IMPACT OF SUPEROXIDE ON THE PHYSIOLOGY OF MODEL BACTERIA

氧化应激与多种人类病理学有关。它 也是细菌致病的关键， 微需氧菌的毒力和因为巨噬细胞使用氧化剂 来攻击细菌入侵者因此，重要的是要实现 从分子水平理解氧损伤的机制 细胞和细胞用来保护自己的策略。的 我们实验室的长期目标是使用模型来解决这些问题 细菌作为研究对象。我们目前的目标是： (1)目的：探讨肺动脉高压氧不耐受的分子基础。 多形拟杆菌初步数据显示，B.θ是 部分原因是它的蛋白酶，一种关键的铁， 在空气中失去活性。如果这个想法得到证实， 那么第二个问题将被探讨：为什么空气会这样膨胀？ B中的铁硫团簇。而不是在E。大肠杆菌？ (2)为了解释超氧化物歧化酶缺陷型E. 杆菌SOD突变体不能合成支链氨基酸， 分解代谢不可发酵的碳源， 诱变这些特征已清楚地解释了铁硫 群集损坏。然而，这些突变体还需要减少硫， 芳香族氨基酸间接证据表明， 表型也是从簇损伤进化而来的。 (3)解释了E.大肠杆菌合成两种顺乌头酸酶。在氧化过程中 应力E.大肠杆菌诱导一种抗超氧化物同工酶， 不稳定的一这就引出了一个问题：为什么要保持不稳定的同工酶， 所有的？一个答案可能是微不足道的--初级顺乌头酸酶是 但更有趣的可能性是 在缺铁期间，主要顺乌头酸酶的失活是有益的， 饥饿 (4)为了揭示SoxRS调节子的防御机制， 氧化应激细胞。SoxRS调节子诱导几种酶 这为超氧化物应激细胞提供了明显的益处，但 其他人的目的更模糊。有理由认为， 后一种酶有助于修复受损的铁硫簇。其他，如 作为葡萄糖-6-磷酸脱氢酶，只有当 这些药物的一些毒性来自NADPH耗竭， 而不是活性氧

Oxidative stress has been linked to a variety of human pathologies. It is also critical to bacterial pathogenesis, both because oxygen limits the virulence of microaerophiles and because macrophages use oxidants to attack bacterial invaders. Therefore it is important to achieve a molecular understanding to the mechanisms by which oxygen species damage cells and to the tactics that cells employ to defend themselves. The long-term goal of our lab is to resolve these issues using model bacteria as study subjects. Our current aims are: (1) To explore the molecular basis of the oxygen intolerance of Bacteroides thetaiotaomicron. Preliminary data suggest that B. theta is consigned to anaerobiosis in part because its fumarase, a key iron- sulfur dehydratase, loses activity in air. If this idea is confirmed, then a second problem will be explored: Why does air inactivate such iron-sulfur clusters in B. theta but not in E. coli? (2) To explain unsolved phenotypes of superoxide dismutase-deficient E. coli. SOD mutants cannot synthesize branched-chain amino acids or catabolize non-fermentable carbon sources, and they suffer rapid mutagenesis. These traits have been clearly explained by iron-sulfur cluster damaged. However, these mutants also require reduced sulfur and aromatic amino acids. Circumstantial evidence suggests that these phenotypes, too, evolve from cluster damage. (3) To explain why E. coli synthesizes two aconitases. During oxidative stress E. Coli induces a superoxide-resistant isozyme to replace the labile one. This begs the question: Why maintain a labile isozyme at all? One answer may be trivial--that the primary aconitase is kinetically superior--but a more interesting possibility is that the inactivation of the major aconitase is beneficial during periods of iron starvation. (4) To uncover the mechanisms by which the SoxRS regulon defends oxidatively stressed cells. The SoxRS regulon induces several enzymes that provide obvious benefits to superoxide-stressed cells, but the purposes of others are more obscure. It is plausible that some of the latter enzymes help to repair damaged iron-sulfur clusters. Other, such as glucose-6-phosphate dehydrogenases, may be understandable only if some of the toxicity of these drugs arises from NADPH depletion rather than from reactive oxygen species.