8qd2

Structural highlights

Function

AYG1_ASPFU Heptaketide hydrolyase; part of the gene cluster that mediates the biosynthesis of dihydroxynaphthalene (DHN)-melanin, a bluish-green pigment and a structural component of the conidial wall (PubMed:10515939, PubMed:11350964, PubMed:15310761, PubMed:19156203). The first step of the pathway is the production of the heptaketide naphtopyrone YWA1 by the polyketide synthase alb1 though condensation of acetyl-CoA with malonyl-CoA (PubMed:10515939). The naphtopyrone YWA1 is then converted to the pentaketide 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) by the heptaketide hydrolyase ayp1 though chain-length shortening (PubMed:10515939, PubMed:11350964). 1,3,6,8-THN is substrate of the hydroxynaphthalene reductase arp2 to yield scytalone (PubMed:10515939, PubMed:11350964, PubMed:15310761). The scytalone dehydratase arp1 then reduces scytalone to 1,3,8-THN (PubMed:10515939). 1,3,8-THN is also substrate of the hydroxynaphthalene reductase arp2 to yield vermelone (PubMed:10515939). Vermelone is further converted by the multicopper oxidase abr1 to 1,8-DHN (PubMed:10515939). Finally the laccase abr2 transforms 1,8-DHN to DHN-melanin (PubMed:10515939). DHN-melanin biosynthesis appears to be initiated in endosomes where early enzymes (abl1, ayg1, arp1 and arp2) localize, with exocytosis leading to melanin deposition on the cell surface where late enzymes (abr1 and abr2) localize (PubMed:26972005). DHN-melanin is an important structural component of the outer cell wall and is required for the presence of conidial surface hydrophobins (PubMed:19703288). DHN-melanin also plays a crucial role in fungal virulence, including a protective role against the host's immune defenses (PubMed:19156203, PubMed:20145078, PubMed:21501368, PubMed:21573171, PubMed:21747802, PubMed:24818666). DHN-melanin protects also conidia against amoeba predation (PubMed:25684622).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]}

References

1. ↑ Tsai HF, Wheeler MH, Chang YC, Kwon-Chung KJ. A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J Bacteriol. 1999 Oct;181(20):6469-77. PMID:10515939 doi:10.1128/JB.181.20.6469-6477.1999
2. ↑ Tsai HF, Fujii I, Watanabe A, Wheeler MH, Chang YC, Yasuoka Y, Ebizuka Y, Kwon-Chung KJ. Pentaketide melanin biosynthesis in Aspergillus fumigatus requires chain-length shortening of a heptaketide precursor. J Biol Chem. 2001 Aug 3;276(31):29292-8. PMID:11350964 doi:10.1074/jbc.M101998200
3. ↑ Fujii I, Yasuoka Y, Tsai HF, Chang YC, Kwon-Chung KJ, Ebizuka Y. Hydrolytic polyketide shortening by ayg1p, a novel enzyme involved in fungal melanin biosynthesis. J Biol Chem. 2004 Oct 22;279(43):44613-20. PMID:15310761 doi:10.1074/jbc.M406758200
4. ↑ Jackson JC, Higgins LA, Lin X. Conidiation color mutants of Aspergillus fumigatus are highly pathogenic to the heterologous insect host Galleria mellonella. PLoS One. 2009;4(1):e4224. PMID:19156203 doi:10.1371/journal.pone.0004224
5. ↑ Pihet M, Vandeputte P, Tronchin G, Renier G, Saulnier P, Georgeault S, Mallet R, Chabasse D, Symoens F, Bouchara JP. Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. BMC Microbiol. 2009 Aug 24;9:177. PMID:19703288 doi:10.1186/1471-2180-9-177
6. ↑ Ben-Ami R, Lewis RE, Leventakos K, Latgé JP, Kontoyiannis DP. Cutaneous model of invasive aspergillosis. Antimicrob Agents Chemother. 2010 May;54(5):1848-54. PMID:20145078 doi:10.1128/AAC.01504-09
7. ↑ Volling K, Thywissen A, Brakhage AA, Saluz HP. Phagocytosis of melanized Aspergillus conidia by macrophages exerts cytoprotective effects by sustained PI3K/Akt signalling. Cell Microbiol. 2011 Aug;13(8):1130-48. PMID:21501368 doi:10.1111/j.1462-5822.2011.01605.x
8. ↑ Mech F, Thywissen A, Guthke R, Brakhage AA, Figge MT. Automated image analysis of the host-pathogen interaction between phagocytes and Aspergillus fumigatus. PLoS One. 2011 May 5;6(5):e19591. PMID:21573171 doi:10.1371/journal.pone.0019591
9. ↑ Thywißen A, Heinekamp T, Dahse HM, Schmaler-Ripcke J, Nietzsche S, Zipfel PF, Brakhage AA. Conidial Dihydroxynaphthalene Melanin of the Human Pathogenic Fungus Aspergillus fumigatus Interferes with the Host Endocytosis Pathway. Front Microbiol. 2011 May 3;2:96. PMID:21747802 doi:10.3389/fmicb.2011.00096
10. ↑ Bayry J, Beaussart A, Dufrêne YF, Sharma M, Bansal K, Kniemeyer O, Aimanianda V, Brakhage AA, Kaveri SV, Kwon-Chung KJ, Latgé JP, Beauvais A. Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response. Infect Immun. 2014 Aug;82(8):3141-53. PMID:24818666 doi:10.1128/IAI.01726-14
11. ↑ Hillmann F, Novohradská S, Mattern DJ, Forberger T, Heinekamp T, Westermann M, Winckler T, Brakhage AA. Virulence determinants of the human pathogenic fungus Aspergillus fumigatus protect against soil amoeba predation. Environ Microbiol. 2015 Aug;17(8):2858-69. PMID:25684622 doi:10.1111/1462-2920.12808
12. ↑ Upadhyay S, Xu X, Lowry D, Jackson JC, Roberson RW, Lin X. Subcellular Compartmentalization and Trafficking of the Biosynthetic Machinery for Fungal Melanin. Cell Rep. 2016 Mar 22;14(11):2511-8. PMID:26972005 doi:10.1016/j.celrep.2016.02.059