Two-carbon units

Fatty acids derived from animal and vegetable sources generally contain an even number of carbon atoms siace they are biochemically derived by condensation of two carbon units through acetyl or malonyl coenzyme A. However, odd-numbered and branched fatty acid chains are observed ia small concentrations ia natural triglycerides, particularly mminant animal fats through propionyl and methylmalonyl coenzyme respectively. The glycerol backbone is derived by biospeciftc reduction of dihydroxyacetone. 

Tiansketolases (TK) aie widely used in oiganic synthesis to extend the chain of an acceptor aldose by two carbon units. 

Fatty acid chains are constructed by the addition of two-carbon units derived from acctyl-CoA. 

The addition of two-carbon units to the growing chain is driven by decarboxylation of malonyl-CoA. 

FIGURE 25.7 The pathway of palmhate synthesis from acetyl-CoA and malonyl-CoA. Acetyl and malonyl building blocks are introduced as acyl carrier protein conjugates. Decarboxylation drives the /3-ketoacyl-ACP synthase and results in the addition of two-carbon units to the growing chain. Concentrations of free fatty acids are extremely low in most cells, and newly synthesized fatty acids exist primarily as acyl-CoA esters. 

As seen already, palmitate is the primary product of the fatty acid synthase. Cells synthesize many other fatty acids. Shorter chains are easily made if the chain is released before reaching 16 carbons in length. Longer chains are made through special elongation reactions, which occur both in the mitochondria and at the surface of the endoplasmic reticulum. The ER reactions are actually quite similar to those we have just discussed addition of two-carbon units... 

One of the most striking features of the common fatty adds is that they have an even number of carbon atoms (Table 27.1, p. 1062). This even number results because all fatty acids are derived biosynthelically from acetyl CoA by sequential addition of two-carbon units to a growing chain. The acetyl CoA, in turn, arises primarily from the metabolic breakdown of carbohydrates in the glycolysis pathway that weTl see in Section 29.5. Thus, dietary carbohydrates consumed in excess of immediate energy needs are turned into fats for storage. 

Part of the diet consists of fats, which are triglycerol esters of fatty acids (FAs). The FAs from digestion of ingested fats can be metabolized in a variety of pathways. Fragments of the original FAs are preserved in these processes and can be utilized in the biosynthesis of other molecules. It is important to note that, during metabolism, almost all FAs are broken down into two-carbon units. The only exceptions are FAs with odd numbers of carbon atoms these are relatively rare in the diet. It ean be shown further that there is a partial barrier to the incorporation of FA-derived carbon into the amino acids which constitute collagen. 

The citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substtates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it fimctions in both oxidative and synthetic processes, it is amphibolic (Figure 16—4). 

In P-oxidation (Figure 22-2), two carbons at a time are cleaved from acyl-CoA molecules, starting at the carboxyl end. The chain is broken between the 0t(2)- and P(3)-carbon atoms—hence the name P-oxidation. The two-carbon units formed are acetyl-CoA thus, palmi-toyl-CoA forms eight acetyl-CoA molecules. 

Fatty acids are degraded by two-carbon units in a reverse manner analogous to their biosynthesis. The acyl-CoAs are first dehydrogenated to a,(3-unsaturated acyl-CoA, and then hydrated to (3-hydroxyacyl-CoA, followed by oxidation to (3-ketoacyl-CoA. The C-C bond between C-2 and C-3 of the latter compound is broken by a free CoA molecule via thiolysis to form an acyl-CoA that is two carbons shorter and acetyl-CoA. Unlike fatty acid biosynthesis, each step of the (3 oxidation of fatty acids is... 

Fatty acids are carboxylic acids, often with a long aliphatic tail (long carbon chains), which can be either saturated (all single bonds) or unsaturated. They are biosynthesized from two-carbon units (acetate, CH3COO ), and therefore usually have an even number of carbons with a range of C4 to C36, although Ci6 and Ci8 are dominant. Figure 7.7 shows the structure of octadecanoic acid (slearic acid, Ci8 o), c/.v-9-octadeccnoic acid (oleic acid, Ci8 i), and... 

