ATP: citrate lyase

Finally, citrate can be exported from the mitochondria and then broken down by ATP-citrate lyase to yield oxaloacetate and acetyl-CoA, a precursor of fatty acids (Figure 20.23). Oxaloacetate produced in this reaction is rapidly reduced to malate, which can then be processed in either of two ways it may be transported into mitochondria, where it is reoxidized to oxaloacetate, or it may be oxidatively decarboxylated to pyruvate by malic enzyme, with subse-... 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

Histidine phosphatases and aspartate phosphatases are well established in lower organisms, mainly in bacteria and in context with two-component-systems . Reversible phosphorylation of histidine residues in vertebrates is in its infancy. The first protein histidine phosphatase (PHP) from mammalian origin was identified just recently. The soluble 14 kD protein does not resemble any of the other phosphatases. ATP-citrate lyase and the (3-subunit of heterotrimeric GTP-binding proteins are substrates of PHP thus touching both, metabolic pathways and signal transduction [4]. 

Pymvate dehydrogenase is a mitochondrial enzyme, and fatty acid synthesis is a cytosohc pathway, but the mitochondrial membrane is impermeable to acetyl-CoA. Acetyl-CoA is made available in the cytosol from citrate synthesized in the mitochondrion, transported into the cytosol and cleaved in a reaction catalyzed by ATP-citrate lyase. 

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). 

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase ... 

Fatland BL, Ke J, Anderson MD, Mentzen WI, Cui LW, Allred CC, Johnston JL, Nikolau BJ and Wurtele ES. 2004. Molecular characterization of a heteromeric ATP-citrate lyase that generates cytosolic acetyl-Coenzyme A in Arabidopsis. Plant Plsy 130 740-756. 

Citrate is transported across the mitochondrial membrane by a specific carrier. In the cytosol, acetyl-CoA is reformed in a reaction catalysed by ATP citrate lyase (Figure 11.3). This reaction involves the hydrolysis of ATP ... 

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... 

Fructose bisphosphate aldolase— aldolase Hydroxymethylglutaryl-CoA lyase Hydroxymethylglutaryl-CoA synthase Citrate synthase ATP-citrate lyase... 

Acetyl-CoA p-Nitroaniline Disappearance Arylamine Acetyltransferase Acetyl-CoA Synthetase, ATP-Citrate Lyase" ... 

ATP CITRATE LYASE ATP GLUCOSE-L-PHOSPHATE ADENYL-YLTRANSFERASE... 

ARYLAMINE ACETYLTRANSFERASE ATP CITRATE LYASE BENZOATE-CoA LIGASE... 

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). 

Coumaroyl-CoA is produced from the amino acid phenylalanine by what has been termed the general phenylpropanoid pathway, through three enzymatic conversions catalyzed by phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), and 4-coumarate CoA ligase (4CL). Malonyl-CoA is formed from acetyl-CoA by acetyl-CoA carboxylase (ACC) (Figure 3.2). Acetyl-CoA may be produced in mitochondria, plastids, peroxisomes, and the cytosol by a variety of routes. It is the cytosolic acetyl-CoA that is used for flavonoid biosynthesis, and it is produced by the multiple subunit enzyme ATP-citrate lyase that converts citrate, ATP, and Co-A to acetyl-CoA, oxaloacetate, ADP, and inorganic phosphate. ... 

There it is cleaved by ATP-citrate lyase. To ensure that the reaction goes to completion, cleavage is coupled to the hydrolysis of ATP to ADP and inorganic phosphate (Eq. 13-39). The value of G given here is extremely dependent upon the concentration of Mg2+ as a result of strong chelation of Mg2+ by citrate.220 The reaction sequence is complex but can be understood in terms of an initial ATP-dependent synthesis of... 

Write a complete step-by-step mechanism for the action of ATP-citrate lyase which catalyzes the following reaction (Eq. 13-39) ... 

ATP-citrate lyase Fatty acid synthase Lipoprotein lipase Hydroxymethylglutaryl-CoA reductase Phosphorylation... 

Write out a complete step-by-step mechanism for the reactions by which citrate can be synthesized from pyruvate and then exported from mitochondria for use in the biosynthesis of fatty acids. Include a chemically reasonable mechanism for the action of ATP-citrate lyase, which catalyzes the following reaction ... 

How do you think that hydroxycitrate, an inhibitor of ATP citrate lyase, would affect the ability of liver to convert dietary fructose into bile acids ... 

Reductive citric acid cycle 5 3 NAD(P)H, 1 unknown donor", 2 ferredoxin 2-Oxoglutarate synthase Isocitrate dehydrogenase6 Pyruvate synthase PEP carboxylase C02 C02 C02 HCOJ Acetyl-CoA, pyruvate, PEP, oxaloacetate, succinyl-CoA, 2-oxoglutarate 2-Oxoglutarate synthase, ATP-citrate lyase... 

Three modifications of the conventional oxidative citric acid cycle are needed, which substitute irreversible enzyme steps. Succinate dehydrogenase is replaced by fumarate reductase, 2-oxoglutarate dehydrogenase by ferredoxin-dependent 2-oxoglutarate oxidoreductase (2-oxoglutarate synthase), and citrate synthase by ATP-citrate lyase [3, 16] it should be noted that the carboxylases of the cycle catalyze the reductive carboxylation reactions. There are variants of the ATP-driven cleavage of citrate as well as of isocitrate formation [7]. The reductive citric acid... 

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