Nitriles metabolism

FIGURE 17.1 Different pathways of nitrile metabolism in microorganisms. 

Martinkova, L., Vejvoda, V., and Kren, V. 2008. Selection and screening for enzymes of nitrile metabolism. Journal of Biotechnology, 133 318-26. 

Aliphatic nitriles metabolize to cyanide in humans, causing in vivo exposures to workers exposed to these chemicals (O Donoghue 1985). Workers exposed to dimethylaminopropionitrile (DMAPN), an aliphatic nitrile, experienced urinary tract problems with concurrent libido changes, irritability, and insomnia (Keogh et al. 1980 O Donoghue 1985). The authors attributed the symptoms to either DMAPN or other nitriles used in the production process. 

Harris, R. E., A. W. Bunch, and C. J. Knowles, Microbial cyanide and nitrile metabolism. Science Progress Oxford, 71, 293-304 (1987). 

Jenrich, R. et al. (2007) Evolution of hetero-meric nitrilase complexes in Poaceae with new functions in nitrile metabolism. Proc. Natl. Acad. Sci. USA 104, 18848-18853... 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The NHase responsible for aldoxime metabolism from the i -pyridine-3-aldoxime-degrading bacterium, Rhodococcus sp. strain YH3-3, was purified and characterized. Addition of cobalt ion was necessary for the formation of enzyme. The native enzyme had a Mr of 130000 and consisted of two subunits (a-subunit, 27 100 (3-subunit, 34500). The enzyme contained approximately 2 mol cobalt per mol enzyme. The enzyme had a wide substrate specificity it acted on aliphatic saturated and unsaturated as well as aromatic nitriles. The N-terminus of the (3-subunit showed good sequence similarities with those of other NHases. Thus, this NHase is part of the metabolic pathway for aldoximes in microorganisms. 

Harper DB (1977) Microbial metabolism of aromatic nitriles. Enzymology of C-N cleavage by Nocardia sp. (Rhodochrous group) NCIB 11216. Biochem J 165 309-319. 

At the moment, only three in vitro studies have been performed on Bfx metabolic behavior, hi one case, it has been shown that Bfxs are able to be reduced by oxyhemoglobin to the corresponding o-nitroaniline derivatives (Scheme 5) [237]. hi the reaction between compoimd 135 and oxyhemoglobin compound 136 was generated as secondary product resulting from both nitrile hydrolysis and deoxygenation. This study indicates that blood is a possible site for metabolism of Bfxs with the consequent methemoglobinemia. 

Zhou, Z., Hashimoto, Y. and Kobayashi, M. (2005) Nitrile degradation by Rhodococcus useful microbial metabolism for industrial productions. Actinomycetologica, 19, 18-26. 

Tanii H, Hashimoto K. 1986. Influence of ethanol on the in vivo and in vitro metabolism of nitriles in mice. Arch Toxicol 58 171-176. 

Our work on thiolato oxidation is of broader relevance, as there is much current interest in the function of protein cysteinyl sulfenates in signal transduction, oxygen metabolism, oxidative stress, and their role in the activity of nitrile hydratase (98-100). 

Vesey et al. 1976) and a series of commercially important, simple, aliphatic nitriles (e.g., acetonitrile, propionitrile, acrylonitrile, n-butyronitrile, maleonitrile, succinonitrile) (Willhite and Smith 1981) release cyanide upon metabolism. These drugs and industrial chemicals have been associated with human exposure to cyanide and have caused serious poisoning and, in some cases, death. 

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

Soil. In soils, Klebsiella pneu/nonrae metabolized bromoxynil to 3,5-dibromo-4-hydroxybenzoic acid and ammonia (McBride et al., 1986). In soil, bromoxynil undergoes nitrile and then amide hydrolysis yielding 3,5-dibromo-4-hydroxybenzoic acid and 3,5-dibromo-4-hydroxybenzamide (Smith, 1988). Degradation was rapid in a heavy clay soil, sandy loam, and clay loam. After 1 wk, only 10% of the applied dosage was recovered. 

Anchel M, Metabolic products of Clitocybe diatreta. I. Diatretyne amide and diatretyne nitrile. Arch Biochem Biophys 78 100—110, 1958. 

The discovery of a Bacillus sp. strain capable of degrading aldoximes via their conversion to nitriles prompted the isolation and purification of an enzyme capable of producing the syn geometrical isomer of phenylacetaldoxime from A-hydroxy-L-phenylalanine, suggesting that amino acid-derived aldoximes are biosynthesized and metabolized in microorganisms like in plants ". 

Enander, I., Sundwall, A., and Sorbo, B. Metabolic studies on N-methylpyridinium-2-aldoxime. II. The conversion to N-methyl-pyridinium-2-nitrile. Biochem. Pharmacol. 7 232-236, 1961. 

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