of α-carboxysomal CAs and advance our understanding of the regulation of photosynthesis in this globally dominant lineage.

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“…The two CAs (CAS1 and CAS2) were distinguished for the type of conformations they assumed: CAS1 resulted in the open “type- I” conformation, while the CAS2 adopted a close “type-II” conformation [ 49 ]. Finally, between 2020 and 2021, CafA and CafB, two of the four β-CAs encoded by the genome of the fungus Aspergillus fumigatus , were crystallized and the structure resolved at 1.8 and 2.0 Å, respectively [ 50 , 51 ]. The catalytic sites of CafA and CafB look similar to those of other β-CAs.…”

Section: Introductionmentioning

confidence: 99%

“…CafA showed the typical open conformation. Surprisingly, CafB revealed a unique active site at a low pH or in an oxidative environment, resulting in an inactive enzyme, with a disulfide bond formed by the two zinc-ligating cysteines [ 50 ]. Of course, CafB also adopts the typical active/inactive configurations in which a conserved aspartic acid is implicated in switching the enzyme in its open/closed state [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium

Supuran

Capasso

2021

IJMS

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Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms’ metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3−) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3− and protons. Opportunistic and pathogenic fungi can sense the environmental CO2 levels, which influence their virulence or environmental subsistence traits. The fungal CO2-sensing is directly stimulated by HCO3− produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO2/HCO3−/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel “pathogen protein” target of many opportunistic, pathogenic fungi.

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Structural insights into novel mechanisms of inhibition of the major β-carbonic anhydrase CafB from the pathogenic fungus Aspergillus fumigatus

Cited by 4 publications

References 60 publications

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP

A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium

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