Carboxylic carbons

Much of protein engineering concerns attempts to explore the relationship between protein stmcture and function. Proteins are polymers of amino acids (qv), which have general stmcture +H3N—CHR—COO , where R, the amino acid side chain, determines the unique identity and hence the stmcture and reactivity of the amino acid (Fig. 1, Table 1). Formation of a polypeptide or protein from the constituent amino acids involves the condensation of the amino-nitrogen of one residue to the carboxylate-carbon of another residue to form an amide, also called peptide, bond and water. The linear order in which amino acids are linked in the protein is called the primary stmcture of the protein or, more commonly, the amino acid sequence. Only 20 amino acid stmctures are used commonly in the cellular biosynthesis of proteins (qv). 

Organic Carboxylic Acids — (RCOOH) are usually weak acids but can be very corrosive to skin. However, The substitution of Cl atoms on the carbon next to the carboxylic carbon produces a stronger acid. Thus, trichloroacetic acid is almost a strong acid whereas acetic acid is a weak one. 

A very interesting steric effect is shown by the data in Table 7-12 on the rate of acid-catalyzed esterification of aliphatic carboxylic acids. The dissociation constants of these acids are all of the order 1(T, the small variations presumably being caused by minor differences in polar effects. The variations in esterification rates for these acids are quite large, however, so that polar effects are not responsible. Steric effects are, therefore, implicated indeed, this argument and these data were used to obtain the Es steric constants. Newman has drawn attention to the conformational role of the acyl group in limiting access to the carboxyl carbon. He represents maximum steric hindrance to attack as arising from a coiled conformation, shown for M-butyric acid in 5. 

When these labeled oxaloacetates enter a second turn of the cycle, both of the carboxyl carbons are lost as CO2, but the methylene and carbonyl carbons survive through the second turn. Thus, the methyl carbon of a labeled acetyl-CoA survives two full turns of the cycle. In the third turn of the cycle, one-half of the carbon from the original methyl group of acetyl-CoA has become one of the carboxyl carbons of oxaloacetate and is thus lost as CO2. In the fourth turn of the cycle, further scrambling results in loss of half of the remaining labeled carbon (one-fourth of the original methyl carbon label of acetyl-CoA), and so on. 

All labelled carboxyl carbon removed by diese two steps... 

FIGURE 25.2 (a) The acetyl-CoA carboxylase reaction produces malonyl-CoA for fatty acid synthesis, (b) A mechanism for the acetyl-CoA carboxylase reaction. Bicarbonate is activated for carboxylation reactions by formation of N-carboxybiotin. ATP drives the reaction forward, with transient formation of a carbonylphosphate intermediate (Step 1). In a typical biotin-dependent reaction, nncleophilic attack by the acetyl-CoA carbanion on the carboxyl carbon of N-carboxybiotin—a transcarboxylation—yields the carboxylated product (Step 2). 

This tertiary ester was developed to reduce aspartimide and piperidide formation during the Fmoc-based peptide synthesis by increasing the steric bulk around the carboxyl carbon. A twofold improvement was achieved over the the standard Fbutyl ester. The Mpe ester is prepared from the acid chloride and the alcohol and can be cleaved under conditions similar to those used for the r-butyl ester. ... 

Carboxylic acids are similar in some respects to both ketones and alcohols. Like ketones, the carboxyl carbon is sp2-hybridized, and carboxylic acid groups are therefore planar with C-C=0 and 0=C-0 bond angles of approximately 120° (Table 20.2). 

Carboxylic acid groups can be detected by both and A3C NMR spectroscopy. Carboxyl carbon atoms absorb in the range 165 to 185 8 in the l3C NMR spectrum, with aromatic and unsaturated acids near the upheld end of the range (—165 8) and saturated aliphatic acids near the downfield end (—185 8). Nitrile carbons absorb in the range 115 to 130 8. 

Assume that acetyl CoA containing a 14C isotopic label in the carboxyl carbon atom is used as starting material for the biosynthesis of mevalonate, as shown in Figure 27.7. At what positions in mevalonate would the isotopic label appear ... 

The a-sulfinyl carbanion attacks a-halocarboxylic acid esters at the carboxylic carbon atom, not at the a-carbon atom, and the corresponding ketones are obtained slereoselectively in high yield62. 

The second step in this case, which is much slower than the first, is the attack of the amide nitrogen on the carboxylic carbon. Unsubstituted and A -substituted amides have been used instead of ammonia. Since the other product of this reaction is RCOOH, this is a way of hydrolyzing such amides in the absence of water. ... 

