Sugar Metabolism In Lactic Acid and Oral Bacteria

膳食中的蔗糖是口腔细菌致病性的主要因素。例如，在龋齿的病因学中：(1)蔗糖为多糖的合成提供了基础，从而促进了链球菌物种对牙齿表面的粘附；(2)糖的细菌发酵产生乳酸，导致牙釉质脱矿。蔗糖本身由葡萄糖和果糖分子组成，它们连接在前者的碳原子1和后者的碳原子2之间。蔗糖在转运到细菌的同时被磷酸化，随后被一种称为蔗糖6-磷酸水解酶（S6PH）的酶水解。葡萄糖的C1和果糖的剩余5个碳原子之间的葡萄糖基键的修饰产生5种蔗糖类似物：海藻糖（1-1）、土聚糖（1-3）、麦芽糖（1-4）、亮糖（1-5）和巴氏糖（1-6）。与蔗糖相反，这些同分异构体化合物不支持口腔微生物的生长，包括链球菌。其中两种相对甜的类似物，帕丁糖和亮糖，已经在工业规模上生产，由于它们的无龋齿性，是膳食蔗糖的潜在替代品。为什么像变形链球菌这样的生物体不能代谢蔗糖异构体，这是我们最近研究的一个话题。主要成就包括：(i)发现肺炎克雷伯菌在蔗糖异构体上生长，（ii）首次生物合成了蔗糖的所有五种磷酸化异构体，以及（iii）证明蔗糖-6-磷酸水解酶不能催化任何这些磷酸化衍生物的水解。值得注意的是，同分异构体磷酸盐被NAD和金属依赖的磷酸- α葡萄糖苷酶水解。分子动力学分析表明，紧密球形蔗糖分子的溶液态构象与同分异构体的线性扩展形式之间的差异是两种酶区分底物的基础。我们的研究结果为合理设计和合成蔗糖类似物提供了见解，这些类似物（通过蔗糖-6-磷酸水解酶的失活）可能允许选择性靶向和抑制引起龋齿的细菌（如变形链球菌和sobrinus链球菌）的生长。

Dietary sucrose is a major contributor to pathogenicity of oral bacteria. For example, in the etiology of dental caries : (1) sucrose provides the building blocks for synthesis of glycans that facilitate adherence of Streptococcal species to the tooth surface, and (2) bacterial fermentation of the sugar generates lactic acid that causes demineralization of tooth enamel. Sucrose itself comprises glucose and fructose molecules that are linked between carbon atom 1 of the former and carbon atom 2 of the latter. Sucrose is phosphorylated simultaneously with transport into the bacteria, where it is subsequently hydrolyzed by an enzyme designated sucrose 6-phosphate hydrolase (S6PH). Modification of the glucosyl- linkages between C1 of glucose and the remaining five carbon atoms of fructose yield five analogs of sucrose designated : trehalulose (1-1), turanose (1-3), maltulose (1-4), leucrose (1-5) and palatinose (1-6).In contrast to sucrose, the isomeric compounds do not support growth of oral microorganisms, including streptococcal species. Two of these relatively sweet analogs, palatinose and leucrose, are produced on an industrial scale and - by virtue of their non-cariogenicity - are potential substitutes for dietary sucrose. Why organisms such as Streptococcus mutans fail to metabolize the sucrose isomers has never been established, and is a topic that we have recently addressed. Major accomplishments included:(i) the discovery of growth of Klebsiella pneumoniae on sucrose isomers, (ii) the first biosynthesis of all five phosphorylated isomers of sucrose, and (iii) the demonstration that sucrose-6-phosphate hydrolase is unable to catalyze the hydrolysis of any of these phosphorylated derivatives. Remarkably, the isomeric phosphates are hydrolyzed by an NAD and metal dependent phospho-alpha glucosidase.Molecular dynamics analysis suggests that solution-state conformational differences between the compact globular sucrose molecule, and the linearly extended forms of the isomers, are the basis for substrate discrimination by the two enzymes. Our findings provide insight to the rational design and synthesis of sucrose analogs that (by inactivation of sucrose-6-phosphate hydrolase) may permit selective targeting and inhibition of growth of caries-inducing bacteria such as Streptococcus mutans and Streptococcus sobrinus.