Enhanced fatty acid biosynthesis and normal surfactant secretion in hypertrophic rat type II cells

1991 ◽  
Vol 260 (6) ◽  
pp. L577-L585 ◽  
Author(s):  
J. Rami ◽  
S. M. Sasic ◽  
S. A. Rooney
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Enzyme Activation ◽  
Type Ii Cells ◽  
Type Ii ◽  
Acid Biosynthesis ◽  
Surfactant Secretion ◽  
Phosphatidylcholine Secretion

Silica instillation causes lung surfactant accumulation as well as hyperplasia and hypertrophy of type II pneumocytes. Two populations of type II cells can be isolated from silica-treated rats: type IIA, which are similar to type II cells from normal animals and type IIB, which are larger and have a higher rate of phosphatidylcholine biosynthesis. We have compared fatty acid biosynthesis and phosphatidylcholine secretion in types IIA and IIB cells and in type II cells from control rats. The cells were isolated by elastase digestion and panning on immunoglobulin G-coated plates and fractionated into types IIA and IIB by centrifugal elutriation. Type IIB cells contained more phospholipid and had an enhanced rate of [3H]choline incorporation into phosphatidylcholine. The activity of choline-phosphate cytidylyltransferase was elevated in the type IIB cells and the extent of the increase was diminished when phosphatidylglycerol was included in the assay, suggesting that the enhanced activity was due to enzyme activation rather than protein synthesis. The basal rate of phosphatidylcholine secretion was the same in all three groups as was the response to a variety of secretagogues. Incorporation of [3H]acetate into fatty acids was elevated in type IIB cells and the activity of fatty acid synthase was eightfold greater than in control cells. These data show that de novo fatty acid biosynthesis is increased in hypertrophic type II cells and that surfactant secretion is not elevated.

Fatty-acid synthase activity and mRNA level in hypertrophic type II cells from silica-treated rats

1994 ◽  
Vol 267 (2) ◽  
pp. L128-L136
Author(s):  
J. Rami ◽  
W. Stenzel ◽  
S. M. Sasic ◽  
C. Puel-M'Rini ◽  
J. P. Besombes ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Mrna Level ◽  
Type Ii Cells ◽  
Mrna Levels ◽  
Type Ii ◽  
Maximum Increase

Silica instillation causes a massive increase in lung surfactant. Two populations of type II pneumocytes can be isolated from rats administered silica by intratracheal injection: type IIA cells similar to type II cells from normal rats and type IIB cells, which are larger and contain elevated levels of surfactant protein A and phospholipid. Activities of choline-phosphate cytidylyltransferase, a rate-regulatory enzyme in phosphatidylcholine biosynthesis, and fatty-acid synthase (FAS) are increased in type IIB cells isolated from rats 14 days after silica injection. In the present study, we examined the increase in FAS and cytidylyltransferase activities in type IIB cells as a function of time after silica administration. FAS activity increased rapidly, was approximately threefold elevated 1 day after silica administration and has reached close to the maximum increase by 3 days. Cytidylyltransferase activity was not increased on day 1, was significantly increased on day 3 but was not maximally increased until day 7. Inhibition of de novo fatty-acid biosynthesis, by in vivo injection of hydroxycitric acid and inclusion of agaric acid in the type II cell culture medium, abolished the increase in cytidylyltransferase activity on day 3 but not FAS and had no effect on activities of two other enzymes of phospholipid synthesis. FAS mRNA levels were not increased in type IIB cells isolated 1-14 days after silica injection. These data show that the increase in FAS activity in type IIB cells is an early response to silica, that it mediates the increase in cytidylyltransferase activity, and that it is not due to enhanced FAS gene expression.

scholarly journals Novel inhibitors of the condensing enzymes of the Type II fatty acid synthase of pea (Pisum sativum)

