Intracellular Growth Is Dependent on Tyrosine Catabolism in the Dimorphic Fungal Pathogen Penicillium marneffei
Fig 2
A. Tyrosine is catabolised to the toxic compound 4-hydroxyphenylpyruvate by an unknown mechanism. Phenylalanine can be degraded by the prephenate pathway to 4-hydroxyphenylpyruvate. 4-hydroxyphenylpyruvate dioxygenase (HpdA) catalyses the conversion of 4-hydroxyphenylpyruvate to homogentisate. Homogentisate can either be oxidized and polymerized to form the brown pigment pyomelanin or metabolised to 4-maleylacetoacetate by homogentisate 1,2-dioxygenase (HmgA). 4-maleylacetoacetate is metabolised to 4-fumarylacetoacetate by maleylacetoacetate isomerase (MaiA). Fumarlacetoacetate hydrolase (FahA) catalyses the conversion of 4-fumarylacetoacetate to acetoacetate and fumarate, which can be utilized as carbon sources via the TCA cycle. B. Genes required for the catabolism of tyrosine are located in a gene cluster which is conserved in filamentous (Talaromyces stipitatus; Ts, Aspergillus nidulans; An and Aspergillus fumigatus; Af, light grey box) and dimorphic (P. marneffei; Pm, Paracoccidioides brasiliensis; Pb, Coccidioides immitis; Ci, Histoplasma capsulatum; Hc and Blastomyces dermatitidis; Bd, dark grey boxes) fungi. Tyrosine catabolism genes are coloured as follows: hpdA; red, hmgA; blue, hypW; aqua, hmgX; yellow, fahA; green, maiA; pink and hmgR; orange. Flanking genes (PMAA_031940, PMAA_032030, TSTA_065640, TSTA_065560, AN1900, AN1892, AFUA_2G04190, AFUA_2G04270, PADG_08469, PADG_08463, CIMG_01309, CIMG_01315, HCEG_08529, HCEG_08533, HCEG_03254, HCEG_03257, BDDG_05746, BDDG_05738, BDDG_08624 and BDDG_12986) with no characterized role in tyrosine catabolism are shown in grey (same shade if orthologous). hypW is present only in P. marneffei (PMAA_032010) and T. stipitatus (TSTA_065580). A. nidulans contains an internal gene (AN1894) with no characterized role in tyrosine catabolism (light green). T. stipitatus fahA and maiA are misannotated in the Talaromyces stipitatus ATCC 10500 genomic database as a single fused gene named fahA (TSTA_065590). The cluster has been divided into two in H. capsulatum and B. dermatitidis. P. brasiliensis, C. immitis, H. capsulatum and B. dermatitidis lack a hmgR orthologue. Gene orthologues used to generate this Figure are as follows: hpdA (PMAA_031950, TSTA_065630, AN1899, AFUA_2G04200, PADG_08468, CIMG_01310, HCEG_08530 and BDDG_05744), hmgA (PMAA_031960, TSTA_065620, AN1897, AFUA_2G04220, PADG_08466, CIMG_01312, HCEG_08532 and BDDG_05741), hypW (PMAA_031970 and TSTA_065610), hmgX (PMAA_031980, TSTA_065600, AN1898, AFUA_2G04210, PADG_08467, CIMG_01311, HCEG_08531 and BDDG_05742), fahA (PMAA_031990, TSTA_065590, AN1896, AFUA_2G04230, PADG_08465, CIMG_01313, HCEG_03255 and BDDG_08623), maiA (PMAA_032000, AN1895, AFUA_2G04240, PADG_08464, CIMG_01314, HCEG_03256 and BDDG_08618), mfpA (PMAA_031010, TSTS_065580), and hmgR (PMAA_032020, TSTA_065570, AN1893 and AFUA_2G04262).