Fatty acids metabolism sites

Primary target site may be fatty acid metabolism cell division in root and meristem... 

Cell division inhibitor. Primary target site may be F fatty acid metabolism... 

FIGURE 21.18 A portion of an animal cell, showing the sites of various aspects of fatty-acid metabolism. The cytosol is the site of fatty-acid anabolism. It is also the site of formation of acyl-CoA, which is transported to the mitochondrion for catabolism by the P-oxidation process. Some chainlengthening reactions (beyond Cjg) take place in the mitochondria. Other chain-lengthening reactions take place in the endoplasmic reticulum (ER), as do reactions that introduce double bonds. 

The aim of this study was to determine the organelle and the specific enzymes involved in the two-carbon shortening process of 24 6n-3 to 22 6n-3. We hypothesized that peroxisomes are not only indispensable, but also the exclusive site for the retroconversion step of 22 6n-3 from 24 6n-3 by measuring the rate of synthesis of radiolabeled 22 6n-3 and its intermediates from [l- C]18 3n-3 in human skin fibroblasts from normal controls and patients with disorders of peroxisomal or mitochondrial fatty acid metabolism. An overview of the patient cell lines studied and their biochemical defect related to fatty acid metabolism is given in Table 1. 

In previous reviews [e.g. 1,3] I have described the action of three groups of herbicides on fatty acid metabolism. Thiocarbamates inhibit fatty acid elongation, substituted pyridazinones inhibit some desaturases while grass-specific herbicides have acetyl-CoA carboxylase as their target site. 

Fig. 3.3. Possible roles of intracellular fatty acid-binding proteins (FABP) in fatty acid metabolism. Fatty acids are delivered to cells by extracellular fatty acid-binding proteins (albumin, lipocalins), by very low-density lipoproteins (VLDL) or by chylomicrons (ChM). After internalization, the FABP may bind the non-esterified fatty acid, and may facilitate their transport to appropriate subcellular sites where metabolism takes place.

Figure 3.7 Model of intermolecular fatty acid synthetase mechanism in the a2 2 protomer of yeast. A, acetyl transferase E, enoyl reductase D, dehydratase P, palmitoyl transferase M, malonyl transferase C, 5-ketoacyl synthase R. )5-ketoacyl reductase ACP, acyl carrier protein. Dotted lines and arrows delineate the route taken by intermediates when sequentially processed on different FAS domains. Numbers indicate the reaction sequence. Catalytically active dohnains, at a specific moment, are marked by bold lines. Shaded areas on E and P domains potentially interact by hydrophobic attraction in the presence of palmitate (b). On the protomer depicted in (a) fatty acyl chain elongation occurs in one half of the a2 2 protomer. In (b) chain termination is induced by hydrophobic interaction between E> bound palmitate and P. Subsequently, palmitate Is transferred to Its O-ester binding site on P. Inactivation of the left half of simultaneously activates its right half (b). Redrawn from Schweizer (1984) with permission of the author and Elsevier Science Publishers, BV. From Fatty Acid Metabolism and its Regulation (1984) (ed. S. Numa), p. 73, Figure 7.

The processes of electron transport and oxidative phosphorylation are membrane-associated. Bacteria are the simplest life form, and bacterial cells typically consist of a single cellular compartment surrounded by a plasma membrane and a more rigid cell wall. In such a system, the conversion of energy from NADH and [FADHg] to the energy of ATP via electron transport and oxidative phosphorylation is carried out at (and across) the plasma membrane. In eukaryotic cells, electron transport and oxidative phosphorylation are localized in mitochondria, which are also the sites of TCA cycle activity and (as we shall see in Chapter 24) fatty acid oxidation. Mammalian cells contain from 800 to 2500 mitochondria other types of cells may have as few as one or two or as many as half a million mitochondria. Human erythrocytes, whose purpose is simply to transport oxygen to tissues, contain no mitochondria at all. The typical mitochondrion is about 0.5 0.3 microns in diameter and from 0.5 micron to several microns long its overall shape is sensitive to metabolic conditions in the cell. 

The metabolic breakdown of triacylglycerols begins with their hydrolysis to yield glycerol plus fatty acids. The reaction is catalyzed by a lipase, whose mechanism of action is shown in Figure 29.2. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine residues, which act cooperatively to provide the necessary acid and base catalysis for the individual steps. Hydrolysis is accomplished by two sequential nucleophilic acyl substitution reactions, one that covalently binds an acyl group to the side chain -OH of a serine residue on the enzyme and a second that frees the fatty acid from the enzyme. 

Insulin also plays a role in fat metabolism. In humans, most fatty acid synthesis takes place in the liver. The mechanism of action of insulin involves directing excess nutrient molecules toward metabolic pathways leading to fat synthesis. These fatty acids are then transported to storage sites, predominantly adipose tissue. Finally, insulin stimulates the uptake of amino acids into cells where they are incorporated into proteins. 

Answer C. Insulin increases glucose transport in only two tissues, adipose and muscle. The major site of glucose uptake is muscle, which decreases hyperglycemia. Glucose and ketone transport and metabolism are insulin independent in the brain (choice D). Insulin would slow gluconeogenesis (choice A) and fatty acid release from adipose (choice B). Insulin would inhibit glycogenolysis in the liver (choice E). 

From Nocardia strains several closely related compounds (nocobactins, formo-bactin, amamistatins) were isolated that contain three typically Fe " binding sites, two hydroxamate units, and ahydroxyphenyloxazole stmcture (cf. Sect. 3.2 below). The C-terminus is A-hydroxy-cyc/o-Lys bound to a long chain 3-hydroxy fatty acid, whose hydroxy group is esterified by A -acyl-A -hydroxy-Lys, the a-amino group of which is bound to 2-o-hydroxyphenyl-5-methyl-oxazole-4-carboxylic acid (Table 4). For the amamistatins the configuration of the cyclic lysine was determined as L, the open one as d, and that of C-3 of the fatty acid as (S). The involvement in the iron metabolism was not investigated. 

The eicosanoids are a group of signaling substances that arise from the C-20 fatty acid arachidonic add and therefore usually contain 20 C atoms (Greek eicosa = 20). As mediators, they influence a large number of physiological processes (see below). Eicosanoid metabolism is therefore an important drug target. As short-lived substances, eicosanoids only act in the vicinity of their site of synthesis (paracrine effect see p.372). 

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