Homology modeling and docking studies of FabH (β-ketoacyl-ACP synthase III) enzyme involved in type II fatty acid biosynthesis ofChlorella variabilis: a potential algal feedstock for biofuel production

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.

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Mechanistic diversity and regulation of Type II fatty acid synthesis

Biochemical Society Transactions ◽

10.1042/bst0301050 ◽

2002 ◽

Vol 30 (6) ◽

pp. 1050-1055 ◽

Cited By ~ 76

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.

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Advances on Mechanism and Drug Discovery of Type-II Fatty Acid Biosynthesis Pathway

Acta Chimica Sinica ◽

10.6023/a20070299 ◽

2020 ◽

Vol 78 (12) ◽

pp. 1383

Author(s):

Jiashen Zhou ◽

Lin Zhang ◽

Liang Zhang

Keyword(s):

Fatty Acid ◽

Drug Discovery ◽

Fatty Acid Biosynthesis ◽

Type Ii ◽

Biosynthesis Pathway ◽

Acid Biosynthesis ◽

Fatty Acid Biosynthesis Pathway

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The Structure of (3R)-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) fromPseudomonas aeruginosa

Journal of Biological Chemistry ◽

10.1074/jbc.m408105200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52593-52602 ◽

Cited By ~ 91

Author(s):

Matthew S. Kimber ◽

Fernando Martin ◽

Yingjie Lu ◽

Simon Houston ◽

Masoud Vedadi ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Biosynthesis ◽

Acyl Carrier Protein ◽

Site Directed Mutagenesis ◽

Isomerization Reaction ◽

Antibacterial Drug ◽

Carrier Protein ◽

Type Ii ◽

Active Site Residues ◽

Acid Biosynthesis

Type II fatty acid biosynthesis systems are essential for membrane formation in bacteria, making the constituent proteins of this pathway attractive targets for antibacterial drug discovery. The third step in the elongation cycle of the type II fatty acid biosynthesis is catalyzed by β-hydroxyacyl-(acyl carrier protein) (ACP) dehydratase. There are two isoforms. FabZ, which catalyzes the dehydration of (3R)-hydroxyacyl-ACP totrans-2-acyl-ACP, is a universally expressed component of the bacterial type II system. FabA, the second isoform, as has more limited distribution in nature and, in addition to dehydration, also carries out the isomerization oftrans-2- tocis-3-decenoyl-ACP as an essential step in unsaturated fatty acid biosynthesis. We report the structure of FabZ from the important human pathogenPseudomonas aeruginosaat 2.5 Å of resolution.PaFabZ is a hexamer (trimer of dimers) with the His/Glu catalytic dyad located within a deep, narrow tunnel formed at the dimer interface. Site-directed mutagenesis experiments showed that the obvious differences in the active site residues that distinguish the FabA and FabZ subfamilies of dehydratases do not account for the unique ability of FabA to catalyze isomerization. Because the catalytic machinery of the two enzymes is practically indistinguishable, the structural differences observed in the shape of the substrate binding channels of FabA and FabZ lead us to hypothesize that the different shapes of the tunnels control the conformation and positioning of the bound substrate, allowing FabA, but not FabZ, to catalyze the isomerization reaction.

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