Acyl adenylate

FIGURE 24.8 The mechanism of the acyl-CoA synthetase reaction involves fatty acid carboxylate attack on ATP to form an acyl-adenylate intermediate. The fatty acyl CoA thioester product is formed by CoA attack on this intermediate. 

Note that the first step in Figure 21.6—reaction of the carboxylate with ATP to give an acyl adenylate—is itself a nucleophilic acyl substitution on phosphorus. The carboxylate first adds to a P=0 bond, giving a five-coordinate phosphorus intermediate that expels diphosphate ion as leaving group. 

In fatty-acid biosynthesis, a carboxylic acid is activated by reaction with ATP to give an acyl adenylate, which undergoes nucleophilic acyi substitution with the — SH group or coenzyme A. (ATP = adenosine triphosphate AMP = adenosine monophosphate.)... 

Acyl CoA s, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage (0 = P—O—P=0) between phosphopantetheine and adenosine 3, 5 -bisphosphate. (The prefix "bis" means "two" and indicates that adenosine 3, 5 -bisphosphate has two phosphate groups, one on C3 and one on C5. ) Reaction of coenzyme A with an acyl phosphate or acyl adenylate... 

The P-alanyl dipeptides carnosine and anserine (A -methylcarnosine) (Figure 31-2) activate myosin ATPase, chelate copper, and enhance copper uptake. P-Alanyl-imidazole buffers the pH of anaerobically contracting skeletal muscle. Biosynthesis of carnosine is catalyzed by carnosine synthetase in a two-stage reaction that involves initial formation of an enzyme-bound acyl-adenylate of P-alanine and subsequent transfer of the P-alanyl moiety to L-histidine. 

After the formation of an acyl adenylate, the similarities between MoeB and El appear to come to an end (Figure 3.2B). In the El enzymes an active-site cysteine residue attacks the ubiquitin adenylate forming the El-ubiquitin thioester. E. coli MoeB contains nine cysteine residues, four of which are involved in coordinating the zinc atom. Sequence alignments show that among the remaining cysteines... 

Conformational Changes during the Formation of the Acyl Adenylate... 

Following the formation of the acyl adenylate the reactions will proceed along different paths. In the MoaD-MoeB complex a thiocarboxylate will be formed and the current knowledge regarding this step has been summarized (Section 3.3.5.). 

Fig. 3.7. Adenylation reaction. (A) Stereo representation of a superposition of the MoaD-MoeB complex in its apo-state (red), in complex with ATP (yellow) and after formation of the acyl adenylate (blue). (B) Proposed reaction scheme for the formation of the acyl adenylate. Arg refers to the second arginine originating either from the second subunit in case of MoeB and hetereodimeric El enzymes,...

Li, T. and Rosazza, J.P.N., NMR Identification of an acyl-adenylate intermediate in the aryl-aldehyde oxidoreductase catalyzed reaction. J. Biol. Chem., 1998, 273, 34230-34233. 

The firefly enzyme (EC 1.13.12.7) catalyzes the intermediate formation of D(-)-luciferyl adenylate and pyrophosphate fromD(-)-luciferin and ATP, followed by the oxidative reaction of the acyl adenylate with molecular oxygen to form an enzyme-bound product in the excited... 

The carboxyl groups of the amino acids are converted to reactive acyl adenylates by reaction with ATP, just as in Eq. 10-1. Each "activated" amino acid is carried on a molecule of transfer RNA (tRNA) and is placed in the reactive site of a ribosome when the appropriate codon of the mRNA has moved into the site. The growing peptide chain is then transferred by a displacement reaction onto the amino group of the activated amino acid that is being added to the peptide chain. In this manner, new amino acids are added one at a time to the carboxyl end of the chain, which always remains attached to a tRNA molecule. The process continues until a stop signal in the mRNA ends the process and the completed protein chain is released from the ribosome. Details are given in Chapter 29. 

Activation of amino acids for incorporation into oligopeptides and proteins can occur via two routes of acyl activation. In the first of these an acyl phosphate (or acyl adenylate) is formed and reacts with an amino group to form a peptide linkage (Eq. 13-4). The tripeptide glutathione is formed in two steps of this type (Box 11-B). In the second method of activation aminoacyl... 

The AG° values for the hydrolysis of any P - O - P bond of ATP, inorganic pyrophosphate, or any acyl CoA thiolester are all about -34 kj / mole, while the corresponding figure for the hydrolysis of a mixed carboxylic phosphate anhydride is about -55 kj / mole. Calculate the value of AG° for the following reaction describing the activation of fatty acids to the fatty acyl adenylate. 

Microparticles composed of each of four homopolyribonucleotides and the same lysine-rich proteinoid is found to influence the incorporation of individual amino-acyl adenylate 59). The incorporation favors the amino acids whose codons are related to the nucleotide in the particles (Fig. 6), when conditions are appropriately chosen. Other conditions yield other preferences. These results support a stereochemical basis for the genetic code. 

Among activated forms of amino acids, mixed anhydrides with inorganic phosphate or phosphate esters require a special discussion because they are universally involved in peptide biosynthesis through the ribosomal and non-ribosomal pathways. These mixed anhydrides have stimulated studies in prebiotic chemistry very early in the history of this field. Amino acyl adenylates 18c have been shown to polymerize in solution [159,160] and in the presence of clays [139]. However, their participation as major activated amino acid species to the prebiotic formation of peptides from amino acids is unlikely for at least two reasons. Firstly, amino acid adenylates that have a significant lifetime in aqueous solution become very unstable as soon as either CO2 or bicarbonate is present at millimolar concentration [137]. Lacey and coworkers [161] were therefore conduced to consider that CO2 was absent in the primitive atmosphere for aminoacyl adenylate to have a sufficient lifetime and then to allow for the emergence of the modern process of amino acid activation and of the translation apparatus. But this proposition is unlikely, as shown by the analysis of geological records in favor of CO2 contents in the atmosphere higher than present levels [128]. It is also in contradiction with most studies of the evolution of the atmosphere of telluric planets [30,32], Secondly, there is no prebiotic pathway available for adenylate formation and ATP proved to be inefficient in this reaction [162]. 

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