Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
FEMS Yeast Res. 2010 Mar;10(2):199-208. doi: 10.1111/j.1567-1364.2009.00600.x. Epub 2009 Dec 18.
Candida albicans is the principal human fungal pathogen that leads to life-threatening mycoses worldwide. To study its pathobiology, we characterized genes for two enzymes involved in the de novo purine biosynthesis pathway: ADE8 (encoding phosphoribosylglycinamide formyl-transferase) and GUA1 (GMP synthase). Heterozygous and homozygous disruption strains were constructed for both genes. We found that ADE8 and GUA1 are conditionally essential; i.e. can be bypassed in the presence of exogenous adenine and guanine, respectively, and that ADE8 plays an additional role in the C1-folate pool. Furthermore, the heterozygotes of ADE8/ade8 and GUA1/gua1 were hypersensitive to methotrexate (an inhibitor of de novo synthesis of tetrahydrofolate) and 6-azauracil (a known inhibitor of the IMP dehydrogenase involved in GMP biosynthesis), respectively. In a murine model of systemic candidiasis, the virulence of both heterozygous strains was marginally attenuated, while the ade8/ade8 and gua1/gua1 strains were completely avirulent. Our results and those of others indicate that many conditional essential genes involved in different biosynthesis pathways are required for systemic candidiasis, likely due to the host nutritional constraints imposed on the pathogen.
白色念珠菌是导致全球危及生命的真菌感染的主要人类真菌病原体。为了研究其病理生物学特性，我们对参与从头嘌呤生物合成途径的两种酶的基因进行了特征分析：ADE8（编码磷酸核糖基甘氨酰胺基转移酶）和 GUA1（GMP 合酶）。我们构建了这两个基因的杂合子和纯合子缺失菌株。我们发现 ADE8 和 GUA1 是条件必需的；即在存在外源腺嘌呤和鸟嘌呤的情况下可以分别被绕过，并且 ADE8 在 C1-叶酸池中发挥额外的作用。此外，ADE8/ade8 和 GUA1/gua1 的杂合子对甲氨蝶呤（四氢叶酸从头合成的抑制剂）和 6-氮尿嘧啶（一种已知的参与 GMP 生物合成的 IMP 脱氢酶抑制剂）分别敏感。在系统性念珠菌病的小鼠模型中，两种杂合子菌株的毒力都略有减弱，而 ade8/ade8 和 gua1/gua1 菌株则完全丧失了毒力。我们的结果和其他人的结果表明，许多参与不同生物合成途径的条件必需基因是系统性念珠菌病所必需的，这可能是由于宿主对病原体施加的营养限制。
