Molecule Information

General Information of the Molecule (ID: Mol02149)

• Name: Heat shock protein HSP 90 (HSP90 ) ,Candida albicans
• Synonyms: HSP90 CAALFM_C702030WA CaJ7.0234 CaO19.13868 CaO19.6515
• Molecule Type: Protein
• Gene Name: HSP90
• Gene ID: 3636951
• Sequence:
  MADAKVETHEFTAEISQLMSLIINTVYSNKEIFLRELISNASDALDKIRYQALSDPSQLE
  SEPELFIRIIPQKDQKVLEIRDSGIGMTKADLVNNLGTIAKSGTKSFMEALSAGADVSMI
  GQFGVGFYSLFLVADHVQVISKHNDDEQYVWESNAGGKFTVTLDETNERLGRGTMLRLFL
  KEDQLEYLEEKRIKEVVKKHSEFVAYPIQLVVTKEVEKEVPETEEEDKAAEEDDKKPKLE
  EVKDEEDEKKEKKTKTVKEEVTETEELNKTKPLWTRNPSDITQDEYNAFYKSISNDWEDP
  LAVKHFSVEGQLEFRAILFVPKRAPFDAFESKKKKNNIKLYVRRVFITDDAEELIPEWLS
  FIKGVVDSEDLPLNLSREMLQQNKILKVIRKNIVKKMIETFNEISEDQEQFNQFYTAFSK
  NIKLGIHEDAQNRQSLAKLLRFYSTKSSEEMTSLSDYVTRMPEHQKNIYYITGESIKAVE
  KSPFLDALKAKNFEVLFMVDPIDEYAMTQLKEFEDKKLVDITKDFELEESDEEKAAREKE
  IKEYEPLTKALKDILGDQVEKVVVSYKLVDAPAAIRTGQFGWSANMERIMKAQALRDTTM
  SSYMSSKKTFEISPSSPIIKELKKKVETDGAEDKTVKDLTTLLFDTALLTSGFTLDEPSN
  FAHRINRLIALGLNIDDDSEETAVEPEATTTASTDEPAGESAMEEVD
• Function: Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (By similarity).
• Uniprot ID: HSP90_CANAL

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Debaryomycetaceae
Genus: Candida
Species: Candida albicans

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Amphotericin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Amphotericin B
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: The fitness and survival of amphotericin B-resistant Candida isolates are critically dependent upon Hsp90 expression and function. As a consequence, pharmacological inhibition of Hsp90 in resistant C. albicans or C. tropicalis strains abolished amphotericin B resistance.

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: The mechanisms through which Hsp90 confers antifungal resistance are complex given its global impact on cellular signaling. A key Hsp90 client that mediates its effects on antifungal drug tolerance and resistance is the calcium-calmodulin activated protein phosphatase calcineurin. Azole treatment activates calcineurin-dependent stress responses in C. albicans, and genetic or pharmacological impairment of the phosphatase renders C. albicans hypersensitive to the azoles. Hsp90 inhibition blocks azole activation of the calcineurin-dependent stress response and phenocopies the effects of calcineurin inhibition, highlighting the interconnectedness between calcineurin and Hsp90 in regulating azole tolerance and resistance.

Investigative Drug(s) 1 drug(s) in total

Echinocandins

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Echinocandins
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: As discussed, Hsp90 regulates the function of calcineurin, as well as a number of stress-activated protein kinases, which is crucial in mediating responses to the echinocandins. Pharmacological or genetic impairment of Hsp90 function potentiates echinocandin activity in C. albicans, C. glabrata, and the distantly related pathogenic mold A. fumigatus. Furthermore, inhibition of Hsp90 reduces echinocandin resistance in C. glabrata clinical isolates with mutations in the echinocandin target gene FKS1.

References

• Ref 1: Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond .Chem Rev. 2021 Mar 24;121(6):3390-3411. doi: 10.1021/acs.chemrev.0c00199. Epub 2020 May 22. 10.1021/acs.chemrev.0c00199