Citrate lyase activation

Cisplatin — see Platinum, cw-dichlorodiammine-Cis-transisomerization, 1, 467 Citrate lyase activation... 

Cinnamic 6-carboxypicolinic monoanhydride hydrolysis metal catalysis, 463 Cinnamic picolinic anhydride hydrolysis metal catalysis, 463 Citrate lyase activation... 

In the ruminant animal, acetate is absorbed directly from the gut and is changed to acetyl-CoA, in the presence of acetyl-CoA synthetase (see p. 206), in the cell cytoplasm. This is the major source of acetyl-CoA in ruminants, in which ATP-citrate lyase activity is greatly reduced and passage of mitochondrial acetyl-CoA to the cytoplasm is limited. 

Microorganisms lacking ATP citrate lyase do not accumulate lipid much above 10-15%, although the corollary, that organisms with ATP citrate lyase activity will accumulate lipid may not always hold because other enzymes, such as AMP deaminase, AMP-dependent isocitrate dehydrogenase or malic enzyme, may be lacking or may not be under sufficiently stringent control to allow extensive lipid accumulation. There is clearly much still to be learnt about lipid accumulation and its attendant biochemistry to explain all these variations at the fundamental level. 

Both dehydrogenases of the pentose phosphate pathway can be classified as adaptive enzymes, since they increase in activity in the well-fed animal and when insulin is given to a diabetic animal. Activity is low in diabetes or starvation. Malic enzyme and ATP-citrate lyase behave similarly, indicating that these two enzymes are involved in lipogenesis rather than gluconeogenesis (Chapter 21). 

Groot.P.H.E.. Synthesis of novel thiol-containing citric acid analogues. Kinetic evaluation of these and other potential active-site-directed and mechanism-based inhibitors of ATP citrate lyase, J.Med.Chem., 38(3), 1995, 537-543... 

In the past decade, a few examples of benzoannulated carbazole ring systems were found in nature as marine products. In 1993, Chan et al. reported a novel marine benzocarbazole alkaloid, purpurone (281) from the marine sponge lotrochota sp. in its racemic form. Purpurone, as indicated by its name, is purple in color. This represents the first example of a benzocarbazole alkaloid with a biphenylene quinone methide functionality. The isolate showed ATP-citrate lyase (ACL) inhibitory activity (247). 

Citrate lyase inhibition. Petroleum ether extract of the fresh fruit, administered to pigs at a concentration of 3.5 g/kg of diet for 29 days, was active on the hepatic enzymes " . 

Figure 2.4. The provision of acetyl-CoA and NADPH for lipogenesis. PPP, pentose phosphate pathway T, tricarboxylate transporter K, a-ketoglutarate transporter. In ruminants, pyruvate dehydrogenase, ATP-citrate lyase and malic enzyme activities are low and perhaps non-functional. (From Murray et al., 1988. Harper s Biochemistry, 21st edn, p. 207, Appleton and Lange, Norwalk, CT reproduced with permission of The McGraw-Hill Companies).

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

Fatty acids are predominantly formed in the liver and adipose tissne, as well as the mammary glands during lactation. Fatty acid synthesis occurs in the cytosol (fatty acid oxidation occurs in the mitochondria compartmentalisation of the two pathways allows for distinct regulation of each). Oxidation or synthesis of fats utilises an activated two-carbon intermediate, acetyl-CoA, but the acetyl-CoA in fat synthesis exists temporarily bound to the enzyme complex as malonyl-CoA. Acetyl-CoA is mostly produced from pyruvate (pyruvate dehydrogenase) in the mitochondria it is condensed with oxaloacetate to form citrate, which is then transported into the cytosol and broken down to yield acetyl-CoA and oxaloacetate (ATP citrate lyase). 

The malic enzyme/citrate lyase pathway is shown in Figure 5.10. The 2-carbon units acetyl groups) for fatty acid synthesis are supplied by the activity of citrate lyase, which may be considered an enzyme of fatty acid biosynthesis. The reduced NADP is Supplied at the point of malic enzyme. Figure 5.10 reveals no net production or utilization of NAD in the cytoplasm. The NADPH + H generated in the cytoplasm is used for fatly acid synthesis, which regenerates NADP. One molecule of CO is produced in the cytoplasm. The diagram reveals no net production or utilization of CO in the mitochondrion. One molecule of NAD is... 

Abbreviations FASN, fatty acid synthase ACC, acetyl-CoA-carboxylase ACL, ATP-citrate lyase NADPH, nicotinamide adenine dinucleotide phosphate MAT, malonyl acetyl transferases KS, ketoacyl synthase KR, p-ketoacyl reductase DH, p-hydroxyacyl dehydratase ER, enoyl reductase TE, thioesterase ACP, acyl carrier protein VLCFA, very long chain fatty acids ELOVL, elongation of very long chain fatty acids SCDl, stearoyl-CoA desaturase-1 AMPK, AMP-activated kinase ME, malic enzyme FASKOL, liver-specific deletion of FAS PPARa, Peroxisome Proliferator-Activating Receptor alpha HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA SREBP, sterol response element binding protein SIP, site-one protease S2P, site-two... 

Malonate decarboxylase (EC 4.1.1.88) and citrate lyase (EC 4.1.3.6) are both large enzyme complexes that consist of multiple subunits, the smallest of which acts as an ACP. These two complexes catalyze the decarboxylation of malonate to acetate and CO2 and the Mg -dependent cleavage of citrate to acetate and oxaloacetate, respectively. Both have been shown to require a thiol-containing prosthetic group for activity. However, unlike the carrier proteins described in the previous section, the ACP subunits of these proteins are not phosphopantetheinylated by a reaction with CoA. Instead, they rely on a unique cofactor, 2 -(5"-triphosphoribosyl)-3 -dephospho-CoA (24, dePCoA-RibPPP), as source of a 2 -(5"-phosphoribosyl)-3 -dephospho-CoA prosthetic group, which is bound to a conserved serine residue of the ACP. ° ° A similar prosthetic group has been identified in citramalate lyase (EC 4.1.3.22). The proposed biosynthesis and subsequent transfer reactions of the cofactor 24 to the ACPs of these complexes are shown in Scheme 5. 

A second ATP-dependent citrate lyase (ACL) activity is responsible for the formation of acetyl-CoA 30 and oxaloacetate 35 from citrate 39 with concomitant hydrolysis of ATP to ADP and phosphate (Equation (22)). ° It is proposed to play a vital role in maintaining acetyl-CoA and oxaloacetate levels in most mammals, whereas in some bacteria it is an essential enzyme of the reductive tricarboxylic acid cycle (RTCA). 

The in vitro effect of 13-MTD on the enzymes involved in fatty acid biosynthesis was studied. Five enzyme activities were assayed FAS, acetyl-CoA carboxylase, glucose-6-phosphate dehydrogenase (G6PDH), adenosine triphosphate (ATP)-citrate lyase, and malic enzyme. Of the enzymes involved in fatty acid biosynthesis, FAS, acetyl-CoA carboxylase, and G6PD from rat liver were inhibited in vitro by 13-MTD [7],... 

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