A Global Regulator of Secondary Metabolism Gene Clusters

丝状真菌是一种独特的生物，只能与放线菌和植物相媲美，它能产生一系列被称为次生代谢物的天然产物。这些化合物通常在生产生物体中具有模糊或未知的功能，但对人类具有巨大的重要性，因为它们显示出广泛的有用的药物活性以及不太理想的植物和真菌毒性活性。对真菌次生代谢的分子和细胞调控的深入了解主要来自对遗传模型无灰子囊菌（即无灰曲霉）中sterigmatocystin和青霉素的研究。破译sterigmatocystin生物合成调控通道的努力在揭示次生代谢物调控的复杂性方面尤其具有洞察力。与大多数真菌次生生物合成基因一样，sterigmatocystin的生物合成基因是集群的，其转录需要集群中第六个基因的活性，即编码sterigmatocystin特异性C2H6转录因子的aflR。aflR受G蛋白/cAMP/蛋白激酶a信号转导通路成员的转录和转录后调控。这个项目的重点是一个基因，laeA （aflR表达缺失），它是由蛋白激酶a调节的，是aflR转录所必需的。LaeA是一种新型的蛋白甲基转移酶，不仅能调控ST合成基因的表达，还能调控PN合成基因的表达。本研究将探讨LaeA是次生代谢基因簇的全球性调节因子的假设。更广泛的影响：该项目将涉及研究生的培训。这项研究的成果将适用于生物学的几个领域。其中包括食品安全、农业和制药科学、生态学和病理学等多个领域。

Filamentous fungi are unique organisms - rivaled only by Actinomycetes and plants - in producing a wide range of natural products called secondary metabolites. These compounds often have obscure or unknown functions in the producing organism but have tremendous importance to humankind in that they display a broad range of useful pharmaceutical activities as well as less desirable phyto- and mycotoxic activities. Insight into the molecular and cellular regulation of fungal secondary metabolism has come largely from studies of sterigmatocystin and penicillin in the genetic model Ascomycete Emericella nidulans (i.e. Aspergillus nidulans). Efforts on deciphering regulatory conduits of sterigmatocystin biosynthesis have been particularly insightful in revealing the complexity of secondary metabolite regulation. Like most fungal secondary biosynthetic genes, the biosynthetic genes of sterigmatocystin are clustered and their transcription requires activity of the sixth gene in the cluster, aflR encoding a sterigmatocystin-specific C2H6 transcription factor. aflR is both transcriptionally and post-transcriptionally regulated by members of a G protein/cAMP/protein kinase A signal transduction pathway. The focus of this project is a gene, laeA (for loss of aflR expression), that is regulated by protein kinase A and required for aflR transcription. LaeA appears be a novel protein methyltransferase that regulates not only expression of ST biosynthetic genes but also PN biosynthetic genes. This research will explore the hypothesis that LaeA is a global regulator of secondary metabolism gene clusters. Broader Impacts: This project will involve training of graduate students. The outcome of this research will be applicable to several fields of biology. These include diverse fields as food safety, agricultural and pharmaceutical sciences, ecology and pathology.