Deoxyguanosine Triphosphate as a Possible Toxic Metabolite in the Immunodeficiency Associated with Purine Nucleoside Phosphorylase Deficiency

Abstract

A B S T R A C T Puiriine nucleoside phosphorviase(PNP) deficiency is associated with a severe defect in thvmnus-derived (T)-lymphocyte function comlbinied with normal bone marrow-derived (B)-lvmphocvte ftinction. To investigate the role of this enzvme deficiency in the resulting immune dysfunction, wve mleastured the levels of ribonucleoside and deoxvriboniucleoside triphosphates in erythrocvtes from twvo unirelated PNP-deficient, T-lymphocvte-deficient patients. Both PNP-deficient patients have abnormally high levels of deoxyguanosine triphosphate (deoxy-GTP) in their erythrocytes (5 and 8 nmol/ml packed ervthrocvtes). In contrast, normal controls and adenosinie deaminase-deficient, immunodeficient patients do not have detectable amounts of deoxvGTP (<0.5 nmol/nml packed erythrocytes). We propose that deoxvguanosine, a substrate of PNP. is the potentially lvImphotoxic metabolite in PNP deficiency. The mechanismii of toxicitv involves phosphorvlation of Dr.

Metabolic Interrelations within Guanine Deoxynucleotide Pools for Mitochondrial and Nuclear DNA Maintenance

“…Early examples are the catabolic phosphorylases that degrade purine (7) or thymine nucleosides (9). Their loss causes overproduction of dGTP or dTTP, with the affected individuals suffering from immune deficiency (7,8) or mitochondrial neurogastrointestinal encephalomyopathy (9), respectively. Later discovered examples are the anabolic mt salvage enzymes deoxyguanosine kinase (dGK) (4) or thymidine kinase 2 (TK2) (5) and more recently the cytosolic small subunit of ribonucleotide reductase p53R2 (6), all leading to mt DNA depletion in terminally differentiated cells.…”

“…Moreover, an increasing number of diseases with depletion of mt DNA arise from genetic deficiency of enzymes in the network (3). In some cases the genetic deficiency leads to depletion of mt deoxyribonucleoside triphosphate (dNTP) (4 -6), in other cases to overproduction (7)(8)(9). In both instances the disturbed normal balance between the four dNTPs results in disease.…”

“…In both instances the disturbed normal balance between the four dNTPs results in disease. Early examples are the catabolic phosphorylases that degrade purine (7) or thymine nucleosides (9). Their loss causes overproduction of dGTP or dTTP, with the affected individuals suffering from immune deficiency (7,8) or mitochondrial neurogastrointestinal encephalomyopathy (9), respectively.…”

“…Both in the cytosol and mitochondria, the 5Ј-deoxynucleotidases cdN and mdN (18) form substrate (futile) cycles together with deoxynucleoside kinases and make possible the diffusion of deoxynucleosides through the plasma membrane into the extracellular space (19). Other catabolic enzymes are nucleoside deaminases and phosphorylases (7,9) that degrade deoxynucleosides to purine or pyrimidine bases. Thus an intricate network of anabolic and catabolic enzymes operates for the supply of both mt and nuclear dNTPs.…”

Ecto-5′-Nucleotidase Activity in Human T Cell Subsets. DECREASED NUMBERS OF ECTO-5′-NUCLEOTIDASE POSITIVE CELLS FROM BOTH OKT4+ AND OKT8+ CELLS IN PATIENTS WITH HYPOGAMMAGLOBULINEMIA

“…Both enzyme deficiencies are the results of mutations in the structural genes coding for the missing enzymes, leading to losses of activity in all tissues (3)(4)(5)(6)(7). In both cases, the patients' loss of immune function can be directly attributed to alterations in purine ribo-and/or deoxyribonucleoside metabolism (8)(9)(10)(11)(12)(13)(14)(15). A deficiency of a third enzyme in the purine catabolic pathway, ecto-5'-nucleotidase (ecto-5'-NT), which is located on the external surface of the plasma membrane, has been reported in the lymphocytes of all patients with congenital agammaglobulinemia (CAG) (16,17) and the majority of patients with common variable immunodeficiency (CVI, or adult onset hypogammaglobulinemia) (18).…”