Fatty Acid Synthesis. Molecular Biochemistry IIContents of this page: Synthesis of malonyl- Co. A via Acetyl- Co. A Carboxylase. Fatty Acid Synthase. Fatty acid elongation and. The input to fatty acid synthesis is acetyl- Co. A. which is carboxylated to malonyl- Co. A. The CO2 is lost. The spontaneous. decarboxylation. Acetyl- Co. A Carboxylase catalyzes the 2- step reaction. Co. A is carboxylated to form. Co. A. ATP- dependent carboxylation of the biotin, carried out at one active site. Co. A at a second active site (2). Regulation of acetyl-CoA carboxylase R.W.The mammalian enzyme. Conformational changes associated with regulation: When in the active conformation. Acetyl- Co. A Carboxylase self- associates to form multimeric filamentous complexes. See electron micrograph p.
Biochemistry, 3rd Edition, by Voet & Voet. Transition to the inactive conformation. AMP functions as an energy sensor and. When ATP production does not keep up with needs, a. AMP. For example, AMP regulates. Co. A. AMP- Activated Kinase. Acetyl- Co. A Carboxylase. ATP- utilizing. production of malonyl- Co. A . Fatty acid synthesis is diminished by. Co. A. Fatty acid oxidation is stimulated due to. Physiological Regulation of Acetyl-Coa Carboxylase Gene-Expression. Effects of Diet, Diabetes, and Lactation on Acetyl-Coa Carboxylase Messenger-Rna. Regulation of Acetyl-CoA Carboxylase by local metabolites: Palmitoyl-CoA, the product of Fatty Acid Synthase. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats Geraldine Harrimana, Jeremy. Acetyl-CoA carboxylase. Co. A of transfer of fatty acids into. A cyclic- AMP. cascade, activated by the hormones glucagon and epinephrine when blood. Acetyl- Co. A Carboxylase. AMP- Dependent Protein Kinase. The antagonistic. Protein Phosphatase. Regulation of. Acetyl- Co. A Carboxylase by local metabolites: Palmitoyl- Co. A, the product of Fatty. Acid Synthase, promotes the inactive. Acetyl- Co. A Carboxylase (diagram above), diminishing production. Co. A, the precursor of fatty acid synthesis. This is an example. Citrate allosterically activates Acetyl- Co. A. Carboxylase. Excess acetyl- Co. A. is then converted via malonyl- Co. A to fatty acids for storage. NADPH as electron donor in the two reactions involving substrate reduction. The NADPH is produced mainly by the. Phosphate Pathway. Prosthetic groups of Fatty Acid. Synthase include: the thiol. Condensing Enzyme domain of the complex. The long flexible arm of. Individual steps of the reaction pathway are catalyzed by the. Fatty Acid Synthase, listed in the diagrams below. As each of the substrates acetyl- Co. A and. malonyl- Co. A bind to the complex (designated steps 1 & 2), the initial attacking group is the oxygen. Malonyl/acetyl- Co. A Transacylase. enzyme domain. Each acetyl or malonyl moiety is transiently in. ACP) domain. Acetate is subsequently. Condensing Enzyme domain. The condensation reaction (step 3). In. steps 4- 6, the b- ketone is reduced to an alcohol, by. NADPH. Dehydration yields a trans double bond. Reduction at the double bond by NADPH yields a saturated chain. Following transfer of the growing fatty acid from. Condensing Enzyme's cysteine sulfhydryl, the cycle begins again, with. Co. A. Product. release: When the fatty acid is 1. Thioesterase domain catalyzes hydrolysis of. The 1. 6- C. saturated fatty acid palmitateis the. Fatty Acid Synthase complex. Fatty Acid Synthase in mammals is a. X- Ray crystallographic analysis at. Each copy of the dimeric. S shape, with the. N- terminal KS (Condensing. Enzyme / b- Ketoacyl Synthase) domain folded. The X- ray analysis does not resolve the C- terminal ACP (acyl carrier protein) and. Thioesterase domains, which are. Ketoacyl Reductase (KR) domains. These domains may be too flexible to be resolved by. There is evidence for. Protein flexibility may facilitate transfer of. ACP- attached reaction intermediates among the several active sites in. Mammalian Fatty Acid. Synthase. Summary of fatty acid synthesis (ignoring H+ and water): acetyl- Co. A + 7 malonyl- Co. A + 1. 4 NADPH. Acetyl- Co. A generated. in the mitochondria is transported to the cytosol via a shuttle. Fatty acid synthesis and b- oxidation. Oxidation Pathway. Fatty Acid Synthesispathwaylocation mitochondrial matrixcytosolacyl. Coenzyme- A phosphopantetheine (ACP) & cysteineelectron. FAD & NAD+NADPHhydroxylintermediate. LD2- C product/donoracetyl- Co. Amalonyl- Co. A (& acetyl- Co. A) Acid Synthase is. Transcription. factors that that mediate the stimulatory effect of insulin include USFs. SREBP- 1. SREBPs (sterol response element. Polyunsaturated fatty acidsdiminish. Fatty Acid Synthase gene in liver cells, by suppressing. SREBPs. In fat cells: Expression of SREBP- 1 and of Fatty Acid Synthase is inhibited. Leptin is produced by. Leptin regulates body weight by decreasing. Elongation. beyond the 1. C length of the palmitate product of Fatty Acid Synthase is mainly. ER). ER enzymes lengthen fatty acids produced by. Fatty Acyl Synthase as well as dietary polyunsaturated fatty acids. Fatty acids. esterified to coenzyme A serve as substrates. Malonyl- Co. A is the donor of. Fatty Acid Synthase. A family of enzymes designated. Elongases or ELOVL (elongation of very long. Desaturases introduce double bonds. Mammalian cells are unable to produce double bonds at certain locations. D1. 2. Thus some polyunsaturated fatty acids are dietary essentials, e. D9,1. 2. (1. 8 carbon atoms long, with cis double bonds at carbons 9- 1. Formation of a double bond in a fatty acid involves the. NADH- cyt b. 5 Reductase. Cytochrome b. 5. which may be a separate protein or a domain at one end of the desaturase. Desaturase. with an active site that contains two. The desaturase catalyzes a mixed function oxidation reaction. Two electrons pass from NADH. FAD- containing reductase andcytochrome b. Fatty Acid Oxidation and Insulin Action. When Less Is More. Type 2 diabetes is a disease of metabolic dysregulation involving impaired uptake and utilization of glucose, altered lipid metabolism, accumulation of various lipid species in the circulation and in tissues, and disruption of metabolic signaling pathways that regulate insulin secretion from pancreatic islet . Normal fuel homeostasis involves reciprocal regulation of glucose and lipid catabolism. Fundamental contributions to our understanding of the interplay between these two key groups of metabolic fuels came from the work of Randle (1), who demonstrated that increased rates of fatty acid oxidation in the fasted state lead to suppression of glucose oxidation and activation of gluconeogenesis, thereby preserving blood glucose for use by the brain and central nervous system. Conversely, the transition from the fasted to the fed state involves a coordinated shift from fatty acid to glucose oxidation. A key element in the latter switch, as elegantly demonstrated by the work of Mc. Garry (2), is the glucose- induced rise in malonyl Co. A, which inhibits fatty acid oxidation via direct binding to and allosteric inhibition of carnitine palmitoyltransferase- 1 (CPT- 1), the rate limiting enzyme for transport of cytosolic long- chain acyl Co. A molecules into the mitochondria for oxidation. The multifaceted roles of malonyl Co. A as a key glucose- derived metabolite, an allosteric inhibitor of fatty acid oxidation, and a biosynthetic precursor for fatty acid synthesis has led to a series of recent studies investigating the effects of manipulating this metabolite in various tissues. A bonus of such experiments is the opportunity to assess the physiological impact of enhanced or diminished fat oxidation in different cell types and in whole animals. In this issue of Diabetes, one such study by Bouzraki et al. ACC- 1 is thought to reside in the cytosol and be primarily responsible for synthesis of the malonyl Co. A pool involved in lipogenesis, whereas ACC- 2 is thought to localize to the outer mitochondrial membrane, where malonyl Co. A can be effectively used for allosteric regulation of CPT- 1 (4). Malonyl Co. A is decarboxylated to acetyl Co. A by malonyl Co. A decarboxylase (MCD), an enzyme that can be variously localized in the mitochondrial matrix, peroxisomes, or the cytosol (5). Both ACC and MCD activities are regulated by 5. The net effect is a rapid decrease in malonyl Co. A levels, relief of CPT- 1 inhibition, activation of fatty acid oxidation, and cessation of lipogenesis. Bouzakri et al. They show that 7. MCD expression with this method results in a doubling of malonyl Co. A levels and a clear shift from fatty acid to glucose oxidation, in effect mimicking the fasted- to- fed transition. MCD inhibition also led to reduced palmitate uptake and decreased expression of fatty acid transport protein 1; conversely, glucose uptake in both the basal and insulin- stimulated states was enhanced in association with increased cell surface levels of GLUT4. Interestingly, although insulin- stimulated glucose uptake was increased in cells with suppressed MCD expression, no enhancement in insulin signaling was detected when measured