Acetyl unit

FIGURE 25.10 Acetyl units are covalently linked to a serine residue at the active site of the acetyl transferase in eukaryotes. A similar reaction links malonyl units to the malonyl transferase. 

In general, pyruvate decarboxylase (EC 4.1.1.1) catalyzes the decarboxylation of a 2-oxocar-boxylic acid to give the corresponding aldehyde6. Using pyruvic acid, the intermediately formed enzyme-substrate complex can add an acetyl unit to acetaldehyde already present in the reaction mixture, to give optically active acetoin (l-hydroxy-2-butanone)4 26. Although the formation of... 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

The first formation of a carbon-carbon bond occurs between malonyl and acetyl units bound to fatty acid synthase. After reduction, dehydration, and further reduction, the acyl enzyme is condensed with more malonyl-CoA and the cycle is repeated until the acyl chain grows to C16. When the growing fatty acid reaches a chain length of 16 carbons, the acyl group is hydrolyzed to give the free fatty acid. 

Oxidation is a cyclical pathway which removes a C2 (acetyl) unit form the fatty acyl-CoA on each cycle. The designation [3 derives from the traditional system of labelling atoms within fatty acid molecules where the carbon attached to the carboxyl group is a and the methyl carbon is always CO (omega) ... 

In principle, fatty acids could be synthesised by the progressive addition of 2-carbon acetyl units to an extending acyl chain and reduction of the carbonyl groups to methylene groups that is, by reversal of the P-oxidation process, until the 16-carbon, palmitic acid is produced. However, for reasons already considered in this text, synthetic reac-... 

The Cg-Cg carbon backbone can be extended further by the addition of units via three iterative acetyl units. These units condense with each other and undergo cyc-lisation to form a new second polyphenolic ring with a final carbon skeleton of Cg-Cg-Cg... 

Their biosynthesis derives from the condensation of three acetyl units and of a derivative of hydroxycinnamic acid leading to the formation of a common intermediate, tetrahydroxychalcone. This chalcone is precursor of several compounds, the most important being the 4-oxo-flavonoids [19]. 

Fatty acids are synthesized in the cytosol. Citrate carries two-carbon acetyl units from the mitochondrial matrix to the cytosol. 

At the end of this sequence, the P-oxoacyl-CoA derivative is cleaved (Fig. 17-1, step e) by a thiolase (see also Eq. 13-35). One of the products is acetyl-CoA, which can be catabolized to C02 through the citric acid cycle. The other product of the thiolytic cleavage is an acyl-CoA derivative that is two carbon atoms shorter than the original acyl-CoA. This molecule is recycled through the P oxidation process, a two-carbon acetyl unit being removed as acetyl-CoA during each turn of the cycle (Fig. 17-1). The process continues until the fatty acid chain is completely degraded. 

The three compounds, acetoacetate, acetone, and 3-hydroxybutyrate, are known as ketone bodies.60b The inability of the animal body to form the glucose precursors, pyruvate or oxaloacetate, from acetyl units sometimes causes severe metabolic problems. The condition known as ketosis, in which excessive amounts of ketone bodies are present in the blood, develops when too much acetyl-CoA is produced and its combustion in the critic acid cycle is slow. Ketosis often develops in patients with Type I diabetes mellitus (Box 17-G), in anyone with high fevers, and during starvation. Ketosis is dangerous, if severe, because formation of ketone bodies produces hydrogen ions (Eq. 17-5) and acidifies the blood. Thousands of young persons with insulin-dependent diabetes die annually from ketoacidosis. 

Rat blood normally contains about 0.07 mM acetoacetate, 0.18 mM hydroxybutyrate, and a variable amount of acetone. These amounts increase to 0.5 mM acetoacetate and 1.6 mM hydroxybutyrate after 48 h of starvation. On the other hand, the blood glucose concentration falls from 6 to 4 mM after 48 h starvation.61 Under these conditions acetoacetate and hydroxybutyrate are an important alternative energy source for muscle and other tissues.62 63 Acetoacetate can be thought of as a transport form of acetyl units, which can be reconverted to acetyl-CoA and oxidized in the citric acid cycle. 

To complete the oxidation of fatty acids the acetyl units of acetyl-CoA generated in the P oxidation sequence must be oxidized to carbon dioxide and water.77 The citric acid (or tricarboxylic acid) cycle by which this oxidation is accomplished is a vital part of the metabolism of almost all aerobic creatures. It occupies a central position in metabolism because of the fact that acetyl-CoA is also an intermediate in the catabolism of carbohydrates and of many amino acids and other compounds. The cycle is depicted in detail in Fig. 10-6 and in an abbreviated form, but with more context, in Fig. 17-4. 

This limitation on the conversion of C2 acetyl units to C3 metabolites is overcome in many organisms by... 