2000 ◽  
Vol 347 (1) ◽  
pp. 205-209 ◽  
Author(s):  
A. Lesley JONES ◽  
Derek HERBERT ◽  
Andrew J. RUTTER ◽  
Jane E. DANCER ◽  
John L. HARWOOD
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Higher Plants ◽  
Acyl Carrier Protein ◽  
Type Ii ◽  
General Activity ◽  
The Individual ◽  
Derivatives Of

The type II fatty acid synthases (FASs) of higher plants (and Escherichia coli) contain three condensing enzymes called β-ketoacyl-ACP synthases (KAS), where ACP is acyl-carrier-protein. We have used novel derivatives of the antibiotic thiolactomycin to inhibit these enzymes. Overall de novo fatty acid biosynthesis was measured using [1-14C]acetate substrate and chloroplast preparations from pea leaves, and [1-14C]laurate was used to distinguish between the effects of the inhibitors on KAS I from those on KAS II. In addition, the activities of these enzymes, together with the short-chain condensing enzyme, KAS III, were measured directly. Six analogues were tested and two, both with extended hydrocarbon side chains, were found to be more effective inhibitors than thiolactomycin. Incubations with chloroplasts and direct assay of the individual condensing enzymes showed that all three compounds inhibited the pea FAS condensing enzymes in the order KAS II > KAS I > KAS III. These results demonstrate the general activity of thiolactomycin and its derivatives against these FAS condensation reactions, and suggest that such compounds will be useful for further detailed studies of inhibition and for use as pharmaceuticals against Type II FASs of pathogens.

Mechanistic diversity and regulation of Type II fatty acid synthesis

2002 ◽  
Vol 30 (6) ◽  
pp. 1050-1055 ◽  
Author(s):  
H. Marrakchi ◽  
Y.-M. Zhang ◽  
C. O. Rock
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Unsaturated Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
Specific Interaction ◽  
Acid Synthesis ◽  
Protein Crystal ◽  
Type Ii ◽  
Acid Biosynthesis

Fatty acid biosynthesis is catalysed in most bacteria by a group of highly conserved proteins known as the Type II fatty acid synthase (FAS) system. The Type II system organization is distinct from its mammalian counterpart and offers several unique sites for selective inhibition by antibacterial agents. There has been remarkable progress in the understanding of the genetics, biochemistry and regulation of Type II FASs. One important advance is the discovery of the interaction between the fatty acid degradation regulator, FadR, and the fatty acid biosynthesis regulator, FabR, in the transcriptional control of unsaturated fatty acid synthesis in Escherichia coli. The availability of genomic sequences and high-resolution protein crystal structures has expanded our understanding of Type II FASs beyond the E. coli model system to a number of pathogens. The molecular diversity among the pathway enzymes is illustrated by the discovery of a new type of enoyl-reductase in Streptococcus pneumoniae [enoyl-acyl carrier protein (ACP) reductase II, FabK], the presence of two enoyl-reductases in Bacillus subtilis (enoyl-ACP reductases I and III, FabI and FabL), and the use of a new mechanism for unsaturated fatty acid formation in S. pneumoniae (trans-2-cis-3-enoyl-ACP isomerase, FabM). The solution structure of ACP from Mycobacterium tuberculosis revealed features common to all ACPs, but its extended C-terminal domain may reflect a specific interaction with very-long-chain intermediates.

scholarly journals A conditional mutant of the fatty acid synthase unveils unexpected cross talks in mycobacterial lipid metabolism

Open Biology ◽  
2017 ◽  
Vol 7 (2) ◽  
pp. 160277 ◽  
Author(s):  
Matías Cabruja ◽  
Sonia Mondino ◽  
Yi Ting Tsai ◽  
Julia Lara ◽  
Hugo Gramajo ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Acid Biosynthesis ◽  
Mycolic Acids ◽  
Storage Lipids ◽  
Conditional Mutant

