Regulation of the synthesis of 5-phosphoribosyl-i-pyrophosphate in intact red blood cells and in cell-free preparations

Hershko, Avram; Razin, A.; Mager, J.

doi:10.1016/0304-4165(69)90099-3

Cited by 210 publications

(37 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutant cells thus generate PP-ribose-P at an excessive rate despite a reduced amount of enzyme. In a prior study (1), a discrepancy of several hundred-fold between erythrocyte PP-ribose-P synthetase catalytic capacity and PP-ribose-P synthesis was found; our studies confirm at least this much modulation of PPribose-P synthetase activity in the normal cell and provide substantiation of the role of nucleotide inhibitors in accounting, at least in part, for this regulation.…”

Section: Resultssupporting

confidence: 81%

“…2.7.6.1) in a reaction requiring Mg2+ and inorganic phosphate (Pi). Studies of PP-ribose-P production by intact cells (1,2) and analyses of the kinetic characteristics of purified microbial (3)(4)(5) and mammalian (6-10) PP-ribose-P synthetases indicate that a substantial number of effector compounds including substrates, inhibitors, activators, and products influence enzyme activity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Becker¹,

Raivio²,

Bakay³

et al. 1980

J. Clin. Invest.

104

View full text Add to dashboard Cite

A B S T R A C T An inherited, structurally abnormal and superactive form of the enzyme 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P) synthetase (EC 2.7.6.1) has been characterized in fibroblasts cultured from a 14-yr-old male (S.M.) with clinical manifestations of uric acid overproduction present since infancy. PPribose-P synthetase from the cells of this child showed four-to fivefold greater than normal resistance to purine nucleotide (ADP and GDP) feedback inhibition ofenzyme activity and hyperbolic rather than sigmoidal inorganic phosphate (Pi) and by an accelerated, age-related decrement in enzyme activity in lysates of erythrocytes separated by specific density. Despite the diminished amount of PP-ribose-P synthetase in the S.M. erythrocyte population, S.M. erythrocytes had increased PPribose-P concentration and increased rates of incorporation of ['4C]adenine and hypoxanthine into acid-soluble nucleotides during incubation at 1 mM Pi. These findings provided further confirmation of the extent to which PP-ribose-P synthesis is modulated in the normal cell at physiological Pi concentration by purine nucleotide inhibition of PP-ribose-P synthetase.The activity and kinetic characteristics of PPribose-P synthetase from fibroblasts of the mother of patient S.M. indicated that this woman was a heterozygous carrier of the enzyme defect expressed in hemizygous manner by her son. INTRODUCTIONThe high-energy sugar phosphate 5-phosphoribosyl I-pyrophosphate (PP-ribose-P)' is an intermediate in the synthesis of purine, pyrimidine and pyridine nucleotides. The synthesis of PP-ribose-P from ATP and ribose-5-phosphate (Rib-5-P) is catalyzed by the enzyme PP-ribose-P synthetase (E.C. 2.7.6.1) in a reaction requiring Mg2+ and inorganic phosphate (Pi). Studies of PP-ribose-P production by intact cells (1, 2) and analyses of the kinetic characteristics of purified microbial (3-5) and mammalian (6-10) PP-ribose-P synthetases indicate that a substantial number of effector compounds including substrates, inhibitors, activators, and products influence enzyme activity.

show abstract

Section: Resultssupporting

confidence: 81%

mentioning

confidence: 99%

Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Becker¹,

Raivio²,

Bakay³

et al. 1980

J. Clin. Invest.

104

View full text Add to dashboard Cite

show abstract

“…Mature erythrocytes lack the enzymes for de novo purine synthesis (1), but possess the ability to take up and release purine bases and nucleosides (2)(3)(4). Hypoxanthine is rapidly transported across the red cell membrane by facilitated diffusion, so that equilibrium is reached within a minute even at millimolar concentrations of the oxypurine (5).…”

Section: Introductionmentioning

confidence: 99%

Oxypurine cycle in human erythrocytes regulated by pH, inorganic phosphate, and oxygen.

Berman¹,

Black²,

Human³

et al. 1988

J. Clin. Invest.

View full text Add to dashboard Cite

The effect of pH, P02, and inorganic phosphate on the uptake and metabolism of hypoxanthine by erythrocytes has been studied. Uptake of hypoxanthine and accumulation of inosine 5'-monophosphate (IMP) were markedly increased at acid pH, high external phosphate concentrations, and low Po2. Release of accumulated IMP as hypoxanthine occurred at alkaline pH values and low external phosphate concentrations. Conditions favoring IMP accumulation gave rise, in the absence of hypoxanthine, to a corresponding increase in 5'-phosphoribosyl-1-pyrophosphate. Intracellular phosphate concentrations were markedly pH dependent and a model is presented whereby hypoxanthine uptake and release are controlled by intracellular concentrations of inorganic phosphate and 2,3-bisphosphoglycerate. These allosteric effectors influence, in opposing ways, two enzymes governing IMP accumulation, namely 5'-phosphoribosyl-l-pyrophosphate synthetase and 5'-nucleotidase. These metabolic properties suggest that the erythrocyte could play a role in the removal of hypoxanthine from anoxic tissue.

show abstract

“…We used RBC, because TPMT activity in RBC correlates with that in lymphoblasts and other tissues [4][5][6][7]. RBC can synthesize 5-phosphoribosyl-l-pyrophosphate [18], an es sential cofactor for the conversion of 6MP into tIMP, but do not manifest an active purine de novo synthesis, as ALL lymphoblasts do [19].…”

mentioning

confidence: 99%

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Keuzenkamp-Jansen

Abreu

Blom

et al. 1996

Biochemical Pharmacology

View full text Add to dashboard Cite

']a r is e n R o n n e y A. De Ahreu,*f HenkJ. Blom* Jos P.M. Bokkerinkf andj. M. Frans Trijbels* ♦ L a b o r a t o r y o f P e d i a t r i c s , a n d t C e n t e r f o r P e d ia t r ic : O n c o l o g y S.E. N e t h e r l a n d s , U n i v e r s i t y H o s p i t a l S t . R a d b o u d , P.O. Box 9101» 6500 HB N ijm e g e n , T h e N e t h e r l a n d s A BSTRA CT. 6 -mercaptopurine (6MP) cytotoxicity is caused by thioguanine and methylthioinosine nucleo tides. Thiopurine méthylation occurs to a large extent in vivo and in vitro. In this reaction, S-adenosyl-Lmethionine (AdoMet), produced from methionine and ATP, is converted into S-adenusy l-L-htunocysreine (AdoHcy) which, in turn, is hydrolyzed into homocysteine. Remethylation of homocysteine into methionine is inhibited by methotrexate (MTX). In cultured lymphoblasts, AdoMenAdoHcy ratio and DNA méthylation decrease after incubation with 6MP. The aim of the present study was to investigate the influence of high-do.se 6MP on the méthylation capacity in children with acute lymphoblastic leukemia. Five patients received 4 courses with high-dose intravenous MTX (5 g • m in 24 hr) immediately followed by high-dose 6MP (1300 mg • m~2 in 24 hr). Five control patients received high-dose MTX and oral 6MP (25 mg • m~2 daily for 8 weeks). Leucovorin rescue was started at .36 hr in both groups.In the intravenous 6MP group, 6-methylmercaptopurine, its riboside, and 6-methylmercapto-8-hydroxypurine were detectable in plasma in concentrations of 0.3-2.6 |jlM (6MP steady state levels: 11.6 (xM). In red blood cells, mean methylthioinosine nucleotide levels were one third of those of ATP (13,1 nmol/10"). AdoHcy levels (10 pmol/108) remained constant in both groups and AdoMet was not detectable (<20 pmol/10,s). In both groups, plasma homocysteine increased and methionine decreased following administration of MTX. The delay in the recovery of methionine in the intravenous 6MP group after MTX infusion is probably the result-of an increased demand on methyl groups during 6MP infusion. BIOCHKM PHARMACOL 51;9:1165-1171, KEY W ORDS. 6 -mercaptopurine; methotrexate; acute lymphoblastic leukemia; méthylation § is used in the treatment of ALL. It has no intrinsic cytotoxic activity, but is converted into active metabolites intracellularly (Scheme 1). 6MP tlMP which, itself, can be conve MetlMP. Both pathways ferase (EC 2.1.1.67) (TPMT). The TPMT activity is con trolled by a genetic polymorphism and the activity in RBC correlates with that in lymphoblasts, lymphocytes, plate lets, liver, and ki •' V ** % oi in cytotoxicity in vitro, ei ther by incorporation of thioguanine nucleotides into DNA and RNA [1,2] or by inhibition of purine de novo synthesis by MetlMP [2,3]. 6MP is methylated into MeMP and 6MP-riboside into MeMPR (Scheme 1). The thiopurine meththe frequency distribution is trimodal with subjects displaying high activity, 11.1% intermediate activ ity, and 1 out of 300 subjects having undeteetahle TPMT . Thiopurine méthylation requires AdoMet as onor [9]. AdoMet is the universa...

show abstract

Regulation of the synthesis of 5-phosphoribosyl-i-pyrophosphate in intact red blood cells and in cell-free preparations

Cited by 210 publications

References 24 publications

Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Variant human phosphoribosylpyrophosphate synthetase altered in regulatory and catalytic functions.

Oxypurine cycle in human erythrocytes regulated by pH, inorganic phosphate, and oxygen.

Effects on transmethylation by high-dose 6-mercaptopurine and methotrexate infusions during consolidation treatment of acute lymphoblastic leukemia

Contact Info

Product

Resources

About