Metabolism schistosome

Capron, A., Riveau, G.J., Bartley, P.B. and McManus, D.P. (2002) Prospects for a schistosome vaccine. Current Drug Targets of Immune Endocrine and Metabolic Disorders 2, 281-290. 

Although sterols like cholesterol are not synthesized de novo by parasitic flatworms, they do possess an active mevalonate pathway (Fig. 20.3) (reviewed in Coppens and Courtoy, 1996). This pathway has been studied in 5. mansoni, and all available evidence indicates that it is similar to the lipid metabolism seen in F. hepatica. The mevalonate pathway was shown to be used by 5. mansoni for the synthesis of dolichols for protein glycosylation, of quinones as electron transporters in the respiratory chain and of farnesyl and geranylgeranyl pyrophosphates as substrates for the isopreny-lation of proteins (Chen and Bennett, 1993 Foster et a/., 1993). A key enzyme in the mevalonate pathway is 3-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) and it was shown that the schistosomal enzyme differs from the mammalian type, both structurally and in its regulatory properties (Rajkovic et ai, 1989 Chen et at., 1991). Farnesyl pyrophosphate plays a key role in the mevalonate pathway as it is the last common substrate for the synthesis of all end products (Fig. 20.3). As mentioned already, the branch leading from farnesyl pyrophosphate via squalene to cholesterol is not operative in parasitic flatworms, whereas the other branches are active, at least in S. mansoni and probably also in F. hepatica and FI. diminuta. 

A variation of the use of standards is the method in which predetermined quantities of a standard radioactive compound are added to the solution. The fractions are collected, and, by plotting the counts of the fractions, the peak of interest can be identified. This method is especially useful in following cell metabolism of purine and pyrimidine analogs. A plot of the nucleotides in a cell extract of schistosomes containing 14C-labeled adenine and guanine nucleotides is shown in Figure 7.3.5... 

Recently it has been shown that strain differences in helminths may lead to differences in end products. Kolhagen and coworkers [26] found a variation from 30-60% in the production of lactate in different strains of H. diminuta. It has been reported by McManus [27] that carbohydrate metabolism in adult schistosomes may exclusively lead to lactate formation and that homolactate fermentation is not per se essential for generating ATP in these worms. 

A few other less studied biochemical approaches such as purine and pyrimidine metabolism protein biosynthesis and lipid metabohsm in helminths also provide targets for antiparasitic drug design [83]. Like protozoal parasites, some helminths such as S. mansoni (adult and larval forms) lack de novo purine biosynthesis and, therefore, depend entirely on the salvage mechanism for their purine requirements. Similarly amino acid metabolism and biosynthesis of proteins has also been not worked out in many parasites [83a]. Although the helminths meet their requirements of amino acids by absorbing freely from the host, they may also synthesize some amino acids. For example. Fasciola hepatica, schistosomes and other trematodes produce proline by a reaction sequence given in Chart 8. Similarly H. diminuta can... 

The mode of action of this drug is not fully understood. It appears that niridazole inhibits phosphorylase phosphatase with subsequent potentiation of phospho-rylase. This may result in depletion of glycogen levels in the schistosomes. Thus, the major action of niridazole seems to be on the glycogen metabolism of the helminths. The drug also causes structural damage to the reproductive system of female schistosomes [95,96]. 

MH Ali, FP Abramson, DD Ferrerolf, VH Cohn. Metabolism studies of the anti-schistosomal drug praziquantel using tandem mass spectrometry Distribution of parent drug and ten metabolites obtained from control and schistosome-infected mouse urine. Biomed Environ Mass Spectrom 19 186, 1990. 

Metrifonate, which was originally introduced as an organic phosphate insecticide, is a pro-drug for dichlorovos,10 a potent acetylcholinesterase inhibitor (Chapter 8) to which it is nonenzymatically metabolized spontaneously in vitro even at neutral pH (Eq. 7.11). The drug s clinical application is exclusively against S. hematobium infections. Although some effectiveness against other schistosomes exists, this is not achieved at safe doses. 

All adult helminths examined to date contain mitochondria and the role played by oxygen in their metabolism has been a source of debate for a number of years. It is now clear that adult helminths exhibit a wide variation in their ability to use oxygen as a terminal electron acceptor. In general, two basic metabolic plans have emerged. Blood and tissue-dwelling helminths, such as schistosomes and filaria, convert most of their abundant supplies of environmental glucose into lactate and survive well, at least in the... 

Senft, A. W. and Crabtree, G. W. (1983) Purine metabolism in the schistosomes potential targets for chemotherapy. Pharmacol. Ther. 20 341-356. 

This flavoprotein, which catalyzes the oxidative deamination of amines, functions in the breakdown of endogenously produced neurotransmitter amines. Vertebrate monoamine oxidase also catalyzes the oxidation of xenobiotic amines, particularly in tissues such as the intestine (4). Whether the schistosome enzyme is also capable of metabolizing xenobiotics has not been investigated. 

Excretion. There is little information on the role of the trematode gastrodermis in excretion of metabolic end-products. Most excretion is believed to occur by way of the highly developed protonephridial system, which is distinct from the tegument or the gastrodermis. In schistosomes and F. hepatica, the byproducts of erythrocyte... 

To contact host skin and invade, schistosome cercariae follow a thermal gradient and then use an elegantly adapted penetration response triggered by specific fatty acids present on the skin (29-31). Specific free fatty acids like linoleic acid will stimulate cercariae to invade in vitro. Whether this is receptor-mediated is not known, but cercariae can metabolize linoleic acid to eicosanoids (29), which are potential second messengers . Upon stimulation cercariae lose their glyocalyx and tails and release a protease from preacetabular gland cells to facilitate invasion. 

Helminths are characterized by a high rate of carbohydrate metabolism associated with incomplete substrate oxidation. This is the case whether they live anaerobically (as intestinal worms do) or aerobically (like schistosomes). The Meyerhof sequence is the major metabolic pathway in worms for the utilization of carbohydrate. Trehalose (see above) plays an important part in helminth carbohydrate metabolism. For a review of helminth biochemistry, see von Brand (1974). 

---