Purple Sweet Potato Colour a Potential Therapy for Galactosemia
Purple sweet potato colour – a potential therapy for galactosemia?
David J Timson*
Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL. UK.
*Author to whom correspondence should be addressed.
Abstract
Galactosemia is an inherited metabolic disease in which galactose is not properly metabolised. There are various theories to explain the molecular pathology, and recent experimental evidence strongly suggests that oxidative stress plays a key role. High galactose diets are damaging to experimental animals and oxidative stress also plays a role in this toxicity which can be alleviated by purple sweet potato colour. This plant extract is rich in acetylated anthocyanins which have been shown to quench free radical production. Thus it is suggested that purple sweet potato colour, or compounds therefrom, may be a viable basis for a novel therapy for galactosemia.
Keywords: galactosemia; galactose 1-phosphate uridylyltransferase deficiency; oxidative stress; anthocyanin; inherited metabolic disease; sweet potato
Abbreviations:
PSPC: Purple sweet potato colour
Galactosemia is an inherited metabolic disease affecting one in 30-60,000 newborns. It is caused by mutations in the genes encoding the enzymes of the Leloir pathway of galactose metabolism (Fridovich-Keil 2006). The most common form is type I, or classical, galactosemia (OMIM #230400). Over 200 mutations in the gene encoding galactose 1-phosphate uridylyltransferasehave been associated with this disease (Bosch 2006; McCorvie and Timson 2011). Types II and III are rarer and are caused by mutations in the galactokinase (OMIM #230200) and UDP-galactose 4’-epimerase (OMIM #230350) genes respectively (Bosch et al. 2002; Timson 2006). The manifestations of the disease vary considerably. The mildest forms have altered blood chemistry and no other detectable pathology. The majority of sufferers will have cataracts in childhood, which can be rectified by surgery. In more severe forms, progressive and irreversible damage to the brain, liver and kidneys occurs through childhood. This damage is associated with ill health and cognitive disability (Bosch et al. 2002; Bosch 2006; Fridovich-Keil 2006).
There is no cure for galactosemia and current therapies rely entirely on diet. To reduce the impact of organ damage, galactose and lactose (a disaccharide of galactose and glucose) are largely removed from the diet (Bosch 2006; Gleason et al. 2000). Critically this means eliminating dairy products and some confectionary. While these diets help minimise the pathology, compliance is often an issue and there appears to be endogenous galactose synthesis in the body which cannot be eliminated.
The molecular causes of pathology are unclear. Although large numbers of disease-associated mutations have been documented there are some common, underlying molecular mechanisms of their impairment. In many cases, the mutation results in a less stable variant of the protein which fails to fold correctly, is more susceptible to proteolysis or forms aggregates (Bang et al. 2009; McCorvie and Timson 2011; McCorvie et al. 2012; McCorvie et al. 2013). This leads to reduced catalytic efficiency and thus reduced throughput in the Leloir pathway. For many years, the build-up of galactose 1-phosphate was believed to be the principal cause of toxicity although the mechanisms of this remain unclear (Bosch et al. 2002; Slepak et al. 2005; Tsakiris et al. 2002). The Leloir pathway enzymes are not only required for the catabolism of galactose but are also involved the biosynthesis of UDP-galactose, UDP-glucose, UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine which are precursors for the synthesis of glycolipids and glycoproteins. Therefore, it has been postulated that improper glycoprotein and glycolipid synthesis may also be implicated in pathology and abnormal glycosylation patterns have been observed in some patients (Liu et al. 2012). More recent work has established that, in a Drosophila melanogaster model for type I galactosemia, oxidative stress resulting from excessive free radical production is a consequence of the build-up of unmetabolised galactose (Jumbo-Lucioni et al. 2013a; Jumbo-Lucioni et al. 2013b).
This partial understanding of the molecular pathology has resulted in some suggestions for improved therapies. Reducing the accumulation of galactose 1-phopshate could be achieved through the inhibition of galactokinase, and some highly selective inhibitors of the human enzyme have been identified (Tang et al. 2012). The observation that many of the disease-associated variant proteins are unstable compared to the wild-type has led to the suggestion that “pharmacological chaperones” (small molecules which stabilise the affected enzyme) could be developed (McCorvie and Timson 2013; McCorvie et al. 2013). However, no such molecules have yet been identified. Free radical scavengers which mimic the action of superoxide dismutase have been shown to alleviate the long-term effects of galactose toxicity in the D. melanogaster model. These manganese-containing porphyrin compounds showed little toxicity and thus have considerable potential as lead compounds for therapeutics(Jumbo-Lucioni et al. 2013b).
It has been shown that naturally occurring plant compounds such as those in purple sweet potato colour (PSPC) mitigate the effects of galactose toxicity in cells (Wu et al. 2008). This appears to be due to regulation of the consequences of oxidative stress. Rats fed on a high d-galactose diet had increased levels of lipid peroxidation in their liver cells; 100 mg PSPC per kg body mass per day reduced this to the same level as seen in the control animals (Zhang et al. 2009). This treatment also increased the activity of protective enzymes such as superoxide dismutase, catalase and glutathione peroxidase (Zhang et al. 2009). The expression of pro-inflammatory molecules such as NF-κB, cyclooxygenase and inducible nitric oxide synthase was reduced (Zhang et al. 2009). Effects were also seen in nerve cells, where PSPC was able to mitigate and reverse damage caused by high d-galactose diets (Lu et al. 2010; Shan et al. 2009; Wu et al. 2008). PSPC is also able to reduce the incidence of d-galactose induced apoptosis (Zhang et al. 2010).
Overall, these results support the hypothesis that high dietary galactose levels result in oxidative stress which can be alleviated by compounds in PSPC. By extension they also support the hypothesis that the molecular pathology of galactosemia results, in part, from oxidative stress resulting from the build-up of galactose. Therefore, it is a reasonable hypothesis that purple sweet potato extracts will have similar effects in animal models of galactosemia as the superoxide dismutase mimics. If so, it would be desirable to identify the active ingredients of the extract and to undertake medicinal chemistry efforts to improve their functionality as in vivo free radical quenchers. The main components of PSPC are acetylated anthocyanins and phenolic compounds (Kano et al. 2005a; Oki et al. 2002). These have been shown to quench free radical production (Kano et al. 2005b; Oki et al. 2002; Philpott et al. 2003).
Sweet potatoes contain relatively low levels of galactose (0.01-0.02 g per 100 g fresh mass) (Kotecha and Kadam 1998) and are already recommended for inclusion in some diets for galactosemia patients (Gleason et al. 2000). Therefore, it may also be worth recommending the inclusion of purple sweet potato in the diets of galactosemic patients. Enhancement of the levels of the active compound and reduction in the galactose levels would be desirable and may be possible through selective breeding programmes(Philpott et al. 2003).
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