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Eukaryotic Cell, October 2008, p. 1699-1711, Vol. 7, No. 10
1535-9778/08/$08.00+0     doi:10.1128/EC.00179-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

New Biosynthetic Step in the Melanin Pathway of Wangiella (Exophiala) dermatitidis: Evidence for 2-Acetyl-1,3,6,8-Tetrahydroxynaphthalene as a Novel Precursor{triangledown}

Michael H. Wheeler,1* Dariusz Abramczyk,2 Lorraine S. Puckhaber,1 Michinori Naruse,3 Yutaka Ebizuka,3 Isao Fujii,4 and Paul J. Szaniszlo2

Cotton Pathology Research Unit, Agricultural Research Service, United States Department of Agriculture, College Station, Texas 77845,1 Section of Molecular Genetics and Microbiology, School of Biological Science and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712,2 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan,3 School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan4

Received 4 June 2008/ Accepted 24 July 2008

The predominant cell wall melanin of Wangiella dermatitidis, a black fungal pathogen of humans, is synthesized from 1,8-dihydroxynaphthalene (D2HN). An early precursor, 1,3,6,8-tetrahydroxynaphthalene (T4HN), in the pathway leading to D2HN is reportedly produced directly as a pentaketide by an iterative type I polyketide synthase (PKS). In contrast, the bluish-green pigment in Aspergillus fumigatus is produced after the enzyme Ayg1p converts the PKS product, the heptaketide YWA1, to T4HN. Previously, we created a new melanin-deficient mutant of W. dermatitidis, WdBrm1, by random molecular insertion. From this strain, the altered gene WdYG1 was cloned by a marker rescue strategy and found to encode WdYg1p, an ortholog of Ayg1p. In the present study, two gene replacement mutants devoid of the complete WdYG1 gene were derived to eliminate the possibility that the phenotype of WdBrm1 was due to other mutations. Characterization of the new mutants showed that they were phenotypically identical to WdBrm1. Chemical analyses of mutant cultures demonstrated that melanin biosynthesis was blocked, resulting in the accumulation of 2-acetyl-1,3,6,8-tetrahydroxynaphthalene (AT4HN) and its oxidative product 3-acetylflaviolin in the culture media. When given to an albino W. dermatitidis strain with an inactivated WdPKS1 gene, AT4HN was mostly oxidized to 3-acetylflaviolin and deacetylated to flaviolin. Under reduced oxygen conditions, cell-free homogenates of the albino converted AT4HN to D2HN. This is the first report of evidence that the hexaketide AT4HN is a melanin precursor for T4HN in W. dermatitidis.

* Corresponding author. Mailing address: Cotton Pathology Research Unit, United States Department of Agriculture, Agricultural Research Service, 2765 F&B Road, College Station, TX 77845. Phone: (979) 260-9516. Fax: (979) 260-9319. E-mail: mwheeler{at}cpru.usda.gov

{triangledown} Published ahead of print on 1 August 2008.

Eukaryotic Cell, October 2008, p. 1699-1711, Vol. 7, No. 10
1535-9778/08/$08.00+0     doi:10.1128/EC.00179-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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