Pityriarubins, Novel Highly Selective Inhibitors of Respiratory Burst from Cultures of the Yeast Malassezia furfur: Comparison with the Bisindolylmaleimide Arcyriarubin A

Abstract

Pityriasis versicolor is the most common skin mycosis in humans worldwide. Yeasts of the genus Malassezia, particularly M. furfur, a saprophyte occurring widely on human skin, are generally regarded as the causative agents. M. furfur is able to convert tryptophan into a variety of indole alkaloids, some of them showing biological properties that correlate well with certain clinical features of pityriasis versicolor. This suggests a possible role for these compounds in the pathophysiology of the disease. We here report that the novel pityriarubins A, B and C, isolated from cultures of the yeast, inhibit respiratory burst in human neutrophils, activated by various agents, in a highly selective, unexpected manner. The release of 5-lipoxygenase products after challenge of neutrophils with the calcium ionophore A23187 is also inhibited in a dose-dependent manner. These activities reflect the close structural relationship of pityriarubins to bisindolylmaleimides, which have recently gained great interest as protein kinase inhibitors.

Analysis of differentially expressed genes associated with tryptophan-dependent pigment synthesis inM. furfurby cDNA subtraction technology

“…Malassezin, for example, induces apoptosis in human melanocytes [14], and therefore may be responsible for depigmentation. Pityriacitrin, which absorbs UV-irradiation, may be responsible for reduced sensitivity against UV-light of the depigmented areas [10,11], while the lack of inflammation may be caused by the suppressive impact of the pityriarubins on the oxidative burst of human granulocytes [15]. The objective of this study was the identification of genes which are involved in the tryptophan-dependent pigment synthesis of M. furfur.…”

Ustilago maydis secondary metabolism—From genomics to biochemistry

“…1d), one of the main constituents of the pigment mixture produced by M. furfur from Trp, is a very potent UV-filter and could explain the UV-resistance of affected skin lesions (Machowinski et al, 2006;Mayser et al, 2002). The novel compounds pityrianhydride (PyA) and the pityriarubins A, B, and C (PitA, PitB, and PitC) have been shown to act as anti-inflammatory agents in vivo, thus potentially explaining the modest levels of inflammation associated with the disease (Krämer et al, 2005). Pityrialactone, a compound that is also produced in large quantities by M. furfur is a fluorochrome and could be responsible for the observed fluorescence of affected lesions that is used for diagnosis of the disease (Mayser et al, 2003).…”

The Malassezia Genus in Skin and Systemic Diseases

“…This has been partly attributed to the production of an array of indolic compounds produced by Malassezia species, in particular M. furfur (213), that have the ability to downregulate aspects of the inflammatory cascade (see below). Thus, indoles like pityriarubins impede the respiratory burst of human neutrophils (183), while indirubin and indolo [3,2-b]carbazole inhibit the phenotypic maturation of human dendritic cells (324). Additionally, malassezin was proposed to induce apoptosis in human melanocytes, and pityriacitrin was initially shown to have UV radiation-absorbing properties (206,215).…”

“…It seems that the synergy between the indole derivatives found in Malassezia can explain some of the clinical symptoms of pityriasis versicolor, like depigmentation (malassezin), resistance to UV light, and reduced inflammatory reactions (pityriarubins) (151,183).…”