Adenylic acid analogues

Although adenylic acid deaminase is a well-known enzyme that has been isolated in crystalline form, little work has been reported on its substrate specificity evidence for the deamination of 4-aminopyrazolo[3,4-d]pyrimidine ribonucleotide has been presented [118], but it is not known if it catabolizes any of the other intracellularly formed adenylic acid analogues. 

The degradation of cyclic AMP is catalyzed by a specific phosphodiesterase which converts it to adenylic acid " (Figure l). Again, the effect of nucleotide analogues or other potential inhibitors on the degradation of cyclic AMP can be studied vitro in this enzyme system, and the possible significance of such agents will be discussed below. 

For example, allopurinol 9.51) inhibits the growth of several species of Leishmania (p. 9). It is converted in the parasite to allopurinol ribonucleoside which is stable in the human host but is rapidly converted by the parasite to the ribonucleotide by a parasite-specific phosphotransferase. The parasite then transforms this product to an analogue of adenylic acid by replacing =0 by —NH2. The product is incorporated into the parasite s RNA, with lethal effect (Nelson et al., 1979). Tryparuosoma cmzi reacts similarly. 

It was therefore concluded that formaldehyde reacts in the culture medium to produce a mutagenic base-analogue(s). Free formaldehyde itself injected into larvae shows no mutagenic effects [6], which indicates that an initial in vitro reaction of formadehyde with either adenosine or adenylic acid is necessary for its mutagenicity. Formaldehyde-treated RNA, from which unreacted formaldehyde is removed by dialysis, shows a strong mutagenic effect [7]. 

It was first assumed [3] that the analogues were effective by incorporation into DNA after conversion to their deoxyribose forms. However, it was later found that only the ribose derivative is effective [11] the deoxyribose derivatives of adenosine and adenylic acid do not mediate formaldehyde mutagenesis when present in the culture medium. 

Nonhydrolyzable aspartyl adenylate analogues (14—16) (Table 4) have been prepared and tested as inhibitors of E. coli AspRS. Sulfamate (14) is a potent competitive inhibitor (A)= 15 nmol P ), whereas l-aspartol adenylate (15) is a weaker inibitor (A) = 45 pmoll ) with respect to aspartic acid. The corresponding /3-ketophosphonate (16) is also a strong inhibitor (A- = 123 nmol 1 ). Replacing the 5 -oxygen on the ribose with an NH group (compound 17) resulted in an equally potent inhibitor of the S. aureus enzyme (i) = 15 nmol 1 ). ... 

Figure 16 (a) Structures of adenylation domain intermediates and inhibitors aminoacyl-sulfamoyl adenosine (AMS) and cisoid -like macrocyclic inhibitor, (b) Alkyne-functionalized chemical probe for NRPS A and PCP domains, (c) Structure of aminoacyl PCP, SNAC substrate analogue, and hydrolytically stable phosphopantetheinyl analogue, (d) Structure of vinylsulfonamide probe. R represents a peptide component and R an amino acid side chain. 

Adenyl-(2 -5 )-adenyl-(2 -5 )-8-azidoadenosine has been prepared by the phosphotriester approach from building blocks containing a 3 -O-(A-nitrophenyl)-ethylsulphonyl group (137). The trinucleotide has been used to label RNase L in L929 cells by uv irradiation in cell culture. A review on the photoreactions of nucleic acids and their constituents with amino acids and related compotinds has recently been published. The affinity analogues of cAMP, 2-[(A-bromo-... 

Adenylation domains utilize free amino acids,97 aryl acids,104 or fatty acids,51 biosynthetic substrates, and one T domain for tethering their substrates on the thiotemplate. C domains have an upstream nucleophile and a downstream electrophile as biosynthetic substrates, and two T domain substrates one upstream and one downstream T domain.93 10 Transferases, such as the aminoacyl transferase CmaE in the crotonine biosynthetic pathway, 6 are similar to C domains in that they use two T domain substrates but they have only one biosynthetic substrate tethered to the downstream T domain. Tailoring enzymes can have two forms of biosynthetic substrates T domain-bound substrates52 5 or non-T domain-bound substrates. Non-T domain-bound substrates can be free carbon acids,46 107 CoA-activated species, or the analogue of the natural product lacking the assayed chemical modification. 

