Purine glycine

Purines Glycine, glutamine, aspartate, carbon dioxide, tetrahydrofolate, PRPP Liver, small amounts in brain and cells of the immune system Adenine and guanine nucleosides and nucleotides. DNA, RNA, and coenzymes, and energy-transferring nucleotides. 

Added support for the supposition that the biosynthesis of riboflavin and cyanocobalamin make use of a common precursor comes from the increased synthesis of riboflavin by Ashbya gossypii in cobalt-supplemented media (Hickey, 1954) and from the stimulation of riboflavin formation in a Saccharomyces cerevisiae mutant by purines, glycine, and methionine (Giri and Krishnswamy, 1964). 

The pathways for thiamine biosynthesis have been elucidated only partiy. Thiamine pyrophosphate is made universally from the precursors 4-amino-5-hydroxymethyl-2-methylpytimidinepyrophosphate [841-01-0] (47) and 4-methyl-5-(2-hydroxyethyl)thiazolephosphate [3269-79-2] (48), but there appear to be different pathways ia the eadier steps. In bacteria, the early steps of the pyrimidine biosynthesis are same as those of purine nucleotide biosynthesis, 5-Aminoimidazole ribotide [41535-66-4] (AIR) (49) appears to be the sole and last common iatermediate ultimately the elements are suppHed by glycine, formate, and ribose. AIR is rearranged in a complex manner to the pyrimidine by an as-yet undetermined mechanism. In yeasts, the pathway to the pyrimidine is less well understood and maybe different (74—83) (Fig. 9). 

Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs. 

Figure 34-1. Sources of the nitrogen and carbon atoms of the purine ring. Atoms 4,5, and 7 (shaded) derive from glycine.

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

Durre P, JR Andreesen (1983) Purine and glycine metabolism by purinolytic Clostridia. J Bacteriol 154 192-199. 

Sterol biosynthesis Bile acid biosynthesis C2rSteroid hormone metabolism Androgen and estrogen metabolism Nucleotide Metabolism Purine metabolism Pyrimidine metabolism Nucleotide sugar metabolism Amino sugar metabolism Amino Acid Metabolism Glutamate metabolism Alanine and aspartate metabolism Glycine, serine, and threonine metabolism... 

The amino acids glycine, aspartate, and glutamine are used in purine synthesis. 

Glycine Creatine Porphyrins (for the synthesis of haemoglobin and cytochromes) Purine nucleotides... 

The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

Orotic acid in the diet (usually at a concentration of 1 per cent) can induce a deficiency of adenine and pyridine nucleotides in rat liver (but not in mouse or chick liver). The consequence is to inhibit secretion of lipoprotein into the blood, followed by the depression of plasma lipids, then in the accumulation of triglycerides and cholesterol in the liver (fatty liver) [141 — 161], This effect is not prevented by folic acid, vitamin B12, choline, methionine or inositol [141, 144], but can be prevented or rapidly reversed by the addition of a small amount of adenine to the diets [146, 147, 149, 152, 162]. The action of orotic acid can also be inhibited by calcium lactate in combination with lactose [163]. It was originally believed that the adenine deficiency produced by orotic acid was caused by an inhibition of the reaction of PRPP with glutamine in the de novo purine synthesis, since large amounts of PRPP are utilized for the conversion of orotic acid to uridine-5 -phosphate. However, incorporation studies of glycine-1- C in livers of orotic acid-fed rats revealed that the inhibition is caused rather by a depletion of the PRPP available for reaction with glutamine than by an effect on the condensation itself [160]. 

The synthesis of the purine ring is more complex. The only major component is glycine, which donates C-4 and C-5, as well as N-7. All of the other atoms in the ring are incorporated individually. C-6 comes from HCOa . Amide groups from glutamine provide the atoms N-3 and N-9. The amino group donor for the inclusion of N-1 is aspartate, which is converted into fumarate in the process, in the same way as in the urea cycle (see p. 182). Finally, the carbon atoms C-2 and C-8 are derived from formyl groups in N °-formyl-tetrahydrofolate (see p. 108). 

Figure 10-1. Overview of purine synthesis. Details of the first two reactions and sources of the atoms of the purine ring in inosine 5 -monophosphate (IMP) are shown. PRPP, 5 -phosphoribosyl-1-pyrophosphate Gin, glutamine Gly, glycine Asp, aspartate THF, tetrahydrofolate.

Tetrahydrofolate is in turn converted to N, N °-methylenetetrahydrofolate, which is an essential cofactor for the synthesis of thymidylate, purines, methionine, and glycine. The major mechanism by which methotrexate brings about cell death appears to be inhibition of DNA synthesis through a blockage of the biosynthesis of thymidylate and purines. 

It plays a vital role in various intracellular reactions e.g. conversion of serine to glycine, synthesis of thymidylate, synthesis of purines, histidine metabolism etc. Due to folic acid deficiency these reactions are affected. 

Phosphoribosyl pyrophosphate (PRPP) is important in both, and in these pathways the structure of ribose is retained in the product nucleotide, in contrast to its fate in the tryptophan and histidine biosynthetic pathways discussed earlier. An amino acid is an important precursor in each type of pathway glycine for purines and aspartate for pyrimidines. Glutamine again is the most important source of amino groups—in five different steps in the de novo pathways. Aspartate is also used as the source of an amino group in the purine pathways, in two steps. 

The purine ring system is built up step-by-step beginning with 5-phosphoribosylamine. The amino acids glutamine, glycine, and aspartate... 

The atoms of the purine ring are contributed by a number of compounds, including amino acids (aspartic acid, glycine, and glutamine), CO2, and N10-formyltetrahydrofolate (Figure 22.5). The purine ring is constructed by a series of reactions that add the donated carbons and nitrogens to a preformed ribose 5-phosphate. (See p. 145 for a discussion of ribose 5-phosphate synthesis by the HMP pathway.)... 

---