Phylogenetic and preliminary phenotypic analysis of yeast PAQR receptors: potential antifungal targets.
Proteins belonging to the Progestin and AdipoQ Receptor (PAQR) superfamily of membrane bound receptors are ubiquitously found in fungi. Nearly, all fungi possess two evolutionarily distinct paralogs of PAQR protein, which we have called the PQRA and PQRB subtypes. In the model fungus Saccharomyces cerevisiae, these subtypes are represented by the Izh2p and Izh3p proteins, respectively. S. cerevisiae also possesses two additional PQRA-type receptors called Izh1p and Izh4p that are restricted to other species within the "Saccharomyces complex". Izh2p has been the subject of several recent investigations and is of particular interest because it regulates fungal growth in response to proteins produced by plants and, as such, represents a new paradigm for interspecies communication. We demonstrate that IZH2 and IZH3 gene dosage affects resistance to polyene antifungal drugs. Moreover, we provide additional evidence that Izh2p and Izh3p negatively regulate fungal filamentation. These data suggest that agonists of these receptors might make antifungal therapeutics, either by inhibiting fungal development or by sensitizing fungi to the toxic effects of current antifungal therapies. This is particularly relevant for pathogenic fungi such as Candida glabrata that are closely related to S. cerevisiae and contain the same complement of PAQR receptors.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610-0485, USA.
Nancy Y
NY
Villa
Patricia
P
Moussatche
Stephen G
SG
Chamberlin
Anuj
A
Kumar
Thomas J
TJ
Lyons
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000494:pharmacology; D058674:Chromosome Duplication; D015825:Chromosomes, Fungal / Q000235:genetics; D017124:Conserved Sequence; D025141:Drug Resistance, Fungal; D019143:Evolution, Molecular; D018628:Gene Dosage; D016681:Genome, Fungal; D057927:Hydrophobic and Hydrophilic Interactions; D025301:Hyphae / Q000254:growth & development / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009761:Nystatin / Q000494:pharmacology; D010641:Phenotype; D010802:Phylogeny; D011090:Polyenes / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000935:Antifungal Agents; C497767:IZH2 protein, S cerevisiae; C571172:Izh3 protein, S cerevisiae; D008565:Membrane Proteins; D011090:Polyenes; D011956:Receptors, Cell Surface; D029701:Saccharomyces cerevisiae Proteins; D009761:Nystatin