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J. Biol. Chem., Vol. 276, Issue 31, 29292-29298, August 3, 2001
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From the Chain lengths and cyclization patterns of
microbial polyketides are generally determined by polyketide synthases
alone. Fungal polyketide melanins are often derived from a pentaketide
1,8-dihydroxynaphthalene, and pentaketide synthases are used for
synthesis of the upstream pentaketide precursor,
1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN). However,
Aspergillus fumigatus, a human fungal pathogen, uses a
heptaketide synthase (Alb1p) to synthesize its conidial pigment through
a pentaketide pathway similar to that which produces
1,8-dihydroxynaphthalene-melanin. In this study we demonstrate that a
novel protein, Ayg1p, is involved in the formation of 1,3,6,8-THN by
chain-length shortening of a heptaketide precursor in A. fumigatus. Deletion of the ayg1 gene prevented the
accumulation of 1,3,6,8-THN suggesting the involvement of
ayg1 in 1,3,6,8-THN production. Genetic analyses of
double-gene deletants suggested that Ayg1p catalyzes a novel biosynthetic step downstream of Alb1p and upstream of Arp2p
(1,3,6,8-THN reductase). Further genetic and biochemical analyses of
the reconstituted strains carrying alb1, ayg1, or
alb1 + ayg1 indicated that Ayg1p is essential for synthesis
of 1,3,6,8-THN in addition to Alb1p. Cell-free enzyme assays, using the
crude Ayg1p protein extract, revealed that Ayg1p enzymatically
shortened the heptaketide product of Alb1p to 1,3,6,8-THN. Thus, the
protein Ayg1p facilitates the participation of a heptaketide synthase
in a pentaketide pathway via a novel polyketide-shortening mechanism in
A. fumigatus.
Pentaketide Melanin Biosynthesis in Aspergillus
fumigatus Requires Chain-length Shortening of a Heptaketide
Precursor*
§,
,,
Laboratory of Clinical Investigation, NIAID,
National Institutes of Health, Bethesda, Maryland 20892-1882, the
¶ Graduate School of Pharmaceutical Sciences, the University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and the ** Cotton
Pathology Research Unit, Agricultural Research Service, United States
Department of Agriculture, College Station, Texas 77845
*
This work was supported in part by Grant-in-Aid 12045213 for
Scientific Research on Priority Area (A) from the Ministry of Education, Sciences, Sports and Culture, Japan.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of the The Japan Society for Promotion of Science
(JSPS ) young research fellowship.
To whom correspondence should be addressed: NIAID, National
Institutes of Health, Bldg. 10, Rm 11C304, 10 Center Dr., MSC 1882, Bethesda, MD 20892-1882. Tel.: 301-496-1602; Fax: 301-402-1003; E-mail: June_Kwon-Chung@nih.gov.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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