An enzyme has been isolated from the FK520 producer which is believed to be the key one responsible for inserting pipecolic acid into the macrocycle [114]. It is reported to be dimeric and activates pipecohc acid and several structural analogues in an ATP-dependent reaction to give an enzyme-bound amino-acyl adenylate. There is evidence that this then reacts to form a thioester linkage to the enzyme. This mechanism of activation is the same as that found in the non-ribosomal biosynthesis of peptide natural products such as gramicidin [112]. 

Oligonucleotide analogues have commonly been considered as nucleic acids even in the absence of an acidic group, e.g., methyl phosphon-ates. In a formal sense, peptide nucleic acids are neither peptides nor composed of nucleic acids, nor should they be confused with peptide/protein oligonucleotide conjugates as described in the previous section. The PNA monomeric unit contains features of both amino acids and nucleosides. The four common base portions of nucleosides—adenyl, cytosyl, guanidyl, and thymidyl—are tethered to the PNA backbone, which carries the functionality of common amino acids. Amide bonds then consecutively link these monomer units. The term polyamide is more chemically appropriate thus an alternative name is polyamide nucleoside analogue, which is still abbreviated PNA. 

The synthesis of the two diastereoisomers of P -l-(2-nitrophenyl)ethyl adenosine S -lri-phosphate (91) has been achieved using resolved (R)- and (5)-l-(2-nilroidienyl)ethanol. The alcohols were converted to (R)- and (5)-l-(2-nitrophenyl)ethyl phosphates by phosphitylation with N,)V-diisopropyl-fi(s-(2-cyanoethyl)phosphoramidite (92) and subsequent oxidation with 3-chlorobenzoic acid. Each of the monophosphates was activated with carbonyidiimidazole and condensed with adenosine diphosphate to give the desired triphosphate. These ATP analogues can be used for the rapid release (by flash photolysis) of ATP in biological systems. The 8-azido-3 -0-anthraniloyl derivatives of 2 -dADP (93) and 2 -dATP (94) have been prepared in seven steps from 8-azido-2 -deoxyadenosine. These compounds are of interest as fluorescent and photoactivatable probes for the nucleotide binding site of kinases and cyclases. In particular, (94) was shown to be a competitive inhibitor of Bordetella pertussis adenylate cyclase and the observed K- (74 pM) was close to tiiat predicted from the K- value of 3 -0-anthraniloyl-2 -dATP. ... 

An extensive paper from Sekine s laboratory has discussed the synthesis of aminoacylamido-derivatives of AMP (192), analogues of aminoacyl adenylates. The syntheses, which were successfully completed using a number of a-amino acids, used as a key step the reaction of 5 -0-phosphoramidite derivatives of adenosine with the amides of the suitably-protected amino acid. The application of similar chemistry in the synthesis of phosmidosine was mentioned above. ... 

The glutamine analogue, diazo-oxo-norleucine, and the aspartate analogue, hadacidin (iV-formyl hydroxyaminoacetic acid), inhibit guanylate synthetase and adenylosuccinate synthetase, respectively. Alanosine (2-amino-3-nitrohydroxylaminopropionic acid) is also an inhibitor of adenylate synthesis from inosinate, but its mechanism of inhibition is not yet clear (52). 

Additional substances of interest which were cited in the literature for their effect in atherosclerosis or related conditions include p-benzal butyric acid °, 2- -(2-diethyl-aminoethoxy)phenyl7benzimidazole and its naphthyl analogue , l,2-a-oxido-4,6-androstadiene-5,17-dione . 2,2 >/ l-methyl-4,4-diphenylbutylidene) -bis (p-phenyleneoxyj7 3istrimethylamine (SQ 10591) , chlorpheniramine ", chlorcyclizine , 2-ethyl-n-caproic acid , glutamic acid , nicotonic acid and 3-methyl-pyrazole-5-carboxylic acid , 2(R),5CR) dihydroxy-4-(9-adenyl)-... 

Firefly luciferin (111 R = R = H, X = OH) and a number of its analogues were synthesized by previously established reaction sequences from a variety of substituted 2-cyanobenzothiazoles (109) and cysteines (110). Amongst others, homoluciferin (112) and 5, 7 -dimethyl-luciferin (113) are accessible in this way. Their adenylates were produced by the condensation of the free acids with adenosine monophosphate in the presence of dicyclohexylcarbodi-imide. These were used in detailed spec-trophotometric studies of their chemiluminescence (initiated by bases), their fluorescence, and their bioluminescence under the influence of luciferase the possible mechanisms of these processes were discussed. ... 

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