Unlike most bacteria, mycobacteria rely on the multi-domain enzyme eukaryote-like fatty acid synthase I (FAS I) to make fatty acids de novo. These metabolites are precursors of the biosynthesis of most of the lipids present both in the complex mycobacteria cell wall and in the storage lipids inside the cell. In order to study the role of the type I FAS system in Mycobacterium lipid metabolism in vivo , we constructed a conditional mutant in the fas-acpS operon of Mycobacterium smegmatis and analysed in detail the impact of reduced de novo fatty acid biosynthesis on the global architecture of the cell envelope. As expected, the mutant exhibited growth defect in the non-permissive condition that correlated well with the lower expression of fas-acpS and the concomitant reduction of FAS I, confirming that FAS I is essential for survival. The reduction observed in FAS I provoked an accumulation of its substrates, acetyl-CoA and malonyl-CoA, and a strong reduction of C 12 to C 18 acyl-CoAs, but not of long-chain acyl-CoAs (C 19 to C 24 ). The most intriguing result was the ability of the mutant to keep synthesizing mycolic acids when fatty acid biosynthesis was impaired. A detailed comparative lipidomic analysis showed that although reduced FAS I levels had a strong impact on fatty acid and phospholipid biosynthesis, mycolic acids were still being synthesized in the mutant, although with a different relative species distribution. However, when triacylglycerol degradation was inhibited, mycolic acid biosynthesis was significantly reduced, suggesting that storage lipids could be an intracellular reservoir of fatty acids for the biosynthesis of complex lipids in mycobacteria. Understanding the interaction between FAS I and the metabolic pathways that rely on FAS I products is a key step to better understand how lipid homeostasis is regulated in this microorganism and how this regulation could play a role during infection in pathogenic mycobacteria.

scholarly journals Function of Heterologous Mycobacterium tuberculosis InhA, a Type 2 Fatty Acid Synthase Enzyme Involved in Extending C20 Fatty Acids to C60-to-C90 Mycolic Acids, during De Novo Lipoic Acid Synthesis in Saccharomyces cerevisiae

2008 ◽  
Vol 74 (16) ◽  
pp. 5078-5085 ◽  
Author(s):  
Aner Gurvitz ◽  
J. Kalervo Hiltunen ◽  
Alexander J. Kastaniotis
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipoic Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Biosynthesis ◽  
Mycolic Acids

ABSTRACT We describe the physiological function of heterologously expressed Mycobacterium tuberculosis InhA during de novo lipoic acid synthesis in yeast (Saccharomyces cerevisiae) mitochondria. InhA, representing 2-trans-enoyl-acyl carrier protein reductase and the target for the front-line antituberculous drug isoniazid, is involved in the activity of dissociative type 2 fatty acid synthase (FASII) that extends associative type 1 fatty acid synthase (FASI)-derived C20 fatty acids to form C60-to-C90 mycolic acids. Mycolic acids are major constituents of the protective layer around the pathogen that contribute to virulence and resistance to certain antimicrobials. Unlike FASI, FASII is thought to be incapable of de novo biosynthesis of fatty acids. Here, the genes for InhA (Rv1484) and four similar proteins (Rv0927c, Rv3485c, Rv3530c, and Rv3559c) were expressed in S. cerevisiae etr1Δ cells lacking mitochondrial 2-trans-enoyl-thioester reductase activity. The phenotype of the yeast mutants includes the inability to produce sufficient levels of lipoic acid, form mitochondrial cytochromes, respire, or grow on nonfermentable carbon sources. Yeast etr1Δ cells expressing mitochondrial InhA were able to respire, grow on glycerol, and produce lipoic acid. Commensurate with a role in mitochondrial de novo fatty acid biosynthesis, InhA could accept in vivo much shorter acyl-thioesters (C4 to C8) than was previously thought (>C12). Moreover, InhA functioned in the absence of AcpM or protein-protein interactions with its native FASII partners KasA, KasB, FabD, and FabH. None of the four proteins similar to InhA complemented the yeast mutant phenotype. We discuss the implications of our findings with reference to lipoic acid synthesis in M. tuberculosis and the potential use of yeast FASII mutants for investigating the physiological function of drug-targeted pathogen enzymes involved in fatty acid biosynthesis.