Fatty acid chains are taken apart two carbon atoms at a time by (3 oxidation. Biosynthesis of fatty acids reverses this process by using the two-carbon acetyl unit of acetyl-CoA as a starting material. The coupling of ATP cleavage to this process by a carboxylation-decarboxylation sequence, the role of acyl carrier protein (Section H,4), and the use of NADPH as a reductant (Section I) have been discussed and are summarized in Fig. 17-12, which gives the complete sequence of... 

In the synthesis of fatty acids the acetyl irnits are condensed and then are reduced to form straight hydrocarbon chains. In the oxo-acid chain elongation mechanism, the acetyl unit is introduced but is later decarboxylated. Tlius, the chain is increased in length by one carbon atom at a time. These two mechanisms account for a great deal of the biosynthesis by chain extension. However, there are other variations. For example, glycine (a carboxylated methylamine), under the influence of pyridoxal phosphate and with accompanying decarboxylation, condenses with succinyl-CoA (Eq. 14-32) to extend the carbon chain and at the same time to introduce an amino group. Likewise, serine (a carboxylated ethanolamine) condenses with... 

The second five-carbon branched unit, in which the branch is one carbon further down the chain, is an intermediate in the biosynthesis of polyprenyl (isoprenoid) compounds and steroids. Three two-carbon units are used as the starting material with decarboxylation of one unit. Two acetyl units are first condensed to form acetoacetyl-CoA. Then a third acetyl unit, which has been transferred from acetyl-CoA onto an SH group of the enzyme, is combined with the acetoacetyl-CoA through an ester condensation. The thioester linkage to the enzyme is hydrolyzed to free the product 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This sequence is illustrated in Eq. 17-5. The thioester group of HMG-CoA is reduced to the... 

Chitosan is produced commercially by deacetylation of chitin. It is a linear polysaccharide composed of randomly distributed /i-( l-4)-linkcd D-glucosamine (deacetylated unit) and N -acetyl-D-glucosamine (acetylated unit). The degree of deacetylation in commercial chitosans is in the range 60-100% (Figure 5.19). 

Note that at this point, the FAS has two activated substrates, the acetyl group bound on the cysteine -SH and the malonyl group bound on the pantothenate -SH. Transfer of the 2-carbon acetyl unit from Acetyl S-cysteine to malonyl-CoA has two features ... 

In the second stage, these numerous small molecules are degraded to a few simple units that play a central role in metabolism. In fact, most of them—sugars, fatty acids, glycerol, and several amino acids—are converted into the acetyl unit of acetyl CoA (Section 14.3.1). Some ATP is generated in this stage, but the amount is small compared with that obtained in the third stage. 

In the third stage, ATP is producedfrom the complete oxidation of the acetyl unit of acetyl CoA. The third stage consists of the citric acid cycle and oxidative phosphorylation, which are the final common pathways in the oxidation offuel molecules. Acetyl CoA brings acetyl units into the citric acid cycle [also called the tricarboxylic acid (TCA) cycle or Krebs cycle], where they are completely oxidized to CO2. Four pairs of electrons are transferred (three to NAD+ and one to FAD) for each acetyl group that is oxidized. Then, a proton gradient is generated as electrons flow from the reduced forms of these carriers to O2, and this gradient is used to synthesize ATP. 

Two carbon atoms enter the cycle in the condensation of an acetyl unit (from acetyl CoA) with oxaloacetate. Two carbon atoms leave the cycle in the form of CO2 in the successive decarboxylations catalyzed by isocitrate... 

Many bacteria and plants are able to subsist on acetate or other compounds that yield acetyl CoA. They make use of a metabolic pathway absent in most other organisms that converts two-carbon acetyl units into four-carbon units (succinate) for energy production and biosyntheses. This reaction sequence, called the glyoxylate cycle, bypasses the two decarboxylation steps of the citric acid cycle. Another key difference is that two molecules of acetyl CoA enter per turn of the glyoxylate cycle, compared with one in the citric acid cycle. 

Driving force. What is the A G° for the complete oxidation of the acetyl unit of acetyl CoA by the citric acid cycle See answer... 

Fatty acid degradation and synthesis are relatively simple processes that are essentially the reverse of each other. The process of degradation converts an aliphatic compound into a set of activated acetyl units (acetyl CoA) that can be processed by the citric acid cycle (Figure 22.2). An activated fatty acid is oxidized to introduce a double bond the double bond is hydrated to introduce an oxygen the alcohol is oxidized to a ketone and, finally, the four carbon fragment is cleaved by coenzyme A to yield acetyl CoA and a fatty acid chain two carbons shorter. If the fatty acid has an even number of carbon atoms and is saturated, the process is simply repeated until the fatty acid is completely converted into acetyl CoA units. 

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