Toxic or Inhibitory Metabolites

There are several examples in which metabolites that toxify the organism responsible for their synthesis are produced. The classic example is fluoroacetate (Peters 1952), which enters the TCA cycle and is thereby converted into fluorocitrate. This effectively inhibits aconitase—the enzyme involved in the next metabolic step—so that cell metabolism itself is inhibited with the resulting death of the cell. Walsh (1982) has extensively reinvestigated the problan and revealed both the complexity of the mechanism of inhibition and the stereospecihcity of the formation of fluorocitrate from fluoroacetate (p. 239). It should be noted, however, that bacteria able to degrade fluoroacetate to fluoride exist so that some organisms have developed the capability for overcoming this toxicity (Meyer et al. 1990). 

The signiflcance of toxic metabolites is important in diverse metabolic situations (a) when a pathway results in the synthesis of a toxic or inhibitory metabolite, and (b) when pathways for the metabolism of two (or more) analogous substrates supplied simultaneously are incompatible due to the production of a toxic metabolite by one of the substrates. A number of examples are provided to illustrate these possibilities that have achieved considerable attention in the context of the biodegradation of chlorinated aromatic compounds (further discussion is given in Chapter 9, Part 1)  

C subfamily of type 1 extradiol dioxygenases (Mars et al. 1999). The alternative extradiol fission of 3-chlorocatechol may take place between the 1 and 6 positions (distal fission), and this has been shown for the 2,3-dihydroxybiphenyl 1,2-dioxygenase from the naphthalene sulfonate degrading Sphingomonas sp. strain BN6 (Riegert et al. 1998). 

There may be several reasons why an analog substrate cannot be metabolized by an organism. This is well illustrated by 4-ethylbenzoate that could not be used by strains that degraded 3- and 4-methylbenzoate (Ramos et al. 1987). There were two reasons  

These limitations could, however, be overcome by the construction of mutant strains. 

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The presence of secondary metabolites in organisms has been proposed as an adaptation against predation [56, 57, 58, 59, 60, 61]. Secondary metabolites, toxic or inhibitory to a range of predators, have been isolated from a whole host of different organisms. Secondary metabolites originating from such diverse organisms as dytiscid beetles, (62], tropical seaweeds [63], gorgonians [64. 65] and sea hares [66] have been shown to exhibit anti-predatory properties. 

Substrate/Product Toxicity. Many volatile organic substrates such as terpenoids can be toxic to the organism and cannot exceed threshold concentration. Many end-products are secondary metabolites with intrinsic toxicological or inhibitory effects on the producing organisms. This can in some cases be minimized by the continuous stripping of finished product from the fermentation broth. 

Bryozoan larvae are often used as test organisms to ascertain activities of extracts from other phyla, but testing bryozoan secondary metabolites for inhibitory or toxic effects on relevant larvae is long overdue. Also it is important not only to consider physical or chemical antifouling strategies in isolation as undoubtedly both mechanisms act in concert. 

Rpnning 0W, Schartum M, Winsnes A Lindberg G (1991) Growth limitation in hybridoma cell cultures the role of inhibitory or toxic metabolites. Cytotech-nology 7 15-24. 

In a homologous series of OP compounds, increasing potency for AChE inhibition and cholinergic toxicity correlates with decreasing potency for NTE inhibition and OPIDN. The relative inhibitory potency (RIP) of an OP compound or its active metabolite for NTE versus AChE in vitro can be used as a convenient index of the probable neuropathic potential of the compound. A commonly used measure of inhibitory potency is the IC50, the concentration required to inhibit 50% of the enzyme activity under a standardized set of reaction conditions and time of incubation of the inhibitor with the enzyme preparation. A better measure of inhibitory potency is the bimolecular rate constant of inhibition, ki. When... 

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

The situation outlined above is subject to dramatic changes in the presence of some transition metal ions. Therefore, as seen for many other phenolics, in the presence of small concentrations of copper or iron ions, a steep increase in the autoxidation rate for HA could be expected. The mechanisms by which copper and iron catalyse the autoxidation of phenolics do not follow the same routes [62], and so, for example in the case of 1,2,4-benzenetriol (a toxic benzene metabolite in the liver), iron(III) was found to be a comparatively inefficient autoxidation catalyst in comparison with copper(II). It is worth noting, however, that in the case of that substrate the addition of SOD shows an inhibitory effect towards autoxidation, evidently because superoxide compulsorily participates as... 

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