Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health. Department of Health and Human Services (contract HHSN266200400001C)National Institutes of Health. Department of Health and Human Services(contract HHSN2722009000018C)Brazil. National Council for Scientific and Technological Developmen

Polymorphic Phase Transition in 4′-Hydroxyacetophenone: Equilibrium Temperature, Kinetic Barrier, and the Relative Stability of <i>Z</i>′ = 1 and <i>Z</i>′ = 2 Forms

Particularly relevant in the context of polymorphism is understanding how structural, thermodynamic, and kinetic factors dictate the stability domains of polymorphs, their tendency to interconvert through phase transitions, or their possibility to exist in metastable states. These three aspects were investigated here for two 4′-hydroxyacetophenone (HAP) polymorphs, differing in crystal system, space group, and number and conformation of molecules in the asymmetric unit. The results led to a Δ_f<i>G</i>_m°-<i>T</i> phase diagram highlighting the enantiotropic nature of the system and the fact that the <i>Z</i>′ = 1 polymorph is not necessarily more stable than its <i>Z</i>′ = 2 counterpart. It was also shown that the form II → form I transition is entropy driven and is likely to occur through a nucleation and growth mechanism, which does not involve intermediate phases, and is characterized by a high activation energy. Finally, although it has been noted that conflicts between hydrogen bond formation and close packing are usually behind exceptions from the hypothesis of <i>Z</i>′ = 1 forms being more stable than their higher <i>Z</i>′ analogues, in this case, the HAP polymorph with stronger hydrogen bonds (<i>Z</i>′ = 2) is also the one with higher density