Carbon atoms are numbered from the carboxyl carbon (carbon No. 1). The carbon atoms adjacent to the carboxyl carbon (Nos. 2, 3, and 4) are also known as the a, P, and y carbons, respectively, and the terminal methyl carbon is known as the CO or n-carbon. 

In another experiment, [l,2- C2-2-dJ double-labeled acetate was fed. First we observed a complete loss of deuterium atoms. In a short incubation, however, we obtained neosaxitoxin partially retaining a deuterium atom (40% equivalent of incorporated acetate molecule). The location of the deuterium atom was on C-5, which was originally the carboxyl carbon of acetate, suggesting that it migrated from the adjacent methyl-derived carbon C-6. 

The REDOR 13C echo spectra of two different PMA/[l-13C]Leu/[15N]Leu samples are shown in Figure 10. Signals from the enriched carboxyl carbon of leucine are sharp at all concentrations. Apparently, even at the lowest concentration, the leucine molecules are not well dispersed throughout the polymer, but instead are clustered in small, ordered, crystalline-like domains. The doubling of the carboxyl signal is also seen for pure, crystalline leucine and is attributable to the detailed packing of the leucine molecules in the solid state. 

Phenylcyclopentanecarboxylic acid, with ethyl chlorocar-bonate to give mixed carboxylic-carbonic anhydride, 51, 48... 

Sodium, with l-bromo-3-chloro-cyclobutane to give bicyclo [l.l.O]butane, 51, 55 Sodium amalgam, 50, 50, 51 Sodium amide, with 2,4-pentane-dione and diphenyliodonium chloride to give l-phenyl-2, 4-pentanedione, 51, 128 Sodium azide, 50, 107 with mixed carboxylic-carbonic anhydrides, 51, 49 Sodium borohydride, reduction of erythro-3-methanesulfony-loxy-2-butyl cyclobutanecar-boxylate, 51, 12 reduction of 2-(1-phenylcyclo-pentyl)-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine to 2-(1-phenylcyclopentyl)-4,4, 6-trimethyltetrahydro-l,3-oxazine, 51, 25 Sodium cyanoborohydride, used... 

Peptides are short chains of amino acids linked by peptide bonds. Most biologically active peptides contain two to ten amino acids. Peptide bonds are formed between the carboxyl carbon of one amino acid and the amino nitrogen of another. Since water is released, this is an example of dehydration synthesis. The bond forms as illustrated in Figure 16.7. 

Odor and color stability problems were also related to the alkyl chains used for SAI. These could be traced to the oxidation of unsaturated carbons, such as oleic acid (Ci8 fatty acid with a single double bond between carbon 9 and 10, i.e. bond position 9 counted from the carboxyl carbon), linoleic acid (Cis fatty acid with two double bonds at position 9 and 12), and linolenic acid (Cis fatty acid with three double bonds at position 9, 12, and 15). Natural coconut fatty acid contains about 6% oleic acid, about 3% linoleic acid, and less than 1% linolenic acid. Tallow fatty acid contains nearly 44% oleic and about 6% of other unsaturates [20]. Partial hydrogenation of the coconut fatty acid used in the manufacture of SCI served to eliminate linoleic and linolenic acids for improved odor stability, while not eliminating oleic acid, which is important for good lather. 

Consider now what happens when the two carboxyl groups react to form a small ring, for example the anhydride. The angle between the carboxyl carbons must be reduced much further, perhaps to around 90°, in the product and in the transition state leading to it. Compared with malonic acid itself, this process has less far to go in the dimethyl compound because the two alkyl groups have already forced the carboxyls part of the way towards each other. The observed diminution in bond angle caused by the introduction of the two alkyl substituents thus specifically favours the formation of the small ring. 

FMF Chen, M Slebioda, NL Benoiton. Mixed carboxylic-carbonic acid anhydrides of acylamino acids and peptides as a convenient source of 2,4-dialky 1 -5(AH)-oxazo-lones. Int J Pept Prot Res 31, 339, 1988. 

S Kim, JL Lee, YC Kim. A simple and mild esterification method for carboxylic acids using the mixed carboxylic-carbonic anhydrides. J Org Chem 50, 560, 1985. 

DS Tarbell, EJ Longosz. Thermal decomposition of mixed carboxylic-carbonic anhydrides. Factors affecting ester formation. J Org Chem 24, 774, 1959. 

DS Tarbell. The carboxylic carbonic anhydrides and related compounds. Acc Chem Res 2, 296, 1969. 

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