Purine Nucleotide Degradation Research Articles

Radical formation in the rat small intestine during and following ischemia.

Oxidative loading during the reperfusion of the proximal jejunum of rats following a one hour-period of complete ischemia was demonstrated in in vivo-experiments by the increases of the GSSG: total glutathione ratio and the concentration of TBA-RS. The pretreatment of the animals with the xanthine oxidoreductase inhibitor allopurinol diminished the accumulation of GSSG and of TBA-RS. It was concluded that the purine nucleotide degradation is an important source of oxygen reduction products in reoxygenated small intestine. The tissue concentrations of nucleotides, nucleosides and nucleobases were measured by an ion-pair reversed-phase HPLC separation. There occurred fast declines of ATP and GTP concentrations during ischaemia leading to temporary increases of nucleoside mono- and diphosphate pools. The hypoxanthine concentration is increased about twentyfold during oxygen deficiency. The ATP and GTP restoration during the reperfusion was accelerated in presence of allopurinol. The shares of the beneficial allopurinol effects are not yet clarified.

Exercise induced alteration of erythrocyte glycolysis associated with myogenic hyperuricemia.

Recently we reported ‘myogenic hyperuricemia’ in muscle glycogenosis types III, V and VII (Kono et al., 1986; Kono et al., 1987; Mineo et al., 1985; Mineo et al., 1987). The mechanism of myogenic hyperuricemia is: when energy production does not fill its requirement for continuing exercise, purine nucleotide degradation is accelerated (Fig. 1). The degradation of purine nucletide occurs even with mild exercise in these diseases. Its degradative metabolites such as inosine, hypoxanthine, and ammonia are released from working muscles into blood stream. Inosine and hypoxanthine are taken up by liver and metabolized to uric acid, causing hyperuricemia. In this study, we report exercise-induced alteration of erythrocyte glycolysis in muscle glycogenoses(Fig. 1), which is another metabolic consequence caused by accelerated purine nucleotide degradation in muscle.KeywordsUric AcidSerum Uric AcidSerum Uric Acid LevelGlycogen Storage DiseaseGlycolytic IntermediateThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Hypoxanthine and xanthine transport through the blood-brain barrier in hypoxanthine phosphoribosyltransferase (HPRT) deficiency.

Purine metabolism in the central nervous system (CNS) is characterized by: (i) reduced de novo purine synthesis (1), (ii) increased HPRT activity (2), and (iii) absence of detectable xanthine oxidase activity (3, 4). These facts determine that, instead of uric acid, the end products of purine nucleotide degradation in the CNS are hypoxanthine for adenine nucleotides and xanthine for guanine nucleotides (2, 5). On the other hand, HPRT hyperactivity seems to be essential to salvage an important amount of hypoxanthine for purine nucleotide synthesis. Hypoxanthine transport from blood to the brain could be another important source for the synthesis of purine nucleotides in the CNS (6, 7). The devastating neurological manifestations of complete HPRT deficiency suggest that hypoxanthine salvage is important for adequate neuronal function (8).KeywordsUric AcidXanthine OxidaseAdenine NucleotidePurine NucleotideHypoxanthine PHOSPHORIBOSYLTRANSFERASEThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The role of 5′nucleotidase in therapy-resistance of childhood leukemia

Purine nucleotides become available for a cell by two routes, namely purine de novo synthesis and the purine salvage pathway. 5′Nucleotidase is a purine pathway enzyme and is present in two forms. Cytoplasmic 5′nucleotidase (cyto 5′NT) catalyzes the intracellular degradation of purine nucleotides into their corresponding nucleosides. The plasmamembrane bound form (ecto 5′NT) has its active site facing the external medium. Its function is the extracellular dephosphorylation of nucleotides, to which cells are generally impermeable, into nucleosides and the transport of these nucleosides through the cell membrane. Lymphoblastic 5′NT activity varies between different children with common-ALL. 5′NT positive cases have a higher relapse rate and thus a poorer prognosis than 5′NT negative cases (10). This can be explained by two hypotheses which are not mutually exclusive: 1. 1. Rescue hypothesis. When purine de novo synthesis is blocked by methotrexate (MTX) and/or 6-mercaptopurine (6-MP), the malignant cell has to rely on the purine salvage pathway. This pathway depends on the ecto-5′NT activity. So, leukemic cells might be resistant to MTX and/or 6-MP because of ecto-5′NT activity. 2. 2. Breakdown hypothesis. Leukemic cells are resistant to 6-MP because of the breakdown of the toxic nucleotide form of 6-MP into the nucleoside form by cyto-5′NT.

