Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering

Beld, Joris; DJ, Lee; Burkart, Michael D.

doi:10.1039/c4mb00443d

Cited by 167 publications

(162 citation statements)

References 274 publications

(421 reference statements)

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“…Cytosolic acetyl-CoA is also used by acetyl-CoA carboxylase to yield malonyl-CoA, a precursor for de novo synthesis of fatty acids (25,26). We have previously shown that acetyl-CoA carboxylase Acc1p regulates homeostasis of nucleocytosolic acetyl-CoA and acetylation of histones and nonhistone proteins in yeast (13).…”

Section: Resultsmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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Edited by Alex TokerAMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetylCoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects.Acetylation is one of the epigenetic post-translational modifications of histones; it affects chromatin structure and regulates diverse cellular functions, such as gene expression, DNA replication and repair, and cellular proliferation (1, 2). Acetylation and deacetylation of chromatin histones, mediated by histone acetyltransferases (HATs) 3 and histone deacetylases (HDACs), respectively, represent the major mechanisms for epigenetic gene regulation. The dynamic balance between histone acetylation and deacetylation, mediated by the activities of HATs and HDACs, is stringently regulated in healthy cells but is often dysregulated in cancer (3, 4).Histone acetylation depends on intermediary metabolism for supplying acetyl-CoA in the nucleocytosolic compartment (5). In mammalian cells, the nucleocytosolic enzyme ATP-citrate lyase is the major source of acetyl-CoA for histone acetylation (6). Another mechanism for generation of acetyl-CoA in the nucleus involves translocation of pyruvate dehydrogenase from mitochondria to the nucleus (7). In yeast, global histone acetylation depends on nucleocytosolic acetyl-CoA produced by acetyl-CoA synthetase (5). In both yeast and mammalian cells, the nucleocytosolic acetyl-CoA is the link among cellular energy, carbon metabolism, histone acetylation, ...

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Section: Resultsmentioning

confidence: 99%

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Galdieri¹,

Gatla

Vancurova

et al. 2016

Journal of Biological Chemistry

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“…A wide range of these compounds has known biological sources, since they serve a variety of purposes, e.g., in cell walls, membranes, and protein modifications, but also as energy storage, such as triacylglycerides, as building blocks for primary and 10 secondary metabolites, or even as messenger molecules. 18,47 Previous studies have shown that lipids, such as phospholipids, glycolipids, and triacylglycerides, are released after cell lysis of phytoplankton cells into the bulk water. Subsequent enzymatic digestion then leads to formation of saturated and unsaturated fatty acids.…”

Section: Resultsmentioning

confidence: 99%

Interfacial photochemistry of biogenic surfactants: a major source of abiotic volatile organic compounds

et al. 2017

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15Films of biogenic compounds exposed to the atmosphere are ubiquitously found on surfaces of cloud droplets, aerosol particles, buildings, plants, soils, and the ocean. These air/water interfaces host countless amphiphilic compounds concentrated there with respect to bulk water, leading to a unique chemical environment. Here, photochemical processes at the air/water interface of biofilmcontaining solutions were studied, demonstrating abiotic VOC production from authentic biogenic 20 surfactants under ambient conditions. Using a combination of online-APCI-HRMS and PTR-ToF-MS, unsaturated and functionalized VOCs were identified and quantified, giving emission fluxes comparable to previous field and laboratory observations. Interestingly, VOC fluxes increased with the decay of microbial cells in the samples, indicating that cell lysis due to cell death was the main source for surfactants, and VOC production. In particular, irradiation of samples containing solely 25 biofilm cells without matrix components exhibited the strongest VOC production upon irradiation. In agreement with previous studies, LC-MS measurements of the liquid phase suggested the presence of fatty acids and known photosensitizers, possibly inducing the observed VOC production via peroxy-radical chemistry. Up to now such VOC emissions were directly accounted to high biological activity in surface waters. However, the obtained results suggest that abiotic photochemistry can 30 lead to similar emissions into the atmosphere, especially in less biologically-active regions.Furthermore, chamber experiments suggested that oxidation (O 3 /OH-radicals) of the photochemically-produced VOCs leads to aerosol formation and growth, possibly affecting 2 atmospheric chemistry and climate-related processes, such as cloud formation or the Earth's radiation budget. 3 IntroductionAir/water interfaces are omnipresent in the ambient atmosphere, reaching from the nm-scale for single aerosol particles to the surface of the ocean, which covers more than 70% of the Earth's surface. In the past, it was shown that unique photochemical reactions with significant implications for atmospheric processes can occur at such interfaces, leading to the formation of volatile organic 5 compounds (VOCs) 1-5 and secondary organic aerosols, 6 or acting as sinks for reactive species, such as NO 2 or ozone. [7][8][9][10] This interfacial photochemistry is exclusively due to the presence of surfactants which tend to concentrate in surface layers with respect to the underlying bulk water. Additionally, such surfactants also increase the propensity of less surface-active compounds to enrich there as well, creating a unique chemical environment, affecting not only chemistry but also trace-gas 10 exchange. 5,[10][11][12][13][14][15][16] A major source of biogenic surfactants in the ambient environment are so-called biofilms, loosely defined as a population of microorganisms (i.e., fungi, algae, archaea) that accumulate at an interface. In addition, such microorganisms can also form cel...

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“…It should be noted that the octanoyl precursor of lipoate is synthesized by a type II fatty acid synthesis system. Such systems, in which each step of fatty acid synthesis is catalyzed by discrete individual proteins, have been studied most thoroughly in bacteria, where they provide all of the fatty acid moieties (97). In eukaryotes, mitochondria and plant plastids (such as chloroplasts) contain type II fatty acid synthesis systems encoded by nuclear genes with the proteins targeted to the organelle, usually by N-terminal sequences.…”

Section: Biosynthesis Of Lipoic Acidmentioning

confidence: 99%

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

Cronan

2016

Microbiol Mol Biol Rev

124

137

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SUMMARYAlthough the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis of this universally conserved cofactor have become understood. Unlike most cofactors, lipoic acid must be covalently bound to its cognate enzyme proteins (the 2-oxoacid dehydrogenases and the glycine cleavage system) in order to function in central metabolism. Indeed, the cofactor is assembled on its cognate proteins rather than being assembled and subsequently attached as in the typical pathway, like that of biotin attachment. The first lipoate biosynthetic pathway determined was that ofEscherichia coli, which utilizes two enzymes to form the active lipoylated protein from a fatty acid biosynthetic intermediate. Recently, a more complex pathway requiring four proteins was discovered inBacillus subtilis, which is probably an evolutionary relic. This pathway requires the H protein of the glycine cleavage system of single-carbon metabolism to form active (lipoyl) 2-oxoacid dehydrogenases. The bacterial pathways inform the lipoate pathways of eukaryotic organisms. Plants use theE. colipathway, whereas mammals and fungi probably use theB. subtilispathway. The lipoate metabolism enzymes (except those of sulfur insertion) are members of PFAM family PF03099 (the cofactor transferase family). Although these enzymes share some sequence similarity, they catalyze three markedly distinct enzyme reactions, making the usual assignment of function based on alignments prone to frequent mistaken annotations. This state of affairs has possibly clouded the interpretation of one of the disorders of human lipoate metabolism.

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Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering

Cited by 167 publications

References 274 publications

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells

Interfacial photochemistry of biogenic surfactants: a major source of abiotic volatile organic compounds

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

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