The Role of Amino Acid Permeases and Tryptophan Biosynthesis in Cryptococcus neoformans Survival

Autor(es)

Santos Fernandes, Joao Daniel ^{[1, 2]} ; Martho, Kevin ^[2] ; Tofik, Veridiana ^[2] ; Vallim, Marcelo A. ^[2] ; Pascon, Renata C. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Ciencias Biol, Inst Ciencias Ambientais Quim & Farmaceut, Lab Interacoes Microbianas, Lab 29, BR-09972270 Diadema, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 10, n. 7 JUL 10 2015.
• Citações Web of Science: 15

Resumo

Metabolic diversity is an important factor during microbial adaptation to different environments. Among metabolic processes, amino acid biosynthesis has been demonstrated to be relevant for survival for many microbial pathogens, whereas the association between pathogenesis and amino acid uptake and recycling are less well-established. Cryptococcus neoformans is an opportunistic fungal pathogen with many habitats. As a result, it faces frequent metabolic shifts and challenges during its life cycle. Here we studied the C. neoformans tryptophan biosynthetic pathway and found that the pathway is essential. RNAi indicated that interruptions in the biosynthetic pathway render strains inviable. However, auxotroph complementation can be partially achieved by tryptophan uptake when a non preferred nitrogen source and lower growth temperature are applied, suggesting that amino acid permeases may be the target of nitrogen catabolism repression (NCR). We used bioin-formatics to search for amino acid permeases in the C. neoformans and found eight potential global permeases (AAP1 to AAP8). The transcriptional profile of them revealed that they are subjected to regulatory mechanisms which are known to respond to nutritional status in other fungi, such as (i) quality of nitrogen (Nitrogen Catabolism Repression, NCR) and carbon sources (Carbon Catabolism Repression, CCR), (ii) amino acid availability in the extracellular environment (SPS-sensing) and (iii) nutritional deprivation (Global Amino Acid Control, GAAC). This study shows that C. neoformans has fewer amino acid permeases than other model yeasts, and that these proteins may be subjected to complex regulatory mechanisms. Our data suggest that the C. neoformans tryptophan biosynthetic pathway is an excellent pharmacological target. Furthermore, inhibitors of this pathway cause Cryptococcus growth arrest in vitro. (AU)

• Processo FAPESP: 11/51298-4 - Avaliacao dos genes da via de biossintese do triptofano no patogeno oportunista cryptococcus neoformans quanto a sua aplicabilidade como alvo de drogas antifungicas.
• Beneficiário: Renata Castiglioni Pascon
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/50536-3 - Cryptococcus neoformans: estudos da via de transdução de sinal que controla o crescimento a 37 graus empregando ferramentas de biologia molecular, e caracterização epidemiológica molecular e enzimática
• Beneficiário: Marcelo Afonso Vallim
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores