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X-ray structures of Sap1 and Sap5: structural comparison of the secreted aspartic proteinases from Candida albicans.

Borelli C, Ruge E, Lee JH, Schaller M, Vogelsang A, Monod M, Korting HC, Huber R, Maskos K
Proteins 72 1308-19 (2008)
Cited: 34 times
EuropePMC logo PMID: 18384081

Abstract

Proteolytic activity is an important virulence factor for Candida albicans (C. albicans). It is attributed to the family of the secreted aspartic proteinases (Saps) from C. albicans with a minimum of 10 members. Saps show controlled expression and regulation for the individual stages of the infection process. Distinct isoenzymes can be responsible for adherence and tissue damage of local infections, while others cause systemic diseases. Earlier, only the structures of Sap2 and Sap3 were known. In our research, we have now succeeded in solving the X-ray crystal structures of the apoenzyme of Sap1 and Sap5 in complex with pepstatin A at 2.05 and 2.5 A resolution, respectively. With the structure of Sap1, we have completed the set of structures of isoenzyme subgroup Sap1-3. Of subgroup Sap4-6, the structure of the enzyme Sap5 is the first structure that has been described up to now. This facilitates comparison of structural details as well as inhibitor binding modes among the different subgroup members. Structural analysis reveals a highly conserved overall secondary structure of Sap1-3 and Sap5. However, Sap5 clearly differs from Sap1-3 by its electrostatic overall charge as well as through structural conformation of its entrance to the active site cleft. Design of inhibitors specific for Sap5 should concentrate on the S4 and S3 pockets, which significantly differ from Sap1-3 in size and electrostatic charge. Both Sap1 and Sap5 seem to play a major part in superficial Candida infections. Determination of the isoenzymes' structures can contribute to the development of new Sap-specific inhibitors for the treatment of superficial infections with a structure-based drug design program.

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  2. Alternative approaches to antifungal therapies. Mehra T, Köberle M, Braunsdorf C, Mailänder-Sanchez D, Borelli C, Schaller M. Exp Dermatol 21 778-782 (2012)
  3. Extracellular proteinases of Candida species pathogenic yeasts. Rapala-Kozik M, Bochenska O, Zajac D, Karkowska-Kuleta J, Gogol M, Zawrotniak M, Kozik A. Mol Oral Microbiol 33 113-124 (2018)

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  2. Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis. Kumar R, Saraswat D, Tati S, Edgerton M. Infect Immun 83 2614-2626 (2015)
  3. Global Identification of Biofilm-Specific Proteolysis in Candida albicans. Winter MB, Salcedo EC, Lohse MB, Hartooni N, Gulati M, Sanchez H, Takagi J, Hube B, Andes DR, Johnson AD, Craik CS, Nobile CJ. mBio 7 e01514-16 (2016)
  4. Scalar nanostructure of the Candida albicans cell wall; a molecular, cellular and ultrastructural analysis and interpretation. Lenardon MD, Sood P, Dorfmueller HC, Brown AJP, Gow NAR. Cell Surf 6 100047 (2020)
  5. A peptide derived from the highly conserved protein GAPDH is involved in tissue protection by different antifungal strategies and epithelial immunomodulation. Wagener J, Schneider JJ, Baxmann S, Kalbacher H, Borelli C, Nuding S, Küchler R, Wehkamp J, Kaeser MD, Mailänder-Sanchez D, Braunsdorf C, Hube B, Schild L, Forssmann WG, Korting HC, Liepke C, Schaller M. J Invest Dermatol 133 144-153 (2013)
  6. HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos. Dos Santos AL. World J Biol Chem 1 21-30 (2010)
  7. Secretion of an endogenous subtilisin by Pichia pastoris strains GS115 and KM71. Salamin K, Sriranganadane D, Léchenne B, Jousson O, Monod M. Appl Environ Microbiol 76 4269-4276 (2010)
  8. Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans. Cadicamo CD, Mortier J, Wolber G, Hell M, Heinrich IE, Michel D, Semlin L, Berger U, Korting HC, Höltje HD, Koksch B, Borelli C. Biochem Pharmacol 85 881-887 (2013)
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  13. Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. Dostál J, Pecina A, Hrušková-Heidingsfeldová O, Marečková L, Pichová I, Řezáčová P, Lepšík M, Brynda J. Acta Crystallogr D Biol Crystallogr 71 2494-2504 (2015)
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  15. N-terminal entrance loop of yeast Yps1 and O-glycosylation of substrates are determinant factors controlling the shedding activity of this GPI-anchored endopeptidase. Dubé AK, Bélanger M, Gagnon-Arsenault I, Bourbonnais Y. BMC Microbiol 15 50 (2015)
  16. Candida albicans Sap6 Initiates Oral Mucosal Inflammation via the Protease Activated Receptor PAR2. Kumar R, Rojas IG, Edgerton M. Front Immunol 13 912748 (2022)
  17. Phytochemical Analysis, Antioxidant, Antimicrobial, and Anti-Swarming Properties of Hibiscus sabdariffa L. Calyx Extracts: In Vitro and In Silico Modelling Approaches. Hamrita B, Emira N, Papetti A, Badraoui R, Bouslama L, Ben Tekfa MI, Hamdi A, Patel M, Elasbali AM, Adnan M, Ashraf SA, Snoussi M. Evid Based Complement Alternat Med 2022 1252672 (2022)
  18. Anti-Fungal Potential of Structurally Diverse FDA-Approved Therapeutics Targeting Secreted Aspartyl Proteinase (SAP) of Candida albicans: an In Silico Drug Repurposing Approach. Dhanasekaran S, Selvadoss PP, Manoharan SS. Appl Biochem Biotechnol 195 1983-1998 (2023)
  19. Fungal biofilm inhibition by piperazine-sulphonamide linked Schiff bases: Design, synthesis, and biological evaluation. Patil RH, Kalam Khan FA, Jadhav K, Damale M, Akber Ansari S, Alkahtani HM, Ali Khan A, Shinde SD, Patil R, Sangshetti JN. Arch Pharm (Weinheim) 351 e1700354 (2018)
  20. Elucidating the structural basis for the enhanced antifungal activity of amide derivative against Candida albicans: a comprehensive computational investigation. Kechi EL, Ubah CB, Runde M, Owen AE, Godfrey OC, Agurokpon DC, Odey MO, Edet UO, Ekpong BO, Iyam SO, Benjamin I, Sampathkumar G. In Silico Pharmacol 12 48 (2024)


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