Fatty acid biosynthesis in developing fetal lung

1989 ◽  
Vol 257 (4) ◽  
pp. L195-L201 ◽  
Author(s):  
S. A. Rooney
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Fetal Lung ◽  
Fetal Life ◽  
Acid Biosynthesis ◽  
Ample Evidence ◽  
Phosphatidylcholine Biosynthesis

Fatty acids are integral components of glycerolipids and hence of the phosphatidylcholine-rich pulmonary surfactant. There is ample evidence that the lung is able to synthesize fatty acids de novo. Toward the end of gestation as the fetus prepares for life outside the uterus, there is a surge in phosphatidylcholine synthesis. At the same time there is an increase in de novo fatty acid biosynthesis as well as in the activity of fatty acid synthase, the enzyme that catalyzes the final steps in fatty acid synthesis. Glucocorticoids have long been known to accelerate phosphatidylcholine biosynthesis in the fetal lung and they have also been found to stimulate fatty acid biosynthesis and fatty acid synthase activity. In fact, fatty acid synthase is the first, and so far the only, enzyme involved in lipid biosynthesis to be clearly identified as glucocorticoid inducible in fetal lung. De novo fatty acid biosynthesis may have two important roles relating to surfactant production during late fetal life. In addition to providing fatty acids for incorporation into surfactant phospholipids, recent data suggest that fatty acids may also directly regulate phosphatidylcholine biosynthesis by activation of choline-phosphate cytidylyltransferase, an enzyme catalyzing a rate-limiting step in its biosynthetic pathway.

scholarly journals ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria

Microbiology ◽  
2009 ◽  
Vol 155 (8) ◽  
pp. 2664-2675 ◽  
Author(s):  
Daniel G. Kurth ◽  
Gabriela M. Gago ◽  
Agustina de la Iglesia ◽  
Bernardo Bazet Lyonnet ◽  
Ting-Wan Lin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Active Sites ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Building Blocks ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Minimal Inhibitory Concentrations ◽  
Mycolic Acids

Mycolic acids are essential for the survival, virulence and antibiotic resistance of the human pathogen Mycobacterium tuberculosis. Inhibitors of mycolic acid biosynthesis, such as isoniazid and ethionamide, have been used as efficient drugs for the treatment of tuberculosis. However, the increase in cases of multidrug-resistant tuberculosis has prompted a search for new targets and agents that could also affect synthesis of mycolic acids. In mycobacteria, the acyl-CoA carboxylases (ACCases) provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I products by the FAS II complex to produce meromycolic acids. By generating a conditional mutant in the accD6 gene of Mycobacterium smegmatis, we demonstrated that AccD6 is the essential carboxyltransferase component of the ACCase 6 enzyme complex implicated in the biosynthesis of malonyl-CoA, the substrate of the two FAS enzymes of Mycobacterium species. Based on the conserved structure of the AccD5 and AccD6 active sites we screened several inhibitors of AccD5 as potential inhibitors of AccD6 and found that the ligand NCI-172033 was capable of inhibiting AccD6 with an IC50 of 8 μM. The compound showed bactericidal activity against several pathogenic Mycobacterium species by producing a strong inhibition of both fatty acid and mycolic acid biosynthesis at minimal inhibitory concentrations. Overexpression of accD6 in M. smegmatis conferred resistance to NCI-172033, confirming AccD6 as the main target of the inhibitor. These results define the biological role of a key ACCase in the biosynthesis of membrane and cell envelope fatty acids, and provide a new target, AccD6, for rational development of novel anti-mycobacterial drugs.

