Department of Biochemical Sciences, Sapienza University of Rome, Rome.
Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Proteins. 2022 Feb;90(2):435-442. doi: 10.1002/prot.26234. Epub 2021 Sep 16.
Aspergillus fumigatus is a saprophytic ubiquitous fungus whose spores can trigger reactions such as allergic bronchopulmonary aspergillosis or the fatal invasive pulmonary aspergillosis. To survive in the lungs, the fungus must adapt to a hypoxic and nutritionally restrictive environment, exploiting the limited availability of aromatic amino acids (AAAs) in the best possible way, as mammals do not synthesize them. A key enzyme for AAAs catabolism in A. fumigatus is AroH, a pyridoxal 5'-phosphate-dependent aromatic aminotransferase. AroH was recently shown to display a broad substrate specificity, accepting L-kynurenine and α-aminoadipate as amino donors besides AAAs. Given its pivotal role in the adaptability of the fungus to nutrient conditions, AroH represents a potential target for the development of innovative therapies against A. fumigatus-related diseases. We have solved the crystal structure of Af-AroH at 2.4 Å resolution and gained new insight into the dynamics of the enzyme's active site, which appears to be crucial for the design of inhibitors. The conformational plasticity of the active site pocket is probably linked to the wide substrate specificity of AroH.
烟曲霉是一种腐生的无处不在的真菌，其孢子可以引发过敏支气管肺曲霉病或致命的侵袭性肺曲霉病等反应。为了在肺部存活，真菌必须适应低氧和营养受限的环境，以最佳方式利用哺乳动物无法合成的有限芳香族氨基酸（AAAs）。烟曲霉中 AAAs 分解代谢的关键酶是 AroH，一种依赖吡哆醛 5'-磷酸的芳香族氨基转移酶。最近的研究表明，AroH 显示出广泛的底物特异性，除了 AAAs 之外，还可以接受 L-犬尿氨酸和α-氨基己二酸作为氨基供体。鉴于其在真菌适应营养条件方面的关键作用，AroH 代表了针对与烟曲霉相关疾病的创新疗法的潜在目标。我们已经解决了 2.4Å 分辨率的 Af-AroH 晶体结构，并深入了解了酶活性位点的动力学，这对于抑制剂的设计至关重要。活性位点口袋的构象灵活性可能与 AroH 的广泛底物特异性有关。
