Pyruvate fatty acid synthesis

FIGURE 20.23 Export of citrate from mitochondria and cytosolic breakdown produces oxaloacetate and acetyl-CoA. Oxaloacetate is recycled to malate or pyruvate, which re-enters the mitochondria. This cycle provides acetyl-CoA for fatty acid synthesis in the cytosol. 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

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.)... 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

Glycolysis, the pentose phosphate pathway, and fatty acid synthesis are all found in the cytosol. In gluconeo-genesis, substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate before formation of glucose. 

Acetyl-CoA, formed from pyruvate by the action of pyruvate dehydrogenase, is the major building block for long-chain fatty acid synthesis in nonruminants. (In ruminants, acetyl-CoA is derived directly from acetate.)... 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Aerobic To convert glucose to pyruvate and ATP. Pyruvate can be burned for energy (TCA) or converted to fat (fatty acid synthesis). 

In the weU-fed, absorptive state (insulin), accumulating acetyl CoA is shuttled into the cytoplasm for fatty acid synthesis. OAA is necessary for this transport, and acetyl CoA can stimulate its formation from pyruvate (see Chapter 15, Figure 1-15-1). 

Thiamine pyrophosphate is a coenzyme for several enzymes involved in carbohydrate metabolism. These enzymes either catalyze the decarboxylation of oi-keto acids or the rearrangement of the carbon skeletons of certain sugars. A particularly important example is provided by the conversion of pyruvic acid, an oi-keto acid, to acetic acid. The pyruvate dehydrogenase complex catalyzes this reaction. This is the key reaction that links the degradation of sugars to the citric acid cycle and fatty acid synthesis (chapters 16 and 18) ... 

S ATP -P acetate <1-18> (<8> acetate kinase/phosphotransacetylase, major role of this two-enzyme sequence is to provide acetyl coenzyme A which may participate in fatty acid synthesis, citrate formation and subsequent oxidation [1] <3> function in the metabolism of pyruvate or synthesis of acetyl-CoA coupling with phosphoacetyltransacetylase [15] <11> function in the initial activation of acetate for conversion to methane and CO2 [19] <10> key enzyme and responsible for dephosphorylation of acetyl phosphate with the concomitant production of acetate and ATP [30]) (Reversibility r <1-18> [1, 2, 5-21, 24-27, 29-33]) [1, 2, 5-21, 24-27, 29-33]... 

This three-step process for transferring fatty acids into the mitochondrion—esterification to CoA, transesterification to carnitine followed by transport, and transesterification back to CoA—links two separate pools of coenzyme A and of fatty acyl-CoA, one in the cytosol, the other in mitochondria These pools have different functions. Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate, fatty acids, and some amino acids, whereas cytosolic coenzyme A is used in the biosynthesis of fatty acids (see Fig. 21-10). Fatty acyl-CoA in the cytosolic pool can be used for membrane lipid synthesis or can be moved into the mitochondrial matrix for oxidation and ATP production. Conversion to the carnitine ester commits the fatty acyl moiety to the oxidative fate. 

FIGURE 23-19 Electron micrograph of heart muscle. In the profuse mitochondria of heart tissue, pyruvate, fatty acids, and ketone bodies are oxidized to drive ATP synthesis. This steady aerobic metabolism allows the human heart to pump blood at a rate of nearly 6 IVmin, or about 350 L/hr—or 200 X 106 L over 70 years. 

Insulin also stimulates the storage of excess fuel as fat (Fig. 23-26). In the liver, insulin activates both the oxidation of glucose 6-phosphate to pyruvate via glycolysis and the oxidation of pyruvate to acetyl-CoA. If not oxidized further for energy production, this acetyl-CoA is used for fatty acid synthesis in the liver, and the fatty acids are exported as the TAGs of plasma lipoproteins (VLDLs) to the adipose tissue. Insulin stimulates TAG synthesis in adipocytes, from fatty acids released... 

Oxidative decarboxylation of pyruvate by pyruvate dehydrogenase complex is an important pathway in tissues with a high oxidative capacity, such as cardiac muscle (Figure 8.24). Pyruvate dehydrogenase irreversibly converts pyruvate, the end product of glycolysis, into acetyl CoA, a major fuel for the tricarboxylic acid cycle (see p. 107) and the building block for fatty acid synthesis (see p. 181). 

The glycolytic pathway produces pyruvate, which is the primary source of the mitochondrial acetyl CoA to be used for fatty acid synthesis. It also produces cytosolic reducing equivalents of NADH. Pyruvate enters the mitochondria. 

Alternate fates of pyruvate Compounds other than lactate to which pyruvate can be converted ALTERNATE FATES OF PYRUVATE (p. 103) Pyruvate can be oxidatively decarboxylated by pyruvate dehydrogenase, producing acetyl CoA—a major fuel for the tricarboxylic acid cycle (TCA cycle) and the building block for fatty acid synthesis. Pyruvate can be carboxylated to oxaloacetate (a TCA cycle intermediate) by pyruvate carboxylase. Pyruvate can be reduced by microorganisms to ethanol by pyruvate decarboxylase. 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

The basic starting substrate for fatty acid synthesis is acetyl-CoA (see below). In ruminants, the provision of this substrate is straightfoward. Acetate from blood (+ CoA + ATP) is converted by the cytosolic acetyl-CoA synthase (EC 2.3.1.169) to AMP and acetyl-CoA, which can then be used for fatty acid synthesis. In non-ruminants, glucose is converted via the glycolytic pathway to pyruvate, which is, in turn, converted to acetyl-CoA in mitochondria. Acetyl-CoA thus formed is converted to citrate which passes out to the cytosol where it is cleaved by ATP-citrate lyase (EC 2.3.3.8) to acetyl-CoA + oxalacetate (OAA). This transport of acetyl-CoA from... 

OAA by pyruvate carboxylase (EC 6.4.1.1), thereby completing the net transport of the C2 unit (acetate) from the mitochondrion to the cytosol with the added advantage of having converted a reducing equivalent as NADH + H+ to NADPH + H+. This mechanism of C2 transport provides up to 50% of the NADPH + H+ for fatty acid synthesis in nonruminants. 

For the conversion of pyruvate to oxaloacetate and the formation of citrate in the mitochondrion, see Chap. 12. Acetyl-CoA for fatty acid synthesis is converted to malonyl-CoA this reaction is catalyzed by acetyl-CoA carboxylase. Seven molecules of acetyl-CoA are converted to malonyl-CoA for the synthesis of one molecule of palmitic acid. 

In animals and fungi there is a similar dichotomy. NADPH can be generated by cytosolic malic enzyme which catalyses the reaction malate + NADP+ — pyruvate + COg + NADPH. Cytosolic malate derives from the following successive reactions the pyruvate/ citrate shuttle on the mitochondrial inner membrane takes pyruvate to the mitochondrion in exchange for citrate cytosolic ATP citrate lyase catalyses ATP + citrate + CoA-SH —> acetylCoA (CH3CO-S-C0A) + oxaloacetate and cytosolic malate dehydrogenase, which catalyses NADH + oxaloacetate NAD+ + malate. This scheme provides both acetylCoA and NADPH for subsequent long chain fatty acid synthesis (see section on Fatty acid synthesis ). 

The depletion of NAD+ (and the change to the NADH to NAD ratio) slows the TCA cycle, resulting in a build-up of pyruvate and acetyl-CoA. Excess acetyl-CoA increases fatty acid synthesis and fat deposits in the liver (fatty hver). An accumulation of fat in the liver can be observed after just a single night of heavy drinking. 

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). 

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