Genetics of Fungal Secondary Metabolism

KellerMCB 9874646真菌发育的一个复杂而迷人的方面是天然产物或次级代谢产物的生产。这些化合物-被认为为生产生物体提供适应性属性-对人类具有巨大的重要性，因为它们显示出广泛的有用的抗生素和免疫抑制剂活性以及不太理想的植物和真菌毒性活性。许多精细和翔实的研究已经阐明了独特的生物化学导致真菌中天然产物的形成，但直到最近，真菌次生代谢的分子遗传学一直落后于生物化学。然而，在过去的几年里，在克隆和表征几种真菌天然产物的代谢基因方面取得了重大进展，例如真菌毒素steregrnatocystin和ariatom以及抗生素青霉素。对这些研究结果的检查表明，次生代谢是以生长依赖性方式调节的。后一个特征是极其重要的，因为它在遗传上验证了将形态分化-通常是孢子形成-与真菌中次级代谢的改变相关联的生理和生化研究。这一验证是通过使用构巢曲霉阐明调节真菌中几个分化过程的细胞内信号来实现的。这些信号是异源三聚体G蛋白信号通路的成员，是A. nidulans。此外，A.寄生蜂产孢和产毒。这为真菌分化过程中保守的遗传机制的维持提供了证据。 - 真菌发育的保守调控信号的可能性是一个非常令人兴奋的前景，将在本项目中解决。本研究的长期目标是确定是否有任何细胞内分子作为真菌次生代谢的全局调节剂发挥作用。研究将直接确定调节剂对A. nidulans。这项研究的结果应该有助于控制所需的次级代谢产物（如青霉素）和不需要的次级代谢产物（如杂色曲霉素和ariatoxin）的产生。

KellerMCB 9874646A complex and fascinating aspect of fungal development is the production of natural products, or secondary metabolites. These compounds - thought to provide fitness attributes to the producing organism - have tremendous importance to man in that they display a broad range of useful antibiotic and immunosuppressant activities as well as less desirable phyto- and mycotoxic activities. Many refined and informative studies have elucidated the unique biochemistry leading to natural product formation in fungi but, until recently, the molecular genetics of fungal secondary metabolism has lagged behind the biochemistry. In the last few years, however, significant progress has been made in cloning and characterizing the metabolic genes of several fungal natural products such as the mycotoxins sterigrnatocystin and ariatom and the antibiotic penicillin. Examination of the results of these studies have shown that secondary metabolism is regulated in a growth dependent manner. This latter characteristic is of extreme importance as it genetically validates the physiological and biochemical studies which have correlated morphological differentiation- typically sporulation - to alterations in secondary metabolism in the fungi. This validation was achieved by using Aspergillus nidulans to elucidate intmcellular signals that regulate several differentiation processes in the fungus. The signals, members of a heterotrimeric G protein signaling pathway, are required for sporulation and sterigrnatocystin biosynthesis in A. nidulans. Furthermore, the same heterotrimeric G protein signaling pathway is required for A. parasit~'cus sporulation and ariatoxin production. This provides evidence for the mainte/uance of conserved genetic mechanisms governing fungal differentiation processes. -The possibility of conserved regulatory signals for fungal development is a very exciting prospect that will be addressed in this project. The long term goals of this research are to determine if any intracellular molecules function as global regulators of fungal secondary metabolism. Studies will directly determine the effects of regulators on production of sterigrnatocystin and penicillin in A. nidulans. Results from this study should help in controlling of production of both desired secondary metabolites (like penicillin) and undesired secondary metabolites (like sterigmatocystin and ariatoxin).