Regulation of Sugar Transport and 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和果糖的剩余五个碳原子之间的交替键产生五种蔗糖类似物，分别是海藻糖（1-1）、葡聚糖（1-3）、麦芽糖（1-4）、亮糖（1-5）和巴丁糖（1-6）。值得注意的是，这些同分异构体化合物（与天然双糖相反）不支持口服链球菌的生长。重要的是，这些相对甜的类似物中的两种，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。过去一年的两项主要成就包括首次生物合成蔗糖的所有五种磷酸化异构体，以及证明S6PH不能催化任何这些磷酸化衍生物的水解。这是我们的论点，微妙的构象差异，在紧凑的球形蔗糖分子和线性扩展形式的异构体之间，是基础的底物区分的S6PH。由此推论，我们的发现为合理合成蔗糖类似物提供了见解，通过灭活S6PH，可以选择性靶向和抑制诱导龋齿细菌的生长。

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). Alternate 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). Remarkably, these isomeric compounds (in contrast to the natural disaccharide) do not support growth of oral streptococci. Importantly, 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. Two major accomplishments of the past year include the first biosynthesis of all five phosphorylated isomers of sucrose, and the demonstration that S6PH is unable to catalyze the hydrolysis of any of these phosphorylated derivatives. It is our contention that subtle conformational differences, between the compact globular sucrose molecule and the linearly extended forms of the isomers, are the basis for substrate discrimination by S6PH. By corollary, our findings provide insight to the rational synthesis of sucrose analogs that - by inactivating S6PH - may permit selective targeting and inhibition of growth of caries-inducing bacteria.