The metabolic and biochemical impact of glucose 6-sulfonate (sulfoquinovose), a dietary sugar, on carbohydrate metabolism Juliana L. Sacoman ⇑ , Lauren N. Badish, Thomas D. Sharkey, Rawle I. Hollingsworth Department of Biochemistry and Molecular Biology, 603 Wilson Rd., Room 116, Michigan State University, East Lansing, MI 48824, United States article info Article history: Received 10 July 2012 Received in revised form 13 September 2012 Accepted 15 September 2012 Available online 24 September 2012 Keywords: Glucose 6-sulfonate Glucosamine 6-sulfonate Pentose phosphate pathway Sulfoquinovose Metabolism abstract Increased activity of the main carbohydrate pathways (glycolysis, pentose phosphate, and hexosamine biosynthetic pathways) is one of the hallmarks of metabolic diseases such as cancer. Sulfoquinovosyl diac- ylglycerol is a sulfoglycolipid found in the human diet that possesses anticancer activity that is absent when its carbohydrate moiety (glucose 6-sulfonate or sulfoquinovose) is removed. This work used bacte- rial systems to further understand the metabolism of this sugar through three main carbohydrate process- ing pathways and how this could influence its biological activity. Using 13 C NMR spectroscopy and enzyme assays, we showed that glucose 6-sulfonate cannot enter the pentose phosphate pathway, hence decreas- ing pentose and nucleotide biosyntheses. In glycolysis, glucose 6-sulfonate only provides one pyruvate per monosaccharide molecule, decreasing the flux of this pathway by half when compared to glucose 6-phos- phate. Glucose 6-sulfonate can enter the hexosamine biosynthetic pathway by producing glucosamine 6- sulfonate, which is a reported antibacterial agent that competitively inhibits hexosamine production. All these interactions with carbohydrate routes might help explain the observed anticancer activity that glu- cose 6-sulfonate has in vitro. This adds to our knowledge of how vegetables rich in glucose 6-sulfonate can also act as metabolic inhibitors of pathways that are increased in metabolic diseases. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction There is a rising tide of evidence linking the long-term activity in certain carbohydrate processing pathways to the susceptibility to various diseases. In recent times, the focus has been placed on the association between the consumption of large amounts of sim- ple sugars and the prevalence of metabolic disorders 1–4 in which there are alterations in the metabolic activity through the main carbohydrate-processing routes. The three main pathways usually in focus are glycolysis, the pentose phosphate pathway, and the hexosamine biosynthetic pathway. For instance, increased flux through the hexosamine biosynthesis pathway is linked to type 2 diabetes, Alzheimer’s, and cancer. 5–7 Hyperactivity in the pentose phosphate pathway and glycolysis is present in cancer. 8–11 Under- standing the dynamics of the processes between these various pathways and determining ways to apportion the activities be- tween the various branches are critical goals for developing a metabolism-based approach to disease management. An overview of the interconnectivities between these three pathways is de- picted in Figure 1 and reinforces how central carbohydrate chem- istry is in cellular biochemistry. An important way of regulating the level of activity in certain segments of these interconnected chemical processes is through the use of specific chemical inhibitors to reduce flux into particular pathways. A broader strategy is to utilize a dietary carbohydrate that is capable of generating intermediates that inhibit several steps or skewing the activity through one or more pathways. Glucose 6-sulfonate (sulfoquinovose) is an important sugar present in the human diet. It is found in all plants, mostly in the form of sulfoquinovosyl diacylglycerol (SQDG) and it is present in high amounts in spinach, green tea, and other green leaves. 12–14 The availability of glucose 6-sulfonate from some plants can be 10 times larger than some amino acids. 15 In these amounts it can exert a profound influence on carbohydrate metabolism in humans. Not much is known about the metabolism of glucose 6-sulfonate in mammals besides the participation of the microbial flora in the digestive tract being responsible for most of the degradation of SQDG. 16 In bacteria, glucose 6-sulfonate follows a catabolic path in which it is converted to fructose 6-sulfonate and then follows a pathway that is similar to the glycolytic breakdown of fructose 6-phosphate. An important difference is that sulfolactate is formed from one half of the molecule instead of glyceraldehyde 3-phos- phate. 17 There is not much known about the metabolism of glucose 0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.carres.2012.09.014 Abbreviations: DNB-Cl, dinitrobenzoyl chloride; GFAT, glutamine: fructose-6- phosphate amido transferase; G6PDH, glucose-6-phosphate dehydrogenase; NMR, nuclear magnetic resonance; PPP, pentose phosphate pathway; SQDG, sulfoquino- vosyl diacylglycerol. ⇑ Corresponding author. Tel.: +1 517 4321113; fax: +1 517 3539334. E-mail address: sacomanj@msu.edu (J.L. Sacoman). Carbohydrate Research 362 (2012) 21–29 Contents lists available at SciVerse ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres