Purine biosynthesis regulation

The lac repressor monomer, a chain of 360 amino acids, associates into a functionally active homotetramer. It is the classic member of a large family of bacterial repressors with homologous amino acid sequences. PurR, which functions as the master regulator of purine biosynthesis, is another member of this family. In contrast to the lac repressor, the functional state of PurR is a dimer. The crystal structures of these two members of the Lac I family, in their complexes with DNA fragments, are known. The structure of the tetrameric lac repressor-DNA complex was determined by the group of Mitchell Lewis, University of Pennsylvania, Philadelphia, and the dimeric PurR-DNA complex by the group of Richard Brennan, Oregon Health Sciences University, Portland. 

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. 

Patients with Lesch-Nyhan syndrome have hyperuricemia, indicating an increased biosynthesis of purine nucleotides, and markedly decreased levels of hypoxanthine phbs-phoribosyl transferase (HPRT). The hyperuricemia can be explained on the basis of a decrease in which regulator of purine biosynthesis ... 

Purine Biosynthesis Is Regulated at Two Levels Pyrimidine Biosynthesis Is Regulated at the Level of Carbamoyl Aspartate Formation Deoxyribonucleotide Synthesis Is Regulated by Both Activators and Inhibitors... 

Regulation of purine biosynthesis. Red arrows show points of inhibition 0 or activation . In addition to the feedback inhibition, GTP stimulates ATP synthesis, and ATP stimulates GTP synthesis, thus helping to ensure a balance between the pools of the two nucleoside triphosphates. The full biosynthetic pathways are shown in figures 23.10 and 23.11. 

Unlike in purine biosynthesis, the pyrimidine ring is synthesized before it is conjugated to PRPP. The first reaction is the conjugation of carbamoyl phosphate and aspartate to make N-carbamoylaspartate. The carbamoyl phosphate synthetase used in pyrimidine biosynthesis is located in the cytoplasm, in contrast to the carbamoyl phosphate used in urea synthesis, which is made in the mitochondrion. The enzyme that carries out the reaction is aspartate transcarbamoylase, an enzyme that is closely regulated. 

There may also be feedback activators, especially where cross-regulation occurs the product of one pathway activates another pathway. Thus, in purine biosynthesis (Chapter 10),... 

Regulation of de novo purine biosynthesis is essential because it consumes a large amount of energy as well as of glycine, glutamine, N °-formyl FH4, and aspartate. Regulation occurs at the PRPP synthetase reaction, the ami-... 

Feedback regulation of the de novo pathway of purine biosynthesis. Solid lines represent metabolic pathways, and broken lines represent sites of feedback regulation. , Stimulatory effect , inhibitory effect. Regulatory enzymes A, PRPP synthetase B, amidophosphoribosyltransferase C, adenylosuccinate synthetase D, IMP dehydrogenase. 

The synthesis of PRA is the first, committed step of de novo purine biosynthesis, and is catalyzed by the enzyme GPATase. This catalytic activity is therefore highly regulated, both at the gene level and by the binding of end products in the purine biosynthetic path way It has been proposed that GPATase forms a transient complex... 

As purines are built on a ribose base (see Fig. 41.2), an activated form of ribose is used to initiate the purine biosynthetic pathway. 5-Phosphoribosyl-l-pyrophosphate (PRPP) is the activated source of the ribose moiety. It is synthesized from ATP and ribose 5 -phosphate (Fig. 41.3), which is produced from glucose through the pentose phosphate pathway (see Chapter 29). The enzyme that catalyzes this reaction, PRPP synthetase, is a regulated enzyme (see section 1I.A.5) however, this step is not the committed step of purine biosynthesis. PRPP has many other uses, which are described as the chapter progresses. 

A primary site of regulation is the synthesis of PRPP. PRPP synthetase is negatively affected by GDP and, at a distinct allosteric site, by ADR Thus, the simultaneous binding of an oxypurine (eg., GDP) and an aminopurine (eg., ADP) can occur with the result being a synergistic inhibition of the enzyme. This enzyme is not the committed step of purine biosynthesis PRPP is also used in pyrimidine synthesis and both the purine and pyrimidine salvage pathways. 

The conversion of PRPP into phosphoribosylamine by glutamine phosphoryl amidotrans-Jerase is the committed step in purine biosynthesis. Compounds a, b, and d are involved in the regulation. 

Wingaarden, J.B. Ashton, D.H. (1959). The regulation of activity of phosphoribosylpyrophosphate amidotransferase by purine ribonucleotides a potential feedback control of purine biosynthesis. ]. Biol. Chem., 234, 1492-6. 

A. The Role of S. cereWs/ee Adenylosuccinate Synthetase in the Regulation of de Novo Purine Biosynthesis... 

B. The Regulation of Gene Expression in Bacteriai Purine Biosynthesis... 

The purine nucleotides GTP and ATP are very important in intermediary metabolism and the regulation of metabolism. Adenine is also a component of cyclic AMP, FAD, NAD, NADP and coenzyme A. Moreover, GTP, ATP and their deoxy derivatives dGTP and dATP are important precursors for the synthesis of RNA and DNA respectively, which are essential for cell growth and division. Purine biosynthesis (Fig. 59.1) needs the amino acids giutamine, giycine and aspartate. Also, tryptophan is needed to supply formate which reacts with tet-rahydrofolate (THF) to produce A "-formyl THF, which donates the formyl group to the purine structure. A molecule of CO2 is also needed. 

K12 Kelley, W. N., Fox, J. and Wyngaarden, J. B. Regulation of purine biosynthesis in cultured human cells. I. Effects of orotic acid. Biochim. Biophys. Acta, 215, 512-516 (1970)... 

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