Acylation reactions amino acid conjugation

Conjugation involves addition of an endogenous moiety to a foreign molecule, which may be a product of a phase 1 reaction. Major phase 2 routes conjugation with glucuronic acid, sulfate, glutathione amino acids acetylation methylation. Enzymes involved are transferases except in the case of amino acid conjugation where the first step is catalyzed by an acyl CoA synthetase, then a transferase is involved. 

Amino Acid Conjugation. In the second type of acylation reaction, exogenous carboxylic acids are activated to form S-CoA derivative in a reaction involving ATP and CoA. These CoA derivatives then acylate the amino group of a variety of amino acids. Glycine and glutamate appear to be the most common acceptor of amino acids in mammals in other organisms, other amino acids are involved. These include ornithine in reptiles and birds and taurine in fish. 

The conjugation of carboxylic acid xenobiotics with amino acids occurs in both liver and kidney and is catalyzed by an enzyme system located in the mitochondria. Conjugation requires initial activation of the xenobiotic to a Co A derivative in a reaction catalyzed by acyl CoA ligase. The acyl CoA subsequently reacts with an amino acid, giving rise to acylated amino acid conjugate and CoA. 

The reactions are catalyzed by acyl-CoA amino acid A-acyltransferase, of which two distinct A-acyltransferases exist in mammalian mitochondria. The predominant transferase conjugates medium-chained fatty acyl CoA and substituted benzoic acid derivatives with glycine and is termed an aralkyl-CoA glycine A-acyltransferase, while the other enzyme conjugates arylacetic acid derivatives with glycine, glutamine, or arginine and is an arylacetyl-CoA amino acid A-transferase. 

Bile acids are also conjugated by a similar sequence of reactions involving a microsomal bile acid CoA ligase and a soluble bile acid A-acyl-transferase. The latter has been extensively purified, and differences in acceptor amino acids, of which taurine is the most common, have been related to the evolutionary history of the species. 

The reactions commonly involved in Phase II conjugation are acylation, sulphate formation and conjugation with amino acids, glucuronic acid, glutathione and mercapturic acid (Table 9.3). Methylation is also regarded as a Phase II reaction although it is normally a minor metabolic route. However, it can be a major route for phenolic hydroxy groups. In all cases, the reaction is usually catalysed by a specific transferase. 

The formation of IAA conjugates is widely believed to be a means for removal of excess IAA produced during certain times of plant development and also in mutant plants where indolic precursors and IAA metabolites accumulate.32 In all higher and many lower plants, applied IAA is rapidly conjugated to form IAA—aspartate.33 The ability of plant tissues to make aspartate conjugates of a variety of active auxins is induced by pretreatment with auxin,34 and this induction was shown to be blocked by inhibitors of RNA and protein synthesis. After almost 50 years of study, an in vitro system from plants was described that accounts for the formation of IAA amide conjugates35 via a mechanism where the acidic auxin is adenylated followed by acyl transfer to the amino acid. The gene for this reaction had been discovered almost 20 years before, when GH3 from soybean was shown... 

Conjugate addition reactions of N-nucleophiles with double stereodifferentiation are known in some cases11-116. While direct reaction of chiral amines with chiral enones11 leads to poor enantiomeric excess of the resulting /l-amino acids, reaction of chiral amines116 with acylated chiral iron complexes gives /J-amino acids with a high enantiomeric excess. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

The conversion of serine to cysteine involves some interesting reactions. The source of the sulfur in animals differs from that in plants and bacteria. In plants and bacteria, serine is acetylated to form O-acetylserine. This reaction is catalyzed by serine acyltransferase, with acetyl-GoA as the acyl donor (Figure 23.13). Conversion of O-acetylserine to cysteine requires production of sulfide by a sulfur donor. The sulfur donor for plants and bacteria is 3 -phospho-5 -adenylyl sulfate. The sulfate group is reduced first to sulfite and then to sulfide (Figure 23.14). The sulfide, in the conjugate acid form HS", displaces the acetyl group of the O-acetylserine to produce cysteine. Animals form cysteine from serine by a different pathway because they do not have the enzymes to carry out the sulfate-to-sulfide conversion that we have just seen. The reaction sequence in animals involves the amino acid methionine. 

Based on previously performed studies on p-turn peptides for asymmetric acylation reactions, the group of Miller expanded the application of such catalysts to the asymmetric conjugate addition of azides to a,p-unsaturated carbonyl compounds (Scheme 13.9a). A screening of several p-turn containing peptides disclosed catalyst 10 as the appropriate catalyst for the preparation of a series of p-azido-pyrrolidinone-derived imides in good yields and with enantioselectivities up to 85%. The obtained products can be further processed towards N-Boc-protected p-amino acids. Subsequent... 

Transacylation reversible transfer of acyl groups (R-CO-) from a donor to an acceptor, e.g. transfer of the acyl residue CH3-CO- from acetyl-CoA to an acceptor Y CH3-CO - S-CoA -t Y -> CH3-CO-Y + CoA. T. is catalysed by transacylases, which are important in the synthesis and degradation of fatty acids, synthesis of conjugated bile acids via cholic acid-CoA compounds, and other reactions such as acetylation of amino acids and amines. 

The Trauner retrosynthesis of amathaspiramide F commenced with a disconnection of the A(-acyl hemiaminal group to amino aldehyde 9, which could be derived from a Nef reaction of nitroalkyl 10 (Scheme 2). It was envisioned that Seebach s asymmetric alkylation of ot-amino acids could be utilized in the conjugated addition of A(,A(-acetal ent-2 with nitrostyrene 3. Trauner initially surmised that o-proline was required as the starting material, since previous work by Seebach had shown that alkylation occurs on the same face as the f-butyl group. 

Pd(II) catalysts in the presence of of Hg(II) salts and alcohols convert heterocycles oxidatively into esters.216 Conjugated dienes, CO and MeOH are oxidatively turned into allylic ethers and unsaturated esters by a Pd(II)/Cu(II)/Aliquat-336 system. Conversions and selectivities are moderate, however.217 jhe amidocarbonylation of allylic alcohols to N-acyl-a-aminoacids has been reviewed. The reaction is catalysed by Co2(C0)8 in the presence of a co-catalyst, e.g. RhH(C0)(PPh3)3, PdCl2(PPb3)2 or F62(C0)9 (scheme 10). The amidocarbonylation of epoxides requires the addition of Lewis acids.218 The dehydration of the allylic alcohol starting material in this reaction may lead to amino acid side-products.219... 

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