at the levels of insulin receptor substrate- 1 tyrosine phosphorylation, phosphatidylinoitol 3- kinase activity, or serine phosphorylation of Akt and glycogen synthase kinase- 3. These results suggest that MCD suppression encourages glucose uptake and utilization through mechanisms that are independent of the known insulin signaling pathway. Based on these findings, the authors reasonably suggest that MCD may be a therapeutic target for patients with insulin resistance and type 2 diabetes. Other recent studies provide direct insights into the potential and also the considerable complexities of developing MCD inhibitors for diabetes therapies. Thus, in one recent study, whole animal knockout of MCD conferred resistance to diet- induced impairment of insulin action, as shown by glucose tolerance testing (6). On the other hand, an earlier report found that overexpression rather than suppression of MCD in liver of rats fed on a high- fat diet ameliorated whole- animal, liver, and muscle insulin resistance (7). A unifying explanation for these seemingly discordant findings has recently been advanced (8). In this model, ingestion of diets high in fat and carbohydrate lead to accumulation of malonyl Co. A in liver, resulting in hepatic steatosis and conversion of excess fats into species associated with hepatic insulin resistance such as diacylglycerol and ceramides. Consistent with this model, overexpression of MCD in liver of high- fat–fed rats resolves hepatic steatosis and lowers circulating fatty acid levels while reversing insulin resistance (7). In contrast, high- fat feeding actually increases rather than decreases . In sedentary animals, this induction appears to occur without a coordinated increase in tricarboxylic acid cycle flux, resulting in incomplete . Knockout of MCD prevented incomplete fat oxidation in muscle and protected against diet- induced insulin resistance, suggesting a potential connection between mitochondrial overload and glucose intolerance (6). Surprisingly, lipid metabolism in the liver appeared to be relatively unaffected by this manipulation. Because MCD is present in three subcellular compartments, the tissue- specific consequences of its absence might reflect distinct distributions of the enzyme activity (5). In light of this possibility, it is important to emphasize that An et al. It is also noteworthy that the liver isoform of CPT- 1 is 1. Co. A than its counterpart in the muscle (1); this too could contribute to tissue- specific metabolic effects of MCD inhibition. The foregoing findings in MCD- null mice appear to be consistent with those of Bouzakri et al. Fitting with the notion that inhibition of muscle fat oxidation promotes glucose uptake, another recent report showed that genetic disruption of oxidative phosphorylation in mice produced an antidiabetic phenotype (1. In this study, a generalized, low- grade impairment of the electron transport chain was accomplished via targeted deletion of the mitochondrial flavoprotein apoptosisinducing factor. Conditional knockout of apoptosis- inducing factor in mouse skeletal muscle not only increased glucose uptake and glycolytic metabolism, but also amplified insulin signaling when animals were fed either a low- or high- fat diet. Taken together, this new wave of evidence implies that insulin action in skeletal muscle couples directly to mitochondrial energetics and substrate selection, such that the internal GLUT4 pools are mobilized only when the muscle must rely on glucose as its primary source of fuel. Still unanswered is the intriguing question of how the muscle cell senses a decline in the oxidation of fat and/or other fuels to engage an increase in glucose uptake and catabolism, especially when insulin signaling pathways are not enhanced. A clearer understanding of the metabolic and molecular signals that permit crosstalk between muscle mitochondria and GLUT4 trafficking now awaits future investigation. Also requiring further study is the impact of body- wide knockout or pharmacologic suppression of MCD, as this maneuver could exacerbate hepatic steatosis and compromise exercise tolerance and might also affect glucose oxidation and regulation of insulin secretion from pancreatic islets. Nonetheless, the emerging story on fat oxidation and insulin action in muscle suggests that perhaps less is better, at least in the context of inactivity and overnutrition. Footnotes. See accompanying original article, p. DIABETESREFERENCES.
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