49 PURINE DEGRADATION IN ISCHEMIC AND NON-ISCHEMIC CONTRACTING MUSCLES OF RATS

Degradation of purine nucleotides was evaluated in different types of rat skeletal muscle during ischemic and non-ischemic contraction. Extensor digitorum longus (EDL, fast) and soleus (slow) muscles were stimulated electrically via the sciatic nerve (5 Hz, 10 min). Under non-ischemic condition, the concentrations of IMP, inosine, adenosine, and hypoxanthine increased in EDL muscles but not in soleus muscles during stimulation. Under ischemic condition, these metabolites increased in both EDL and soleus muscles and the changes in concentrations of IMP and inosine were greater in ischemic EDL muscles. The increase in inosine had a strong positive correlation with that in IMP in ischemic EDL and soleus muscles, but the ratio, Δinosine/ΔIMP was smaller in EDL muscles. The increase in adenosine under ischemic condition was not significantly different between the two muscles. These findings suggest that ischemia enhances overall degradation of purine nucleotides in contracting fast and slow muscles, and that although the degradation of adenine nucleotides to IMP is greater in fast muscles than in slow muscles, the relative degradation rate of IMP to inosine with respect to the intramuscular IMP concentration is rather smaller in fast muscles.

68 INCREASED PURINE NUCLEOTIDE DEGRADATION IN THE CENTRAL NERVOUS SYSTEM (CNS) IN PRPP SYNTHETASE SUPERACTIVITY

The end products of purine metabolism in the CNS are hypoxanthine for adenine nucleotides and xanthine for guanine nucleotides. Previous reports of two families with PRPP synthetase superactivity associated with neurodevelopmental defects have not documented metabolism of purines in the CNS. Fibroblasts extracts from an eight-year-old male with tophaceous gout and sensorineural deafness and from his mother with gout showed an aberrant PRPP synthetase characterized by resistance to purine nucleotide inhibition of enzyme activity. Hypoxanthine and xanthine concentrations in plasma and cerebrospinal fluid (CSF) were simultaneously measured by HPLC in both patients. In 4 normal subjects hypoxanthine and xanthine levels in plasma were (mean±SEM) 1.7±0.4 μM and 0.9±0.2 μM, respectively, and 3.3±1.1 and 2.0±0.2 μM in CSF. The hemizigous male showed a substantially increased hypoxanthine concentration of 5.6 μM in plasma and of 22.1 μM in CSF. Xanthine levels were 1.8 μM in plasma and 4.5 μM in CSF. The heterozigous female had moderately elevated plasma and CSF hypoxanthine concentrations (3.9 and 10.6 μM) and normal xanthine levels (1.3 and 1.8 μM). These results suggest an increased purine nucleotide degradation in the CNS of patients with PRPP synthetase superactivity and neurological symptoms. The predominance of hypoxanthine over xanthine may indicate a relatively enhanced adenine nucleotide over guanine nucleotide degradation.

84 ENHANCED ADENINE NUCLEOTIDE DEGRADATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): THE EFFECT OF OXYGEN THERAPY

Hypoxemia may result in tissue hypoxia and increased production and excretion of adenine triphosphate (ATP) degradation intermediates and uric acid (UA). If this hypothesis is correct, then adenine nucleotide degradation should diminish following increased delivery of oxygen to hypoxic tissues. Five patients with clinically stable COPD were infused with [8-14C]adenine to radiolabel the adenine nucleotide poool. Cumulative 3 days radioactivity excretion and urinary hypoxanthine (Hx), xanthine (X), UA and total purines (TP=sum of Hx, X and UA) were measured to assess purine nucleotide degradation before and after inhalation of oxygen (FiO2, 24%) for 4 days. Results (mean±SEM) were compared to those obtained in 4 normal subjectsThe increased basal excretion of 14C and urinary purines in COPD patients suggest that hypoxemia accelerates adenine nucleotide degradation. The decrease in these parameters elicited by oxygen therapy lends further support to the hypothesis.

Differential effects of exercise intensity on serum uric acid concentration.