It is generally accepted that w-oxidation of LAS is followed by successive oxidative shortening of the alkyl chain by two-carbon units, termed (3-oxidation (Fig. 5.1.2) [77,81]. The resulting very short-chain SPCs are further broken down by ring cleavage, which is considered the rate-determining step within the total process, and desulfonation then occurs to result in complete degradation. 

Fig. 5.1.8. Presumed major pathway for intracellular aerobic biodegradation of LAS (as acetyl-CoA derivatives) to SPC via w-oxidation followed by successive oxidative shortening of the alkyl chain by two carbon units ((3-oxidation). Intermediates of 13-oxidation, such as SPC-2H formed by enzymatic dehydrogenation, are also transported out of the cell after cleavage of the CoA...

The heat of hydrogenation of one carbon-carbon double bond of allene is 41 kcal mol-1, whereas that of an ordinary alkene is around 29 kcal mol-1. Thus the cumulated double bond of allene liberates 12 kcal mol-1 more than that of a simple alkene on hydrogenation. Accumulation of two carbon-carbon double bonds imparts an extra reactivity to allene, making it a remarkably active component participating in a variety of cycloaddition reactions as a two-carbon unit. 

Figure 11.4 Condensation, dehydration and reduction reactions in fatty add synthesis. These reactions constitute the major components of the pathway of fatty acid synthesis and are all catalysed by fatty acid synthase. The reduction reactions, indicated by addition of 2H in the diagram, involve the conversion of NADPH to NADP . (The re-conversion of NADP back to NADPH occurs in the pentose phosphate pathway.) The condensation reaction results in an increase in size of acyl-ACP by two carbon units in each step. The two carbons for each extension are each provided by malonyl-CoA. ACP - acyl carrier protein.

Glycerol provides a minor source of energy, in that it can be modified readily to glyceraldehyde 3-phosphate, one of the intermediates in the glycolytic pathway. The fatty acids are metabolized by a process termed P-oxidation, which involves the sequential removal of two-carbon units via oxidation at the P-position. The process for saturated fatty acids will now be described. 

The first step is carboxylation of acetyl CoA to malonyl CoA. This reaction is catalyzed by acetyl-CoA carboxylase [5], which is the key enzyme in fatty acid biosynthesis. Synthesis into fatty acids is carried out by fatty acid synthase [6]. This multifunctional enzyme (see p. 168) starts with one molecule of ace-tyl-CoA and elongates it by adding malonyl groups in seven reaction cycles until palmi-tate is reached. One CO2 molecule is released in each reaction cycle. The fatty acid therefore grows by two carbon units each time. NADPH+H is used as the reducing agent and is derived either from the pentose phosphate pathway (see p. 152) or from isocitrate dehydrogenase and malic enzyme reactions. 

A Fatty acids are constmcted by stepwise addition of two-carbon units by a large multi-enzyme complex located in the cytoplasm of all cells. 

B. The precursor for donation of two-carbon units to build fatty acids is actually the three-carbon compound, malonyl CoA. 

Subsequent reactions reduce the carbonyl group and reset the enzyme to accept the next two-carbon unit. 

Figure 8-4. 3-Oxidation of palmitate. Oxidation of an even-numbered, saturated fatty acid involves repetitive cleavage at the (1 carbon of the acyl chain. Removal of two-carbon units occurs in a cycle of four steps initiated by one of the acyl CoA dehydrogenases. Acetyl CoA is produced at each cycle until all that remains of the acyl CoA is acetyl CoA itself.

A number of procedures have been reported for the synthesis of indolocarbazoles by the addition of a two-carbon unit to biindolyl precursors. Thus, reaction of dimethylaminoacetaldehyde dimethyl or diethyl acetal with biindolyl in refluxing acetic acid provides a convenient route for the construction of the indolocarbazole ring system (Equation 103) <1999T2371, 20030L3721, 2004TL7273>. 

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