Amino acid adenylates

Taking this one step further, perhaps even an inorganic gene may have been provided by clay mineral sources. Earliest clay samples are of a mineral called montmorillonite that consists of sheets of aluminosilicates in which Fe2+, Fe3+ and Mg2+ are substituted for some of the Al3+, and Al3+ is substituted for Si4+. The oxygen content of the layers does not change and the alternative valencies allow the production of positive and negatively charged layers. Dramatically, Paecht-Horowitz and co-workers showed that the amino acid adenylate could be polymerised with up to 50 units on the montmorillonite surface in aqueous solution. Similar condensation reactions for carbohydrates on hydrotalcite surfaces have... 

Acidic proteinoid potentiates the active structure of lysine-rich proteinoid participating in forming microspheres in neutral buffer. Physical surface effects and providing micro condition in the microspheres could be surmised. Activation of amino acids generally requires acidic condition. Amino acids are activated by ATP and Mg2+ at pH 4-5 32 33). Aminoacyl adenylate anhydride and ester is formed preferentially from amino acid and adenylate imidazolide at pH 6.0J7). On the other hand, polycondensation of activated amino acids undergoes at pH values higher than 7. Peptides are formed from aminoacyl adenylate in basic buffer (the optimum pH is 10 for alanyl adenylate 40) from amino acid adenylate phosphoramidate and imidazole at pH 7.0 from N-(aminoacyl)-imidazole at pH 6-9 43). In this context, acidic and basic environments may be provided inside and/or on the surface of the microspheres composed of acidic and basic proteinoids in neutral buffer. Acidic micro condition suitable for the activation of amino acids and basic micro environment favorable for peptide formation from activated amino add may be provided. 

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]. 

Several systems based on the potentialities of amino acid-phosphoric acid mixed anhydrides have been devised to check the idea that the genetic code developed from an early pathway of RNA-dependent peptide synthesis in an RNA world [168]. RNA sequences have thus been selected that are capable of self-aminoacylation using amino acid adenylates, catalyzing a reaction chemically similar to the aminoacylation of fRNA by the protein aminoacyl fRNA synthetases [169]. 

Cell-free systems capable of synthesising polypeptides have been prepared from protoscoleces of E. granulosus (7), larval T. crassiceps (588) and H. diminuta (633). In general, these studies have demonstrated that protein synthesis in cestodes, although showing some specificity, is similar to that in mammals in that it requires polysomes, amino acid adenylates, aminoacyl-tRNAs, pH 5 fraction, ATP, GTP, magnesium and either sodium or potassium ions. 

Acyl adenylate Amino acid adenylate Amino acid + AMP -13... 

It has been shown that the first step in ribosome-dependent peptide synthesis is activation of amino acids to form amino acid adenylates. The amino acids are then transferred to RNA present in the soluble extract of the cell, the so-called transfer RNA (tRNA) to which the amino acids become fixed by an ester linkage. These two steps are usually referred to as the formation of aminoacyl-tRNA. The next step, the translation step of codons in messenger RNA (mRNA), which is associated with ribosomes, to provide a polypeptide includes three stages (1) chain initiation by mutual coordination with initiation factors, (2) chain elongation in aid of elongation factors, and (3) chain termination in support of release factors. 

Thiol groups enter some biologically important thiol compounds by the direct incorporation of cysteine itself. Most frequently this involves peptide bond formation. The incorporation of cysteine into proteins does not differ from any other amino acid involving activation as an amino acid adenylate, transfer to a specific transfer ribonucleic acid (t-RNA), and assembly by ribosomal enzymes as coded by messenger ribonucleic acid (m-RNA). It should be pointed out that cystine, the two-headed ... 

Paecht-Horowitz, M., Berger, J. and Katchalsky, A. (1970) Prebiotic synthesis of polypeptides by heterogenous polycondensation of amino acid adenylates. Nature, 228, 63 639. 

A transfer of the adenylyl group i.e., a P—0 split has not been obtained so far (or maybe has not been looked for) with the adenylates in the absence of enzyme. In the presence of the activating enzymes, on the other hand, the adenylyl group is veiy readily transferred onto pyrophosphate to give ATP 116, 169, 164, 177). This reaction, however, is not specific, since tryptophan activating enzyme, for example, can synthetize ATP from all the amino acid adenylates tested 116) as well as from the adenylate of D-tiyptophan 169). The same transfer of the AMP moiety onto PP does, of course, also occur in the amino acid catalyzed ATP-PP exchange reaction. 

The chemical synthesis of several mixed anhydrides such as DPN SS6), XJDP-glucose (336), butyryl adenylate (336a), and amino acid adenylates (336b) have been reported. Cytidine diphosphate choline was formed in good yield by condensing phosphorylcholine with cytidine 5 -... 

The amino acid adenylate enzyme complex combines with a t-RNA molecule which is specific for the particular amino acid (Fig. 5.15)—indeed there are more than one species of t-RNA for some of the amino acids. 

J (339), a 28-amino acid peptide, is a member of a family of stmctuially related peptides that includes secretin [1393-25-5] (340), growth hormone releasing factor (GRF), and pituitary adenylate cyclase-activating peptide (PACAP) [137061(341) (83). 

Figure 11.5 Amino acid building blocks are incorporated into daptomycin backbone successively by NRPS subunits DptA, DptBC and DptD (a). Structural diversity of daptomycin peptide core can be obtained by genetic modifications of dpt gene cluster (b). C, condensation domain A, adenylation domain PCP, peptidyl carrier protein E, epimerase TE, thioesterase domain... 

At present it is not known if all H3 receptor isoforms similarly activate the wide array of signaling pathways. In transfected cells, the rat H3(413) and H3(397) isoforms both inhibit adenylate cyclase more efficiently than does the hill length rat H3 receptor isoform (445 amino acids), but the former are less efficient in activating the MAPK pathway. Much less information is available for the human H3 receptor isoforms but shorter isoforms seem to couple more efficiently to G -proteins to inhibit cAMP production in transfected cells [40],... 

Parathyroid hormone (PTH) regulates calcium levels in blood and bone remodeling. The activation domain of that 84-amino acid polypeptide locates around the N-terminal (1-34 amino acids). Parathyroid hormone receptor is a typical G-protein coupled receptor, which is coupled to both adenyl cyclase/cAMP and PLCy/IP3/cytosolic Ca2+ intracellular signaling pathways. In order to identify the structural elements involved in the peptide hormone binding and signal initiation, Chorev et al. employed a photoaffinity scanning approach. The N-terminal amino acids were successively deleted or modified and the new N-terminus was replaced for photoreactive Bpa. The most active peptide ana-... 

In humans the intronless gene encoding HR2 is located on chromosome 5. The human HR2 is a protein of 359 amino acids coupled to both adenylate cyclase and phosphoinositide second messenger systems by separate GTP-dependent mechanisms including Ga and also induces activation of c-Fos, c-Jun PKC and p70S6 kinase [16], Studies in different species and several human cells demonstrated that inhibition of characteristic features of the cells by primarily cAMP formation dominates in HR2-dependent effects of histamine. 

Figure 12 Aminoacyl-adenylates and stable bioisosteres. Ad, adenosine R, amino acid side chain.

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