To investigate the effects of exercise intensity and short-term training on alterations in plasma uric acid, two series of experiments were performed using untrained male subjects. In series 1, 6 subjects (age 19 to 23 yr) cycled at 120% VO2max for 1 min followed by 4 min recovery until fatigue or until 24 repetitions had been completed. In series 2, 7 subjects (age 19 to 25 yr) cycled continuously at 65% VO2max for 2 h. In both experiments, short-term training was performed by repeating the exercise protocol for three consecutive days. In series 1, a progressive increase of 40% (P less than 0.05) was observed on day 1 in plasma uric acid concentration over the duration of the exercise. On day 2, pre-exercise values remained elevated over day 1 (mean +/- SD, 476 +/- 77 vs 352 +/- 30 mumol.l-1) and showed a further 23% increase (P less than 0.05) with exercise. Although resting uric acid concentrations on day 3 were elevated (P less than 0.05) over day 1, the exercise levels between day 1 and day 3 were not different (P greater than 0.05). In contrast, in series 2, prolonged sub-maximal exercise failed to stimulate increases in uric acid concentration either between days or within days. It is concluded that exercise intensity rather than total work output is a critical factor mediating increases in blood uric acid concentration. These results are consistent with the interpretation that uric acid formation may arise from purine nucleotide degradation and fast-twitch fiber utilization during conditions of high energy utilization.

Damage of erythrocytes by activated oxygen generated in hypoxic rat liver.

The implication of activated oxygen in the interaction between hypoxic rat liver and circulating erythrocytes was investigated. Reduced species of oxygen generated in hypoxic liver owing to accelerated purine nucleotide degradation via xanthine oxidase initiate alterations of plasma membrane and glutathione system of erythrocytes. Osmotic fragility, hemolysis rate and erythrocytic GSSG:GSH ratio may be considered as appropriate indicators of oxidative load in liver and other tissues. Addition of erythrocytes to the perfusion medium attenuates the GSSG efflux of hypoxic liver from 2.7 +/- 0.5 nmol x g w.w.-1 x min-1 to 1.4 +/- 0.2 nmol x g w.w.-1 x min-1 Thus, circulating erythrocytes protect the liver against oxidative attack.

H2O2 formation during nucleotide degradation in the hypoxic rat liver: a quantitative approach.

In the hypoxic liver an increased rate of cytosolic and peroxisomal H2O2 generation is due to the accelerated purine nucleotide degradation. The relative contribution of the oxidase type of xanthine oxidoreductase activity increases in hypoxia by less than 10%, the dehydrogenase type of this enzyme is hardly inhibited by the increased concentration of free NADH. Nevertheless, due to the high hypoxanthine supply the xanthine oxidase related H2O2 formation is increased six-fold and together with the peroxisomal uricase-mediated share it accounts for half of the oxygen consumption.

Formation of activated oxygen in the hypoxic rat liver.

The biliary GSSG efflux rate of normoxic perfused rat liver was 1.5 +/- 0.2 nmol/min/g liver wet weight. The GSSG efflux rate as indicator for the flux through the glutathione peroxidase reaction and, therefore, for an oxidative loading increased with the extent of hypoxia. 2.6 +/- 0.5 nmol/min/g were released from the severely hypoxic liver. The hydroxyl radical scavenger formate as well as the xanthine oxidase inhibitor allopurinol reduced the efflux rate of GSSG. GSH was released from the perfused liver at a rate of 15.5 nmol/min/g which was nearly unchanged in severe hypoxia. The high rate of glucose liberation from the hypoxic liver declined to almost that of the normoxic organ in the presence of formate. There is an 'oxidative stress' during hypoxic liver perfusion which probably originates from increased generation of activated oxygen species in the degradation of purine nucleotides.

