Uridine pseudouridine

As shown in Sec. I, uracils have represented, for more than 90 years, a class of compounds that continually attract organic chemists, biochemists, medicinal chemists, and photobiologists. Uracils were first detected as constituents of ribonucleic acids, from which they were prepared by hydrolysis. Nucleosides derived from uracil are called uridine, pseudouridine, and uridine phosphate, respectively. Recently, uracil moieties were detected in the antibiotic Tunicamycin (85JA7761). 

Oxidation of the 5 -hydroxyl groups of uridine, - pseudouridine, and other nucleosides has made it possible to conjugate these compounds to proteins by methods amenable for the reaction of carboxylic acid derivatives with proteins. 

The sequence of nucleotides in yeast phenylalanine transfer RNA. D, 1, and Y represent the nucleotides 4,5-dihydro-uridine, pseudouridine, and dimethyl-guanosine, respectively. 

Eurther quantum chemical studies involving uracil derivatives concern the conformations and properties of uridines [98CEJ621,98JA5488,98JOC1033, OOJCS (P2)677], the nucleophilic attack in pseudouridine synthases [99JA9928], and the aza analogs of uracil [99JST349]. 

Thymine, hypoxanthine, xanthine, uridine, thymidine, adenine, inosine, adenosine, and guanosine are purchased from Calbiochem. Orotic acid, pseudouridine,... 

FIGURE 8-5 Some minor purine and pyrimidine bases shown as the nucleosides (a) Minor bases of DNA. 5-Methylcytidine occurs in the DNA of animals and higher plants, A/6-methyladenosine in bacterial DNA, and 5-hydroxymethylcytidine in the DNA of bacteria infected with certain bacteriophages (b) Sbme minor bases of tRNAs Inosine contains the basehypoxanthine. Note that pseudouridine, like uridine, contains uracil they are distinct in the point of attachment to the ribose—in uridine, uracil is attached through N-1, the usual attachment point for pyrimidines in pseudouridine, through C-5. 

A remarkable transformation is that of uridine into pseudouridine ( /). 

Pseudouridine is formed by enzymatic rearrangement of uridine in the original transcript (Eq. 28-3). It can form a base pair with adenine in the same manner as does uracil. Pseudouridine is found not only in tRNA but also in several places in both large and small ribo-somal RNA subunits. For example, it is present at position 516 in the E. coli 16S RNA,364 at a specific position in the 23S RNA, and at many more locations in eukaryotic rRNA. 

Transfer RNA molecules are notable for containing unusual nucleotides (Fig. 5) such as 1-methylguanosine (m G), pseudouridine OF), dihydrouridine (D), inosine (I) and 4-thiouridine (S4U). These are created by modification of guano-sine and uridine after tRNA synthesis. For example, inosine is generated by deamination of guanosine. 

The C-glycosyl nucleoside antibiotic showdomycin (38) was first isolated from Streptomyces showdoensis [72]. Its structure has striking similarity to uridine (39) and pseudouridine (40), but is distinguished by exhibiting a maleimide moiety (Fig. 19). The known high electrophilicity of this group towards S -nucleophiles... 

Unlike the (3-lactones and (3-lactams, the mode of action of the unusual C-glucosyl nucleoside-based natural product showdomycin is unknown. Nevertheless, this compound has been shown to possess potent antibiotic properties, with results obtained in vitro suggesting a role as a suicide inhibitor of uridine metabolism [11]. Isolated from the bacteria Streptomyces showdoensis, showdomycin contains an electrophilic moiety, malaimide, in place of the base (cf. the structures of uridine or pseudouridine). 

The proton signals of uridine (36) dissolved in deuterium oxide are well separated at 220 MHz, and a complete analysis and simulation of the spectrum by means of the LAOCOON II computer program (see Section V, p. 74) has been reported.107 It was concluded from the temperature-independence of the coupling constants and chemical shifts of the D-ribofuranoid moieties of uridine, /3-pseudouridine (40), and a-pseudouridine (41), that each of these compounds... 

Certain metabolites of the pyrimidine pathway are excreted in excess of the normal in inherited metabolic disorders of the urea cycle. They include orotic acid, uridine, and uracil. Of these substances, only uracil is a normal constituent of urine, the other two either being absent or present in very small amount. They are readily detected qualitatively as dark bands at the appropriate Rf values when a paper chromatogram of the urine is examined under ultraviolet light. They may be estimated by an ion exchange method similar to that for urinary pseudouridine (R13). 

Posttranscription modification of tRNA The synthesis of tRNA involves modification of some uridine nucleotides to unusual nucleotides, such as pseudouridine, ribothymidine, and dihydrouridine. 

Sodium ferf-butoxide in N,N-dimethylformamide at KXP was found to be very effective in promoting intramolecular displacements408 and 2,5 -anhydrothymidine was obtained directly from 5 -0-(methyl-sulfonyl)thymidine with these reagents. The same conditions have also been used to synthesize the anhydronucleosides 121 and 122 from a pseudouridine derivative408 and from a D-ribosyl derivative of 2,4-quinazolinedione.410 The same reagents with 3 -0-p-tolylsulfonyl-uridine gave mainly 1 -(2,3 -anhydro-y3-D-xylofuranosyl)uracil.408... 

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