Uridine metabolism

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). 

Iyer L, King CD, Whitington PF et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998 101 847-854. 

Isselbacher, K. J., cited by Kalckar, H. M., and Maxwell, G. S., Biosynthesis and metabolic function of uridine diphosphoglucose in mammalian organisms and its relevance to certain inborn errors. Physiol. Revs. 38, 88 (1958). 

C. P. Landowski, X. Song, P. L. Lorenzi, J. M. Hilfinger, and G. L. Amidon. Flox-uridine amino acid ester prodrugs enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. Pharm Res 22 1510-1518 (2005). 

T. Kimura, M. Miki, K. Watanabe, S. Kondo, I. K. Ho, I. Yamamoto, Metabolism of a Novel Hypnotic, /VLphcnacy I uridine, and Hypnotic and Sedative Activities of Its Enantiomer Metabolites in Mouse , Xenobiotica 2000, 30, 643 - 653. 

The fact that many agents which interrupt the synthesis of pyrimidine nucleotides from orotic acid in animals can also inhibit the growth of experimental neoplasms suggests a search for additional antimetabolites whose locus of action is in this metabolic sequence. Two in vitro biological screening systems were developed for this purpose [202—207]. From a study of systems with oxidative energy sources, 5-bromo-[208—209] (Villa), 5-chloro-[210] (Vlllb) and 5-diazo-orotic acid [211] (IX) were found to inhibit the conversion of orotic acid to the uridine nucleotides by 40—100 per cent [202]. 

Although FdUrd produces only DNA-medicated cyotoxicity, 5-FU can also be metabolized to fluorouracil monophosphate (FUMP) and ultimately to fluorouracil triphosphate (FUTP), which can be incorporated into RNA in place of uridine triphosphate (UTP). In other words, incorporation of 5-FU into RNA mimics uracil de novo synthesis and affects the production of ribosomal RNAs (rRNAs) (16,17). 5 -FU also affects several aspects of messenger RNA (mRNA) function, including transcription (18), translation (19), and slicing (20). 

Figure 9-8. Pathway for metabolism of heme and excretion as bilirubin. Heme degradation begins with heme oxygenase, which catalyzes a complex set of reactions that simultaneously open the protoporphyrin ring structure and release iron in the ferric (Fe ) state. This is the only physiologic reaction that makes endogenous CO in the body a portion of the small amounts made is expired via the lungs. The structure of the main form of bilirubin is shown. Symbols for the side groups indicate M, methyl V, vinyl P, propyl. Formation of the diglucuronide is catalyzed by bilirubin uridine diphosphate (UDP) glucuronyltransferase. RE, reticuloendothelial.

This is the most common single metabolic reaction undergone by drugs, which occurs in the liver. These reactions are catalyzed by a family of enzymes known as uridine diphosphate (UDP) glucuronyl transferases. These enzymes are present in liver, kidney, intestine and lungs. 

Studies of canavanine interaction with the tobacco hornworm and J-. miTior also revealed the marked ability of canavanine.to inhibit whole organism incorporation of [ Hjthymidine and uridine into trichloroacetic acid-precipitated materials. When canavanine is provided simultaneously with the appropriate radio-labeled precursor, ample evidence for curtailed nucleic acid metabolism emerges but protein synthesis is unaffected (Table I, exp. I). In experiment II, canavanine is allowed to assimilate... 

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