HUMAN PLACENTAL CYTOPLASMIC 5′-NUCLEOTIDASE: PURIFICATION AND MOLECULAR PROPERTIES: 115

Purine nucleotide degradation in human tissues is highly regulated. Dephosphorylation of nucleoside 5'-monophosphates is the first committed and irreversible reaction of purine nucleotide catabolism. Recent studies indicate that cytoplasmic 5'-nucleotidase may have an important role in intracellular nucleotide degradation. We purified cytoplasmic 5'-nucleotidase from human placenta 8075-fold to a specific activity of 58.85 μmol/ min/mg. The enzyme showed absolute requirement for magnesium with a Km of 6 mM and pH optimum from 7.4 to 9.0. CMP and UMP are preferred substrates. A large variety of purine, pyrimidine and pyridine compounds exert an inhibitory effect on enzyme activity. IMP, GMP and NADH produce almost 100% inhibition at 1.0 mM. Nucleoside di- and triphosphates are potent inhibitors. ATP and ADP are competitive inhibitors with respect to AMP and IMP as substrates with Ki values of 100 μM and 15 μM, respectively. Inorganic phosphate is a noncompetitive inhibitor with Ki values of 19 mM and 43 mM. The estimated molecular weight is 143,000 and the stokes radius is 46.1A. The subunit molecular weight is 76,000, suggesting that the enzyme is a dimeric protein. These data elucidate the nature of cytoplasmic 5'-nucleotidase enzyme and its role in purine nucleotide degradation in human tissues.

URIC ACID METABOLISM IN PSORIASIS: 166

Enhanced epidermal turnover is believed to increase uric acid synthesis in psoriasis. Fifteen patients with psoriasis (less than 30% skin surface involvement) showed normal serum urate concentrations and urinary hypoxanthine and xanthine excretion but increased uric acid excretion (patients vs. controls, 3.2 ± 0.1 vs. 2.0 ± 0.1 mmol/g creatinine, P<0.01). The reanl physiological response to RNA loading is to increase uric acid excretion due to reduced tubular urate postsecretory reabsorption. To test whether increased uric acid excretion in psoriasis indicates enhanced purine nucleotide degradation we examined the intrarenal handling of uric acid and the capacity of the nucleotide catabolic pathway to accelerate in response to fructose infusion. The probenecid test evidenced a significantly diminished tubular urate postsecretory reabsorption in psoriatic patients. Intravenous fructose promoted a mean increase in hypoxanthine and xanthine excretion, with respect to mean baseline values, of 1257 and 1387 percent vs. 342 and 380 percent in patients vs. controls, respectively (P<0.001) These data indicate accelerated purine nucleotide degradation in psoriasis. A diminished tubular urate postsecretory reabsorption with normal serum urate levels may reflect increased uric acid synthesis.

Ethanol-induced activation of adenine nucleotide turnover. Evidence for a role of acetate.

Consumption of alcohol causes hyperuricemia by decreasing urate excretion and increasing its production. Our previous studies indicate that ethanol administration increases uric acid production by increasing ATP degradation to uric acid precursors. To test the hypothesis that ethanol-induced increased urate production results from acetate metabolism and enhanced adenosine triphosphate turnover, we gave intravenous sodium acetate, sodium chloride and ethanol (0.1 mmol/kg per min for 1 h) to five normal subjects. Acetate plasma levels increased from 0.04 +/- 0.01 mM (mean +/- SE) to peak values of 0.35 +/- 0.07 mM and to 0.08 +/- 0.01 mM during acetate and ethanol infusions, respectively. Urinary oxypurines increased to 223 +/- 13% and 316 +/- 44% of the base-line values during acetate and ethanol infusions, respectively. Urinary radioactivity from the adenine nucleotide pool labeled with [8-14C] adenine increased to 171 +/- 27% and to 128 +/- 8% of the base-line values after acetate and ethanol infusions. These data indicate that both ethanol and acetate increase purine nucleotide degradation by enhancing the turnover of the adenine nucleotide pool. They support the hypothesis that acetate metabolism contributes to the increased production of urate associated with ethanol intake.

Regulation of purine metabolism by plasma membrane and cytoplasmic 5'-nucleotidases.

