Inactivation of Thiolase by 2-Alkynoyl-CoA via Its Intrinsic Isomerase Activity

Wu, Long-Fei; Zeng, Jia; Deng, Guoliang; Guo, Fei; Li, Nan; Liu, Xiaojun; Chu, Xiaoyan; Li, Ding

doi:10.1021/ol0712677

Cited by 5 publications

(2 citation statements)

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“…This 3,4-2,3 isomerization reaction probably was catalyzed by enoyl-CoA isomerase PaaG, which was present in the assay. However, PaaJ itself also may carry out this reaction, because intrinsic isomerase activity has been described for rat liver thiolase (29). Note also that the cis configuration of 2,3-dehydroadipyl-CoA (Fig.…”

Section: Discussionmentioning

confidence: 97%

Bacterial phenylalanine and phenylacetate catabolic pathway revealed

Teufel

Mascaraque²,

Ismail³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

333

363

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Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or styrene) is metabolized by bacteria via phenylacetate. Surprisingly, the bacterial catabolism of phenylalanine and phenylacetate remained an unsolved problem. Although a phenylacetate metabolic gene cluster had been identified, the underlying biochemistry remained largely unknown. Here we elucidate the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida. This strategy is exceptional in several aspects. Intermediates are processed as CoA thioesters, and the aromatic ring of phenylacetyl-CoA becomes activated to a ring 1,2-epoxide by a distinct multicomponent oxygenase. The reactive nonaromatic epoxide is isomerized to a seven-member O-heterocyclic enol ether, an oxepin. This isomerization is followed by hydrolytic ring cleavage and β-oxidation steps, leading to acetyl-CoA and succinyl-CoA. This widespread paradigm differs significantly from the established chemistry of aerobic aromatic catabolism, thus widening our view of how organisms exploit such inert substrates. It provides insight into the natural remediation of man-made environmental contaminants such as styrene. Furthermore, this pathway occurs in various pathogens, where its reactive early intermediates may contribute to virulence.enoyl-CoA hydratase | epoxide | oxepin | oxygenase | phenylacetic acid T he biggest challenge for organisms using aromatic compounds as growth substrates is to overcome the stabilizing resonance energy of the aromatic ring system. This aromatic structure makes the substrates unreactive toward oxidation or reduction and thus requires elaborate degradation strategies. How microorganisms cope with this problem depends primarily on the availability of oxygen (1). Aerobic pathways use oxygen both for hydroxylation and for cleavage of the ring (2, 3). In contrast, under anaerobic conditions the common strategy consists of activation by CoA-thioester formation, shortening of the side chain, and energy-driven ring reduction, which also applies to phenylacetate catabolism (ref. 4 and literature cited therein).The aerobic strategy is illustrated by the metabolism of phenylacetate and phenylacetyl-CoA, which are derived from a variety of substrates such as phenylalanine, lignin-related phenylpropane units, 2-phenylethylamine, phenylalkanoic acids with an even number of carbon atoms, or even environmental contaminants such as styrene and ethylbenzene (5-7). Rarely, phenylalanine is hydroxylated to tyrosine, which can be converted into 4-hydroxyphenylpyruvate, followed by hydroxylation to homogentisate (2,5-dihydroxyphenylacetate) as the central intermediate. The aromatic ring of homogentisate then is split by a ring-cleaving homogentisate dioxygenase, and finally fumarate and acetoacetate are produced (8). In most cases, however, phenylalanine is converted into phenylacetate. A conventional aero...

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Section: Discussionmentioning

confidence: 97%

Bacterial phenylalanine and phenylacetate catabolic pathway revealed

Teufel

Mascaraque²,

Ismail³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

333

363

View full text Add to dashboard Cite

show abstract

“…This result indicates that the triple bond between C-2 and C-3 is mainly responsible for the inhibitory activity of oct-2-yn-4-enoyl-CoA. It should be noted that inactivation of acyl-CoA dehydrogenase by 2-alkynoyl-CoA has been well studied in the past . It has been well demonstrated that the inactivation process involves an initial abstraction of the γ-proton followed by protonation at the α-carbon resulting in formation of 2,3-alkadienoyl-CoA as an active intermediate, which subsequently traps a nucleophile at the active-site resulting in enzyme inactivation.…”

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confidence: 81%