The Entner-Doudoroff (ED) pathway was first discovered in 1952 in Pseudomonas saccharophila (21) and several years later was shown to be present in Escherichia coli (23). Although generally considered to be restricted to gram-negative bacteria, the ED pathway is present in all three phylogenetic domains, including the most deeply rooted Archaea (18). The ubiquity of the ED pathway suggests that it is of far greater importance in nature than was previously recognized. In fact, a recent essay on the evolution of glycolytic pathways suggested that the ED pathway predates the Embden-Meyerhof-Parnas pathway (60). E. coli is generally recognized as a member of the normal gastrointestinal microbiota and is extremely versatile, with the ability to grow on many of the nutrients that can be found there (45). But what exactly are the nutrients preferred by E. coli to support its growth in the intestine? And what about growth of E. coli outside of the intestine? Certainly E. coli spends periods of time in aquatic, aerobic habitats when it is in between host intestinal tracts. Mounting evidence suggests that sugar acid metabolism via the ED pathway is important for growth of E. coli in both intestinal and aquatic habitats. The role of the ED pathway, especially with regard to colonization of the mammalian large intestine, will be discussed below. The biochemistry and physiology of sugar acid metabolism in E. coli are very well understood, and several newly discovered genes encoding sugar acid transporters, associated regulatory proteins, and a novel pathway for sugar acid catabolism have been identified as a result of the E. coli genome project (12). Homology searches reveal that the genes of the ED pathway are present on several other genomes (Table 1), and it is becoming clear that there will be additional, perhaps even novel, sugar acid catabolic pathways revealed by analysis of these genomes. OVERVIEW OF THE ED PATHWAY The ED pathway can be properly considered as one of three pathways found in nature, in addition to the Embden-Meyerhof-Parnas and pentose phosphate pathways, that feed into the “bottom half” of glycolysis, which is central to all of intermediary metabolism (18, 28). The overall schemes of the ED and Embden-Meyerhof-Parnas pathways are quite similar: 6-carbon sugars are primed by phosphorylation and subsequently cleaved by aldolase enzymes into two 3-carbon intermediates (Fig. 1). The primary distinction between the two pathways lies in the nature of the 6-carbon metabolites that serve as substrates for aldol cleavage: for the ED pathway this intermediate is 2-keto-3-deoxy-6-phosphogluconate (KDPG). The first of the two key enzymes is unique to the ED pathway, 6-phosphogluconate dehydratase (Edd), which catalyzes a dehydration of 6-phosphogluconate to form KDPG. The second enzyme of the ED pathway, KDPG aldolase (Eda), catalyzes an aldol cleavage of KDPG to form pyruvate and glyceraldehyde3-phosphate. The triose phosphate intermediate is further metabolized by the glycolytic pathway and provides energy via substrate-level phosphorylation.