Metabolic analogs

Because 226Ra and 90Sr are metabolic analogs of calcium, they are deposited in the skeleton. Both isotopes are associated with bone cancers (Hobbs and McClellan 1986). In pregnant rats, the total amount of 226Ra transferred from the dam to the 8 to 10 fetuses in a litter was low after a single... 

The view that this is true net biosynthesis of fibrinogen is supported by a variety of ancillary observations. Fibrinogen biosynthesis is suppressed in the presence of metabolic analogs, such as L-ethionine and puromycin, most markedly by the latter in spite of the maximal stimulus for production. Mitomycin C, which is believed to interfere with biosynthetic processes in the nucleus, also caused some suppression of fibrinogen biosynthesis. The isolated perfused liver in the presence of any of the three inhibitors used continues to function in an apparently normal manner in terms of bile secretion, linear urea production, amino acid oxidation, and glucose utilization. The effects of these inhibitors on the biosynthesis of the other plasma proteins will be described elsewhere. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Citrate synthase is the first step in this metabolic pathway, and as stated the reaction has a large negative AG°. As might be expected, it is a highly regulated enzyme. NADH, a product of the TCA cycle, is an allosteric inhibitor of citrate synthase, as is succinyl-CoA, the product of the fifth step in the cycle (and an acetyl-CoA analog). 

W. Pfleiderer, H. Schirmeister, T. Reiner, M. Pfister, and R. Charubala, Biophosphates and Their Analogs-Synthesis, Structure, Metabolism and Activity, Bioact. Mol. 3, 133(1987). 

Butaprost (82) not only has the typical C-15 hydroxyl of the natural prostaglandins moved to C-16, as do several of the analogues discussed above, but it has a rather interesting gem dialkyl substitution at C-17, presumably for metabolic protection, in the form of a cyclobutyl ring. It is a bronchodilator and is prepared in a manner analogous to that of rioprostil discussed above [17]. 

Oxepin and its derivatives have attracted attention for several reasons. Oxepin is closely related to cycloheptatriene and its aza analog azepine and it is a potential antiaromatic system with 871-elcctrons. Oxepin can undergo valence isomerization to benzene oxide, and the isomeric benzene oxide is the first step in the metabolic oxidation of aromatic compounds by the enzyme monooxygenase. 

In the soil, an imbalance of amino acids, the presence of D-amino acids derived from microbial metabolism, or analogs and homologs of constituent protein amino acids could produce a deviation in the... 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Pyridoxal phosphate mainly serves as coenzyme in the amino acid metabolism and is covalently bound to its enzyme via a Schiff base. In the enzymatic reaction, the amino group of the substrate and the aldehyde group of PLP form a Schiff base, too. The subsequent reactions can take place at the a-, (3-, or y-carbon of the respective substrate. Common types of reactions are decarboxylations (formation of biogenic amines), transaminations (transfer of the amino nitrogen of one amino acid to the keto analog of another amino acid), and eliminations. 

---