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First discovery of two polyketide synthase genes for mitorubrinic acid and mitorubrinol yellow pigment biosynthesis and implications in virulence of Penicillium marneffei.

Woo PC, Lam CW, Tam EW, Leung CK, Wong SS, Lau SK, Yuen KY - PLoS Negl Trop Dis (2012)

Bottom Line: Sequence analysis showed that PKS11 and PKS12 are fungal non-reducing PKSs.The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants was significantly better than those challenged with wild type P. marneffei (P<0.05).There was also statistically significant decrease in survival of pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants compared to wild type P. marneffei in both J774 and THP1 macrophages (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.

ABSTRACT

Background: The genome of P. marneffei, the most important thermal dimorphic fungus causing respiratory, skin and systemic mycosis in China and Southeast Asia, possesses 23 polyketide synthase (PKS) genes and 2 polyketide synthase nonribosomal peptide synthase hybrid (PKS-NRPS) genes, which is of high diversity compared to other thermal dimorphic pathogenic fungi. We hypothesized that the yellow pigment in the mold form of P. marneffei could also be synthesized by one or more PKS genes.

Methodology/principal findings: All 23 PKS and 2 PKS-NRPS genes of P. marneffei were systematically knocked down. A loss of the yellow pigment was observed in the mold form of the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants. Sequence analysis showed that PKS11 and PKS12 are fungal non-reducing PKSs. Ultra high performance liquid chromatography-photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry (MS) and MS/MS analysis of the culture filtrates of wild type P. marneffei and the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants showed that the yellow pigment is composed of mitorubrinic acid and mitorubrinol. The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants was significantly better than those challenged with wild type P. marneffei (P<0.05). There was also statistically significant decrease in survival of pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants compared to wild type P. marneffei in both J774 and THP1 macrophages (P<0.05).

Conclusions/significance: The yellow pigment of the mold form of P. marneffei is composed of mitorubrinol and mitorubrinic acid. This represents the first discovery of PKS genes responsible for mitorubrinol and mitorubrinic acid biosynthesis. pks12 and pks11 are probably responsible for sequential use in the biosynthesis of mitorubrinol and mitorubrinic acid. Mitorubrinol and mitorubrinic acid are virulence factors of P. marneffei by improving its intracellular survival in macrophages.

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Related in: MedlinePlus

Survival of mice challenged with wild type P. marneffei or pks11/pks12/pks11pks12 knockdown mutants.Groups of 10 BALB/c mice were challenged intravenously with 8×106 spores. Survival was recorded daily for 60 days.
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pntd-0001871-g005: Survival of mice challenged with wild type P. marneffei or pks11/pks12/pks11pks12 knockdown mutants.Groups of 10 BALB/c mice were challenged intravenously with 8×106 spores. Survival was recorded daily for 60 days.

Mentions: The survival of mice after intravenous challenge with wild type P. marneffei or the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants on day 60 was summarized in Fig. 5. The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants were significantly better than those challenged with wild type P. marneffei (P<0.05).


First discovery of two polyketide synthase genes for mitorubrinic acid and mitorubrinol yellow pigment biosynthesis and implications in virulence of Penicillium marneffei.

Woo PC, Lam CW, Tam EW, Leung CK, Wong SS, Lau SK, Yuen KY - PLoS Negl Trop Dis (2012)

Survival of mice challenged with wild type P. marneffei or pks11/pks12/pks11pks12 knockdown mutants.Groups of 10 BALB/c mice were challenged intravenously with 8×106 spores. Survival was recorded daily for 60 days.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475676&req=5

pntd-0001871-g005: Survival of mice challenged with wild type P. marneffei or pks11/pks12/pks11pks12 knockdown mutants.Groups of 10 BALB/c mice were challenged intravenously with 8×106 spores. Survival was recorded daily for 60 days.
Mentions: The survival of mice after intravenous challenge with wild type P. marneffei or the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants on day 60 was summarized in Fig. 5. The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants were significantly better than those challenged with wild type P. marneffei (P<0.05).

Bottom Line: Sequence analysis showed that PKS11 and PKS12 are fungal non-reducing PKSs.The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants was significantly better than those challenged with wild type P. marneffei (P<0.05).There was also statistically significant decrease in survival of pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants compared to wild type P. marneffei in both J774 and THP1 macrophages (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.

ABSTRACT

Background: The genome of P. marneffei, the most important thermal dimorphic fungus causing respiratory, skin and systemic mycosis in China and Southeast Asia, possesses 23 polyketide synthase (PKS) genes and 2 polyketide synthase nonribosomal peptide synthase hybrid (PKS-NRPS) genes, which is of high diversity compared to other thermal dimorphic pathogenic fungi. We hypothesized that the yellow pigment in the mold form of P. marneffei could also be synthesized by one or more PKS genes.

Methodology/principal findings: All 23 PKS and 2 PKS-NRPS genes of P. marneffei were systematically knocked down. A loss of the yellow pigment was observed in the mold form of the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants. Sequence analysis showed that PKS11 and PKS12 are fungal non-reducing PKSs. Ultra high performance liquid chromatography-photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry (MS) and MS/MS analysis of the culture filtrates of wild type P. marneffei and the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants showed that the yellow pigment is composed of mitorubrinic acid and mitorubrinol. The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants was significantly better than those challenged with wild type P. marneffei (P<0.05). There was also statistically significant decrease in survival of pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants compared to wild type P. marneffei in both J774 and THP1 macrophages (P<0.05).

Conclusions/significance: The yellow pigment of the mold form of P. marneffei is composed of mitorubrinol and mitorubrinic acid. This represents the first discovery of PKS genes responsible for mitorubrinol and mitorubrinic acid biosynthesis. pks12 and pks11 are probably responsible for sequential use in the biosynthesis of mitorubrinol and mitorubrinic acid. Mitorubrinol and mitorubrinic acid are virulence factors of P. marneffei by improving its intracellular survival in macrophages.

Show MeSH
Related in: MedlinePlus