The contribution of plasma membrane 5'-nucleotidase (E.C. 3.1.3.5) to intracellular purine degradation and release was evaluated in cultured human lymphoblasts. B-lymphoblasts and T-lymphoblasts are characterized by high and low levels of plasma membrane 5'-nucleotidase activity, respectively. After radiolabeling of the cellular adenine nucleotide pools with [8-14C]adenine, deoxyglucose-induced purine nucleotide degradation resulted in a 2-2.5 times greater release of cellular radioactivity from the B-lymphoblasts than from the T-lymphoblasts. Specific inhibition of plasma membrane 5'-nucleotidase with 50 microM alpha, beta-methylene adenosine diphosphate (AMPCP) did not decrease purine release during deoxyglucose-induced nucleotide degradation. Similarly, the inhibition of B-lymphoblast membrane 5-nucleotidase did not alter the incorporation of [8-14C]adenine into the nucleotide pool. Therefore, to explain the relatively high release of purine nucleotide degradation products in B-lymphoblasts when compared with T-lymphoblasts, cytoplasmic 5'-nucleotidase activity was investigated in these cell lines. B-lymphoblasts have seven times more cytoplasmic 5'-nucleotidase activity for dAMP and two to three times more activity for other purine nucleoside 5'-monophosphates than do T-lymphoblasts at pH 7.4. Membrane and cytoplasmic nucleotidase activities are produced by different enzymes that can be distinguished by differences in pH optima, Michaelis constants for purine substrates, divalent cation requirements, and susceptibilities to AMPCP inhibition. The data suggest that plasma membrane 5'-nucleotidase hydrolyzes extracellular nucleoside 5'-monophosphates only. Cytoplasmic 5'-nucleotidase most likely regulates the degradation of intracellular nucleoside 5'-monophosphates and may be responsible for the increased purine release observed in B-lymphoblasts.

Effects of fructose on synthesis and degradation of purine nucleotides in isolated rat hepatocytes

The effects of fructose on purine nucleotide synthesis and degradation were studied in isolated rat hepatocytes. Incubation of the hepatocytes with fructose resulted in dece;eration of the rate of de novo purine synthesis, gauged by the rate of incorporation of precursor [ 14C]formate into total purines produced, and in acceleration of purine nucleotide degradation, as measured by the rate of conversion of prelabelled purine nucleotides into end-product allantoin. These effects were found to be associated with decreases in cellular content of ATP and P i and in the metabolic availability of 5-phosphoribosyl 1-pyrophosphate. The results support the suggestion that the fructose-induced acceleration of purine degradation is mediated through activation of AMP deaminase. However, the results also suggest that decreased reutilization of hypoxanthine for IMP synthesis, due to the decreased PP-Rib- P availability, is an additional mechanism for the acceleration of purine degradation. The decreased PP-Rib- P availability is also suggested to be the main mechanism for the fructose-induced deceleration of purine synthesis.

Hyperuricemia in acute illness: a poor prognostic sign

To clarify the role of the serum urate level and its change as a potential marker for severe tissue hypoxia, we have measured serum urate levels and urine uric acid excretion in 16 patients with acute cardiovascular disease. The six patients who died had a baseline mean serum urate level of 11.1 mg/dl (range, 6.6 to 15.5 mg/dl) and reached a peak mean value of 20.7 mg/dl (range, 13.6 to 33.0 mg/dl). Five of these patients had findings to suggest increased production of uric acid, in addition to decreased excretion of uric acid from impaired renal function. The 10 survivors had a baseline mean serum urate level of 6.8 mg/dl (range, 1.3 to 14.0 mg/dl) and a maximal mean peak value of 7.1 mg/dl (range, 3.9 to 14.0 mg/dl). There was no consistent evidence for increased production or decreased excretion of uric acid. Patients who died had a lower systolic blood pressure, arterial pH and plasma bicarbonate level and a higher heart rate and serum creatinine level compared with the patients who survived. The observations suggest that marked hyperuricemia at the height of an illness may predict a fatal outcome. Tissue hypoxia may contribute to this sequence of events by leading to the depletion of adenosine triphosphate (ATP) and activation of purine nucleotide degradation to uric acid.

Metabolic basis for disorders of purine nucleotide degradation

Purine nucleotide degradation refers to a regulated series of reactions by which human purine ribonucleotides and deoxyribonucleotides are degraded to uric acid in humans. Two major types of disorders occur in this pathway. A block of degradation occurs with syndromes involving immune deficiency, myopathy or renal calculi. Increased degradation of nucleotides occurs with syndromes characterized by hyperuricemia and gout, renal calculi, anemia or acute hypoxia. Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.

