Fatty Acid Synthesis and Metabolism

Acetyl-CoA carboxylase (ACC) catalyses the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA, the rate limiting, first committed step in fatty 

ACC2 selective inhibitors exemplified by 16 (ACC1 IC50 30 gM, ACC2 IC50 38 nM) have also been reported and were shown to reduce malonyl CoA levels in muscle tissues of Sprague-Dawley rats [51]. Although ACC inhibitors have 

SCD1-deficient asebia mice bred onto a leptin-deficient (ob/ob) background show reduced adiposity despite higher food intake and have a corrected hypo-metabolic phenotype, suggesting that down-regulation of SCD1 is an important component of leptin s metabolic actions [79]. SCD1 knockout mice are viable and 

A number of patent applications that describe small molecule inhibitors of SCD-1 have recently published. For example, a series of patent applications describe related piperazine-based inhibitors of SCD-1 (exemplified by 19) [85]. Piperazine replacements, such as piperidine, 4-aminopiperidine, and 3-amino-azetidine are tolerated, as are thiadiazole and pyridine surrogates of the 1,2-diazine [86-90]. 

Constrained variants, such as 20 and 21 have also been reported [91,92], Interestingly, the diazine-amide portion of 19 can be mimicked by the imidazo[l,2-b]pyridazine in 22 [93]. Presently, work in this field remains at a pre-clinical stage. 

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Pantothenic acid Functional part of CoA and acyl carrier protein fatty acid synthesis and metabolism ... 

Essential Fatty Acid Synthesis and Metabolism in the Brain... 

All forms of plant ACP that have been studied are common In their small size (9000 to 11,000 daltons) and In their acidic nature (pH 4.0 -4.2). Acyl carrier proteins have highly conserved structures based both on amino acid sequence homology and antibody cross-reactivity. In addition plant and bacterial acyl carrier proteins can be Interchanged In several reactions of fatty acid synthesis and metabolism (1,7). 

Generally, NAD-linked dehydrogenases catalyze ox-idoreduction reactions in the oxidative pathways of metabolism, particularly in glycolysis, in the citric acid cycle, and in the respiratory chain of mitochondria. NADP-linked dehydrogenases are found characteristically in reductive syntheses, as in the extramitochon-drial pathway of fatty acid synthesis and steroid synthesis—and also in the pentose phosphate pathway. 

Before discussing the specific aspects of regulation of fatty acid metabolism, let us review the main steps in fatty acid synthesis and degradation. Figure 18.18 illustrates these processes in a way that emphasizes the parallels and differences. In both cases, two-carbon units are involved. However, different enzymes and coenzymes are utilized in the biosynthetic and degradative processes. Moreover, the processes take place in different compartments of the cell. The differences in the location of the two processes and in the... 

The synthesis of palmitic acid occurs in the cytosol, from acetyl-CoA. When glucose is abundant and the amount of citrate in the mitochondrial matrix exceeds the demand by the citric acid cycle, the excess citrate is transported out of the mitochondria into the cytosol (Fig. 13-8). Citrate in the cytosol is the source of acetyl groups for fatty acid synthesis, and its metabolism there involves the following enzyme reactions ... 

There is a rapid turnover of phosphopantetheine between AGP and CoA, in response to the metabolic state, and the need for fatty acid synthesis (and thus AGP in the fed state) or fatty acid oxidation (and thus GoAin the fasting state). Apo-AGP has a half-life of 6 to 7 days, whereas the prosthetic group turns over with a half-life of a few hours (Tweto and Larrabee, 1972 Volpe and Vagelos, 1973). 

The main goal of this chapter is to leam how to determine the body s overall style of energy metabolism, via respiratory quotient (RQ) measure-ntents, and to derive the daily energy requirement. A view of the stoichiometries of the glycolytic pathway, Krebs cycle, and pathways of fatty acid synthesis and oxidation will allow RQ calculations for each individual pathway. Glycolysis and the Krebs cycle were presented in Chapter 4, Fatt> add synthesis and oxidation are detailed here. The locations, at points along various metabolic pathways, whereCO2 is produced (in the Krebs cycle) and Oj is consumed (in the respiratory chain), are points of focus in this chapter... 

Niacin is a water-soluble vitamin. The RDA of niacin for the adult man is 19 mg. Niacin is converted in the bi>dy to the cofactor nicotinamide adenine dinucleotide (NAD). NAD also exists in a phosphorylated form, NADP The phosphate group occurs on the 2-hydrr>xyl group of the AMP half of the coenzyme, NAD and NADP are used in the catalysis of oxidation and reduction reactions. These reactions are called redox reactions. NAD cycles between the oxidized form, NAD, and the reduced form, NADH + H. The coenzyme functions to accept and donate electrons. NADP behaves in a similar fashion. It occurs as NADP and NADPH + HT The utilization of NAD is illustrated in the sections on glycolysis, the malatc-aspartate shuttle, ketone body metabolism, and fatty acid oxidation. The utilization of NADP is illustrated in the sectirrns concerning fatty acid synthesis and the pentose phosphate pathway. 

The utilization of NAD is illustrated in the sections on glycolysis, the malate-aspartate shuttle, ketone body metabolism, and fatty acid oxidation. The utilization of NADP is illustrated in the sections concerning fatty acid synthesis and the pentose phosphate pathway. 

ACC is the rate-limiting enzyme in fatty acid synthesis and fatty acid oxidation, and its inhibition is attractive for treatment of metabolic diseases.9 10 Indeed, ACC2 knockout mice are resistant to diet-induced obesity and type 2... 

This disease is of considerable interest in relation to oxypurine metabolism, although a wide variety of potential metabolic abnormalities have been said to be associated with it. In a review in 1961 Tickner (T4) asserted that there was evidence to support the postulate that psoriasis was associated with alterations in lipid, protein, carbohydrate, and mineral metabolism as well as in serum protein level. Investigators have since supported a myriad of hypotheses. Note has been taken of variations in carbohydrate metabolism (R16), and of changes in the synthesis of hyaluronic acid with resultant alterations in transport mechanisms (CIO). Changes in fatty acid levels and metabolism (C8), alterations of aldolase activity (C6), increased proteolytic activity (S33), and alterations in the composition of proteins in psoriatic scales (L20) have been suggested. Changes in serum copper content in psoriatic patients have been observed (L18). 

Tie reactions constitute a metabolic motif that we will see again in fatty acid synthesis and degradation as well as in the degradation of some amino acids. A methylene group (CH2) is converted into a carbonyl group (C=0) in three steps an oxidation, a hydration, and a second oxidation reaction, Oxaloacetate is thereby regenerated for another round of the cycle, and more energy is extracted in the form of FADH and NADH. 

The addition of water to carbon-carbon double bonds is very common to biology, and a large variety of enzymes from different sources representing almost a hundred different hydro-lyase types have been characterized biochemically. Hydro-lyases are for instance involved in the metabolism of a variety of carbohydrates and play a prominent role in fatty acid synthesis and degradation as well. Despite the abundant presence of hydro-lyases in nature, however, applications of these enzymes in organic chemical synthesis are not as widespread. This is mainly due to the limited availability of these enzymes and the fact that many of the enzymes cannot easily be stably maintained during catalysis. 

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