Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation

Neil English, Colin N.A. Palmer, William L. Alworth, Lan Kang, Valerie Hughes, C. Roland Wolf

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

In previous publications we have demonstrated that peroxisome proliferators and non-steroidal anti-inflammatory drugs are inducers of the cytochrome P-450(BM-3) gene in Bacillus megaterium ATCC14581. Their mechanism of action involves binding to and subsequent displacement of the transcriptional repressor, Bm3R1, from its operator site, which results in the activation of cytochrome P-450(BM-3) gene transcription. We now present evidence that the branched-chain fatty acid, phytanic acid, is a potent inducer of cytochrome P-450(BM-3). We have also observed that phytanic acid and peroxisome proliferators are inducers of Bm3R1 protein accumulation and associated DNA-binding activity. In contrast, several barbiturates, although capable of inducing cytochrome P-450(BM-3) and Bm3R1 gene transcription, were unable to induce the Bm3R1 protein. We also demonstrate that cytochrome P-450(BM-3) readily oxidizes phytanic acid, and provide evidence that, although the ω-1 hydroxy acid derivatives of phytanic acid can associate with Bm3R1, they do so with an affinity two orders of magnitude lower than the unmodified fatty acid. As a consequence, the ability of the hydroxylated product to induce cytochrome P-450(BM-3) gene expression in vivo is markedly reduced. These data collectively suggest that metabolism of fatty acids by cytochrome P-450 leads to an attenuation of their ability to activate the transcription of the BM-3 operon. This work places the action of bacterial fatty acid hydroxylases in an autoregulatory loop where they may be responsible for the inactivation or clearance of the inducing fatty acid signal.

Original languageEnglish
Pages (from-to)363-368
Number of pages6
JournalBiochemical Journal
Volume327
Issue number2
DOIs
Publication statusPublished - 15 Oct 1997

Fingerprint

Bacillus megaterium
Phytanic Acid
Hydroxylation
Bacilli
Cytochrome P-450 Enzyme System
Fatty Acids
Transcription
Peroxisome Proliferators
Genes
Hydroxy Acids
Barbiturates
Operon
Mixed Function Oxygenases
Metabolism
Gene expression
Workplace
Proteins
Anti-Inflammatory Agents
Chemical activation
Derivatives

Cite this

English, Neil ; Palmer, Colin N.A. ; Alworth, William L. ; Kang, Lan ; Hughes, Valerie ; Wolf, C. Roland. / Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation. In: Biochemical Journal. 1997 ; Vol. 327, No. 2. pp. 363-368.
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Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation. / English, Neil; Palmer, Colin N.A.; Alworth, William L.; Kang, Lan; Hughes, Valerie; Wolf, C. Roland.

In: Biochemical Journal, Vol. 327, No. 2, 15.10.1997, p. 363-368.

Research output: Contribution to journalArticle

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T1 - Fatty acid signals in Bacillus megaterium are attenuated by cytochrome P-450-mediated hydroxylation

AU - English, Neil

AU - Palmer, Colin N.A.

AU - Alworth, William L.

AU - Kang, Lan

AU - Hughes, Valerie

AU - Wolf, C. Roland

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N2 - In previous publications we have demonstrated that peroxisome proliferators and non-steroidal anti-inflammatory drugs are inducers of the cytochrome P-450(BM-3) gene in Bacillus megaterium ATCC14581. Their mechanism of action involves binding to and subsequent displacement of the transcriptional repressor, Bm3R1, from its operator site, which results in the activation of cytochrome P-450(BM-3) gene transcription. We now present evidence that the branched-chain fatty acid, phytanic acid, is a potent inducer of cytochrome P-450(BM-3). We have also observed that phytanic acid and peroxisome proliferators are inducers of Bm3R1 protein accumulation and associated DNA-binding activity. In contrast, several barbiturates, although capable of inducing cytochrome P-450(BM-3) and Bm3R1 gene transcription, were unable to induce the Bm3R1 protein. We also demonstrate that cytochrome P-450(BM-3) readily oxidizes phytanic acid, and provide evidence that, although the ω-1 hydroxy acid derivatives of phytanic acid can associate with Bm3R1, they do so with an affinity two orders of magnitude lower than the unmodified fatty acid. As a consequence, the ability of the hydroxylated product to induce cytochrome P-450(BM-3) gene expression in vivo is markedly reduced. These data collectively suggest that metabolism of fatty acids by cytochrome P-450 leads to an attenuation of their ability to activate the transcription of the BM-3 operon. This work places the action of bacterial fatty acid hydroxylases in an autoregulatory loop where they may be responsible for the inactivation or clearance of the inducing fatty acid signal.

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