EFFECTS OF HEXOSE ANALOGUES ON FUNGI: MECHANISMS OF INGIBITION AND OF RESISTANCE

I. SUMMARYAlthough the effects of a number of sugar analogues are discussed in this review, most attention is devoted to 2‐deoxy‐D‐glucose (deGlc) and L‐sorbose. The growth of fungi is not uniformly inhibited by sugar analogues since some species or strains can metabolize sugars which severely inhibit others. Sugar analogues usually cause inhibitions by being used in metabolism in place of glucose. Both deGlc and sorbose are metabolized by several species but, in general, only a small fraction of the analogue is utilized.The uptake and phosphorylation of readily metabolized sugars are inhibited by deGlc. Inhibitions by sugar analogues occur on media containing non‐carbohydrate sources of carbon, so inhibition of sugar uptake is unlikely to be a major component of the growth inhibition which occurs on sugar‐containing media. Hexokinase phosphorylates deGlc, and its 6‐phosphate inhibits the activity of especially phosphohexose isomerase and glucose 6‐phosphate dehydrogenase. Apart from an involvement in synthesis of more complex sugars, formation of deGlc‐6P is the usual limit of metabolism of this sugar analogue. Accumulation of the phosphate ester leads to a considerable drain on phosphate pools and ATP levels decline drastically. Indeed, deGlc rapidly initiates degradation of purine nucleotides which can proceed at least to the level of hypoxanthine. In Saccharomyces cerevisiae, deGlc can be condensed to dideoxytrehalose and, in most fungi, polysaccharide synthesis is affected. Preformed wall material is eroded and synthesis of new wall components is prevented by sequestering of uridine and guanosine nucleotides through reaction with deGlc. Interference with the structure of the wall greatly reduces osmotic stability, and cell lysis is the major cause of inhibition of growth by deGlc in yeasts and filamentous fungi alike.L‐Sorbose is not phosphorylated, and the biochemical basis of the inhibitions caused by this analogue is obscure. Some enzymes involved in polysaccharide synthesis are sensitive to inhibition by sorbose, and a characteristic of growth on this sugar is formation of an abnormally thick cell wall. Filamentous fungi grown on solid medium containing sorbose assume an abnormal growth form in which cells are much shortened and branching frequency is increased. There are indications that sorbose, perhaps by interfering with cell wall structure, affects hyphal morphogenesis and that this effect may be magnified into a macroscopic change in the characteristics of the colony during growth on solid medium by secondary environmental effects.Mutants, resistant to deGlc, have alterations in either transport, hexokinase or phosphatase functions, thus emphasizing the important of accumulation of deGlc‐6P in the inhibitions caused by this analogue. Generalization is less easy about mutants resistant to sorbose. The majority are defective in transport, but others show defects in phosphoglucomutase and polysaccharide synthases and there are some correlations with morphological changes which underline the involvement of the sugar in the observed alterations in cell walls. Many aspects of early carbohydrate metabolism need investigation and, for such studies, the sugar analogues have much to offer. However, there is also particular scope for their use in studies of hyphal morphogenesis, especially in relation to the connection between wall construction and morphology. Counterparts of the abnormal hyphal growth forms caused by sugar analogues can be found in normal hyphal cells which contribute to the tissues of complex fungal structures such as the basidiomycete carpophore. Experimental induction of these cell forms in vegetative culture by the sugar analogues shows promise for study of events which contribute to the morphogenesis of these fungal structures.

Lymphocyte 5′-nucleotidase deficiency in hypogammaglobulinemia: Clinical characteristics

Twelve patients with congenital agammaglobulinemia, 2 of 10 patients with selective IgA deficiency, and 4 of 15 patients with common variable immunodeficiency have reduced 5′-nucleotidase activity on lymphocyte plasma membranes. In congenital agammaglobulinemia and common variable immunodeficiency, enzyme-deficient patients have an early onset of immune dysfunction, low levels or an absence of circulating B-lymphocytes, and a positive family history of similar immunodeficiency. The enzyme deficiency involves peripheral E-rosette-forming lymphocytes, suggesting an abnormality of T-lymphocytes in these diseases. No systemic disorder of purine nucleotide degradation to uric acid is detectable in the enzyme-deficient patients. No direct relationship between 5′-nucleotidase activity and in vitro production of IgG is evident, since inhibition of the enzyme did not decrease IgG synthesis. At present the data do not allow a distinction between two hypotheses to explain the role of 5′-nucleotidase in hypogamma-globulinemia, that is, whether 5′-nucleotidase deficiency causes the immune dysfunction or is simply a marker for an intrinsic lymphocyte abnormality. However, this enzyme deficiency may provide a useful means of classifying disorders of immunoglobulin synthesis.