title: Kinin release from human kininogen by 10 aspartic proteases produced by pathogenic yeast Candida albicans.
abstract: BACKGROUND
  Candida albicans yeast produces 10 distinct secreted aspartic proteases (Saps), which are some of the most important virulence factors of this pathogenic fungus. One of the suggested roles of Saps is their deregulating effect on various proteolytic cascades that constitute the major homeostatic systems in human hosts, including blood coagulation, fibrinolysis, and kallikrein-kinin systems. This study compared the characteristics of the action of all 10 Saps on human kininogens, which results in generating proinflammatory bradykinin-related peptides (kinins).
  
  
  RESULTS
  Recombinant forms of Saps, heterologously overexpressed in Pichia pastoris were applied. Except for Sap7 and Sap10, all Saps effectively cleaved the kininogens, with the highest hydrolytic activity toward the low-molecular-mass form (LK). Sap1-6 and 8 produced a biologically active kinin-Met-Lys-bradykinin-and Sap3 was exceptional in terms of the kinin-releasing yield (>60% LK at pH 5.0 after 24 hours). Des-Arg(1)-bradykinin was released from LK by Sap9 at a comparably high yield, but this peptide was assumed to be biologically inactive because it was unable to interact with cellular B2-type kinin receptors. However, the collaborative actions of Sap9 and Sap1, -2, -4-6, and -8 on LK rerouted kininogen cleavage toward the high-yield release of the biologically active Met-Lys-bradykinin.
  
  
  CONCLUSIONS
  Our present results, together with the available data on the expression of individual SAP genes in candidal infection models, suggest a biological potential of Saps to produce kinins at the infection foci. The kinin release during candidiasis can involve predominant and complementary contributions of two different Sap3- and Sap9-dependent mechanisms.
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. andrzej.kozik@uj.edu.pl.
authors: Andrzej
authors: A
authors: Kozik
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. ubichinon@gmail.com.
authors: Mariusz
authors: M
authors: Gogol
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. olivia.bochenska@uj.edu.pl.
authors: Oliwia
authors: O
authors: Bochenska
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. justyna.karkowska@uj.edu.pl.
authors: Justyna
authors: J
authors: Karkowska-Kuleta
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. natalia.wolak@uj.edu.pl.
authors: Natalia
authors: N
authors: Wolak
authors: Faculty of Pharmacy, Medical University of Gdansk, Al. Hallera 107, 80-416, Gdansk, Poland. info@lipopharm.pl.|LipoPharm.pl, Koscielna 16A, 83-210, Zblewo, Poland. info@lipopharm.pl.
authors: Wojciech
authors: W
authors: Kamysz
authors: Department of Applied Physics, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. w-aoki@ap.eng.osaka-u.ac.jp.
authors: Wataru
authors: W
authors: Aoki
authors: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan. miueda@kais.kyoto-u.ac.jp.
authors: Mitsuyoshi
authors: M
authors: Ueda
authors: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-University, Pettenkoferstrasse 9b, 80336, Munich, Germany. alexander.faussner@med.uni-muenchen.de.
authors: Alexander
authors: A
authors: Faussner
authors: Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Krakow, Poland. maria.rapala-kozik@uj.edu.pl.
authors: Maria
authors: M
authors: Rapala-Kozik
mesh_terms: D000595:Amino Acid Sequence; D057055:Aspartic Acid Proteases / Q000737:chemistry* / Q000235:genetics; D012898:Autacoids / Q000737:chemistry*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000737:chemistry; D002176:Candida albicans / Q000737:chemistry* / Q000201:enzymology / Q000472:pathogenicity; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics; D007704:Kininogens / Q000737:chemistry*; D007705:Kinins / Q000737:chemistry*; D008969:Molecular Sequence Data; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D014774:Virulence
chemical_list: D012898:Autacoids; D005656:Fungal Proteins; D007527:Isoenzymes; D007704:Kininogens; D007705:Kinins; D011994:Recombinant Proteins; C018103:bradykinin, Met-Lys-; D057055:Aspartic Acid Proteases; D001920:Bradykinin