Metabolism, and Chemical Analysis of Okadaic Acid Group Toxins

Seafood and Freshwater Toxins Pharmacology, Physiology, and Detection 

This review snmmarizes the chemical natnre of OA gronp toxins especially as it relates to toxicity. A brief summary of the chemical nature of PP binding is given. The metabolism of OA gronp toxins is discussed with particular reference to the biotransformations that occur in shellfish. The chapter concludes with a look at analysis of OA gronp toxins and some example protocols are included for convenience. 

OA is a polyether compound containing a 38 carbon backbone. There are 17 chiral centers within the molecule and 3 spiroketal moieties. Of the many fnnctional groups, the C-1 carboxyl terminus and the C-7 hydroxyl gronp are both commonly modified by esterification. The two known natural analogs of OA are 35(R)-methyl OA (DTX-1) and 35(5)-methyl 31-desmethyl OA (DTX-2). The stereochemistry at C-35 has recently been confirmed as R for DTX-1 (Sasaki et al., 1998) and S for DTX-2 (Larsen et al., 2007). This variation in the stereochemistry may explain why DTX-1 and DTX-2 are each known to co-occur with OA but rarely with each other. It has been hypothesized (Larsen et al., 2007) that a specific methylation enzyme is responsible for adding a methyl group at C-35 and that it will add either an equatorial (DTX-1) or an axial methyl (DTX-2). Despite the complicated nature of the task, three full syntheses of OA have been completed (Ichikawa et al., 1987 Ley et al., 1998 Urbanek et al., 1998) and these are worthy of note. 

It is widely accepted that DSP is caused by the inhibition of serine/threonine PPs (for comprehensive review, see Dounay and Forsyth, 2002). In mammalian cells protein phosphatase 1 (PPl) and protein phosphatase 2A (PP2A) are the most common phosphatases however, OA also inhibits a range of other phosphatases including PP3 and PP4. OA, DTX-1, and DTX-2 are potent inhibitors of both PPl and PP2A, with over a thousand times more affinity for PP2A than PPl enzymes (Takai et al., 1992). Table 10.1 shows the relative afhnity of OA, DTX-1, and DTX-2 for a range of 

FIGURE 10.1 The structure of the key OA group toxins. (Courtesy of Dr Chris Miles.) 

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Chemistry, Metabolism, and Chemical Analysis of Okadaic Acid Group Toxins... 

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