Inhibition of early steps of de novo fatty-acid biosynthesis by different xenobiotica

1991 ◽  
Vol 81 (2) ◽  
pp. 251-255
Author(s):  
Manfred Focke ◽  
Andrea Feld ◽  
Hartmut K. Lichtenthaler
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Acid Biosynthesis

scholarly journals Serratia symbiotica Enhances Fatty Acid Metabolism of Pea Aphid to Promote Host Development

2021 ◽  
Vol 22 (11) ◽  
pp. 5951
Author(s):  
Xiaofei Zhou ◽  
Xiaoyu Ling ◽  
Huijuan Guo ◽  
Keyan Zhu-Salzman ◽  
Feng Ge ◽  
...  
Keyword(s):  
Body Weight ◽  
Fatty Acid ◽  
Myristic Acid ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
Acid Biosynthesis ◽  
Pea Aphids ◽  
Serratia Symbiotica ◽  
Aphid Host ◽  
Host Development

Bacterial symbionts associated with insects are often involved in host development and ecological adaptation. Serratia symbiotica, a common facultative endosymbiont harbored in pea aphids, improves host fitness and heat tolerance, but studies concerning the nutritional metabolism and impact on the aphid host associated with carrying Serratia are limited. In the current study, we showed that Serratia-infected aphids had a shorter nymphal developmental time and higher body weight than Serratia-free aphids when fed on detached leaves. Genes connecting to fatty acid biosynthesis and elongation were up-regulated in Serratia-infected aphids. Specifically, elevated expression of fatty acid synthase 1 (FASN1) and diacylglycerol-o-acyltransferase 2 (DGAT2) could result in accumulation of myristic acid, palmitic acid, linoleic acid, and arachidic acid in fat bodies. Impairing fatty acid synthesis in Serratia-infected pea aphids either by a pharmacological inhibitor or through silencing FASN1 and DGAT2 expression prolonged the nymphal growth period and decreased the aphid body weight. Conversely, supplementation of myristic acid (C14:0) to these aphids restored their normal development and weight gain. Our results indicated that Serratia promoted development and growth of its aphid host through enhancing fatty acid biosynthesis. Our discovery has shed more light on nutritional effects underlying the symbiosis between aphids and facultative endosymbionts.

Inhibition of de novo Fatty-Acid Biosynthesis in Isolated Chloroplasts by the Antibiotic Cerulenin and Its Synthetic Derivatives

1992 ◽  
Vol 47 (5-6) ◽  
pp. 382-386 ◽  
Author(s):  
Bernd List ◽  
Andrea Golz ◽  
Wilhelm Boland ◽  
Hartmut K. Lichtenthaler
Keyword(s):  
Fatty Acid ◽  
Inhibitory Activity ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Specific Inhibitor ◽  
Hydrocarbon Chain ◽  
Acetate Incorporation ◽  
Acid Biosynthesis ◽  
Structural Element ◽  
Isolated Chloroplasts

The antibiotic cerulenin was shown to be a potent dose-dependent inhibitor of de novo fattyacid biosynthesis in intact isolated chloroplasts of different plants (measured as [14C]acetate incorporation into the total fatty-acid fraction). Various chemical derivatives of cerulenin were synthesized and tested in the chloroplast assay-system of oat, spinach and pea. Modifications of the hydrocarbon chain of cerulenin (e.g. tetrahydro-cerulenin and its short-chain cis-2,3-epoxy-4-oxoheptanamide derivative) decreased the inhibitory activity of cerulenin, whereas variations of the epoxy-oxo-amide structural element led to a complete loss of inhibition potency. The results indicate that the naturally occurring antibiotic cerulenin is the most active specific inhibitor of de novo fatty-acid biosynthesis, but the formation of the hydroxylactam ring seems to be an essential requirement for the inhibitory activity. Those structural analogues of cerulenin, which can no longer form a hydroxylactam ring, do not possess any inhibitory capacity.

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