Structural basis of lipid biosynthesis regulation in Gram-positive bacteria

Schujman, Gustavo E.; Guerin, Marcelo E.; Buschiazzo, Alejandro; Schaeffer, Francis; Llarrull, Leticia I.; Reh, Georgina; Vila, Alejandro J.; Alzari, Pedro M.; Mendoza, Diego de

doi:10.1038/sj.emboj.7601284

Cited by 101 publications

(165 citation statements)

References 49 publications

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“…Similarly, in light of the observation that malonyl-CoA is a direct and specific inducer of FapR, a conserved and transcriptional repressor that regulates expression of genes involved in de novo lipogenesis and phospholipid synthesis in bacteria [131,132], it is plausible that sequestration of malonyl-CoA by CPT1C may affect gene expression, and therefore, alter ceramide synthesis and/or fatty acid composition in neurons. Thus, some effects of CPT1C may be related to its putative role of regulating malonyl-CoA concentration, which is not only the product of the first reaction of fatty acid synthesis, but may also be a modulator of gene expression.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

105

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

105

101

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“…In bacteria, fatty acid incorporation and degradation are controlled at the transcriptional level. They have been mainly studied in Escherichia coli DiRusso & Nyström, 1998;Marrakchi et al, 2002;Rock & Cronan, 1996;Zhang et al, 2002) and Bacillus subtilis Schujman et al, 2003Schujman et al, , 2006. In E. coli, four regulatory systems, i.e.…”

Section: Introductionmentioning

confidence: 99%

TetR-family transcriptional repressor Thermus thermophilus FadR controls fatty acid degradation

Agari

Sakamoto

et al. 2011

Microbiology

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In the extremely thermophilic bacterium Thermus thermophilus HB8, one of the four TetR-family transcriptional regulators, which we named T. thermophilus FadR, negatively regulated the expression of several genes, including those involved in fatty acid degradation, both in vivo and in vitro. T. thermophilus FadR repressed the expression of the target genes by binding pseudopalindromic sequences covering the predicted "10 hexamers of their promoters, and medium-to-long straight-chain (C10-18) fatty acyl-CoA molecules were effective for transcriptional derepression. An X-ray crystal structure analysis revealed that T. thermophilus FadR bound one lauroyl (C12)-CoA molecule per FadR monomer, with its acyl chain moiety in the centre of the FadR molecule, enclosed within a tunnel-like substrate-binding pocket surrounded by hydrophobic residues, and the CoA moiety interacting with basic residues on the protein surface. The growth of T. thermophilus HB8, with palmitic acid as the sole carbon source, increased the expression of FadR-regulated genes. These results indicate that in T. thermophilus HB8, medium-to-long straight-chain fatty acids can be used for metabolic energy under the control of FadR, although the major fatty acids found in this strain are iso-and anteiso-branchedchain (C15 and 17) fatty acids.

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“…Limited Proteolysis Assays-Purified His 6 -BzdR (10 M) was incubated with trypsin (0.02 mg/ml, Sigma) in 20 l of reaction buffer (25 mM Tris-HCl, pH 7.5, 10 mM CaCl 2 ) in the absence or presence of 2 mM benzoyl-CoA for 0 -60 min at 37°C (45). The reactions were finished by the addition of the stop buffer.…”

mentioning

confidence: 99%

Biochemical Characterization of the Transcriptional Regulator BzdR from Azoarcus sp. CIB

Durante‐Rodríguez

Valderrama

Mancheño

et al. 2010

Journal of Biological Chemistry

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The BzdR transcriptional regulator that controls the P N promoter responsible for the anaerobic catabolism of benzoate in Azoarcus sp. CIB constitutes the prototype of a new subfamily of transcriptional regulators. Here, we provide some insights about the functional-structural relationships of the BzdR protein. Analytical ultracentrifugation studies revealed that BzdR is homodimeric in solution. An electron microscopy three-dimensional reconstruction of the BzdR dimer has been obtained, and the predicted structures of the respective N-and C-terminal domains of each BzdR monomer could be fitted into such a reconstruction. Gel retardation and ultracentrifugation experiments have shown that the binding of BzdR to its cognate promoter is cooperative. Different biochemical approaches revealed that the effector molecule benzoyl-CoA induces conformational changes in BzdR without affecting its oligomeric state. The BzdRdependent inhibition of the P N promoter and its activation in the presence of benzoyl-CoA have been established by in vitro transcription assays. The monomeric BzdR4 and BzdR5 mutant regulators revealed that dimerization of BzdR is essential for DNA binding. Remarkably, a BzdR⌬L protein lacking the linker region connecting the N-and C-terminal domains of BzdR is also dimeric and behaves as a super-repressor of the P N promoter. These data suggest that the linker region of BzdR is not essential for protein dimerization, but rather it is required to transfer the conformational changes induced by the benzoyl-CoA to the DNA binding domain leading to the release of the repressor. A model of action of the BzdR regulator has been proposed.

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Structural basis of lipid biosynthesis regulation in Gram-positive bacteria

Cited by 101 publications

References 49 publications

Carnitine palmitoyltransferase 1C: From cognition to cancer

Carnitine palmitoyltransferase 1C: From cognition to cancer

TetR-family transcriptional repressor Thermus thermophilus FadR controls fatty acid degradation

Biochemical Characterization of the Transcriptional Regulator BzdR from Azoarcus sp. CIB

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