Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.
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PMID:Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in common variable immunodeficiency. 960 97

We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
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PMID:Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice. 1085 43

The rate and extent of hydrogen/deuterium (H/D) exchange into purine nucleoside phosphorylase (PNP) was monitored by electrospray ionization mass spectrometry (ESI-MS) to probe protein conformational and dynamic changes induced by a substrate analogue, products, and a transition state analogue. The genetic deficiency of PNP in humans is associated with severe T-cell immunodeficiency, while B-cell immunity remains functional. Inhibitors of PNP have been proposed for treatment of T-cell leukemia, to suppress the graft-vs.-host response, or to counter type IV autoimmune diseases without destroying humoral immunity. Calf spleen PNP is a homotrimer of polypeptide chains with 284 amino residues, molecular weight 31,541. Immucillin-H inhibits PNP with a Kd of 23 pM when only one of the three catalytic sites is occupied. Deuterium exchange occurs at 167 slow-exchange sites in 2 h when no catalytic site ligands are present. The substrate analogue and product prevented H/D exchange at 10 of the sites. Immucillin-H protected 32 protons from exchange at full saturation. When one of the three subunits of the homotrimer is filled with immucillin-H, and 27 protons are protected from exchange in all three subunits. Deuterium incorporation in peptides from residues 132-152 decreased in all complexes of PNP. The rate and/or extent of deuterium incorporation in peptides from residues 29-49, 50-70, 81-98, and 112-124 decreased only in the complex with the transition state analogue. The peptide-specific H/D exchange demonstrates that (1) the enzyme is most compact in the complex with immucillin-H, and (2) filling a single catalytic site of the trimer reduces H/D exchange in the same peptides in adjacent subunits. The peptides most highly influenced by the inhibitor surround the catalytic site, providing evidence for reduced protein dynamic motion caused by the transition state analogue.
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PMID:Immucillin-H binding to purine nucleoside phosphorylase reduces dynamic solvent exchange. 1104 13

Patients with purine nucleoside phosphorylase (PNP) deficiency present a selective T-cell immunodeficiency. Inhibitors of PNP are, therefore, of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP from various species including human, mouse, rat, monkey and dog, with IC50 values ranging from 0.48 to 1.57 nM. BCX-1777, in the presence of 2'-deoxyguanosine (dGuo, 3-10 microM), inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction (MLR) and phytohemagglutinin (PHA) (IC50 values < 0.1-0.38 microM). BCX-1777 is a 10-100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors like PD141955 and BCX-34. Nucleotide analysis of human lymphocytes indicate that inhibition of proliferation by BCX-1777 correlates with dGTP levels in the cells. BCX-1777 has excellent oral bioavailability (63%) in mice. At a single dose of 10 mg/kg in mice, BCX-1777 elevates dGuo to approximately 5 microM. BCX-1777 was not effective in mouse T-cell models such as delayed type hypersensitivity (DTH) and splenomegaly because mouse T-cells do not accumulate dGTP as do human T-cells. However, in the human peripheral blood lymphocyte severe combined immunodeficiency (hu-PBL-SCID) mouse model, BCX-1777 was effective in prolonging the life span 2-fold or more. This is the first known example of a PNP inhibitor that elevates dGuo in mice similar to the levels observed in PNP-deficient patients. Furthermore, these dGuo levels are also required for in vitro T-cell inhibition by BCX-1777. Thus, BCX-1777 represents a novel class of selective immunosuppressive agents that could have therapeutic utility in various T-cell disorders.
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PMID:Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)--a novel potent and orally active immunosuppressive agent. 1140 14

Newborns with a genetic deficiency of purine nucleoside phosphorylase (PNP) are normal, but exhibit a specific T-cell immunodeficiency during the first years of development. All other cell and organ systems remain functional. The biological significance of human PNP is degradation of deoxyguanosine, and apoptosis of T-cells occurs as a consequence of the accumulation of deoxyguanosine in the circulation, and dGTP in the cells. Control of T-cell proliferation is desirable in T-cell cancers, autoimmune diseases, and tissue transplant rejection. The search for powerful inhibitors of PNP as anti-T-cell agents has culminated in the immucillins. These inhibitors have been developed from knowledge of the transition state structure for the reactions catalyzed by PNP, and inhibit with picomolar dissociation constants. Immucillin-H (Imm-H) causes deoxyguanosine-dependent apoptosis of rapidly dividing human T-cells, but not other cell types. Human T-cell leukemia cells, and stimulated normal T-cells are both highly sensitive to the combination of Imm-H to block PNP and deoxyguanosine. Deoxyguanosine is the cytotoxin, and Imm-H alone has low toxicity. Single doses of Imm-H to mice cause accumulation of deoxyguanosine in the blood, and its administration prolongs the life of immunodeficient mice in a human T-cell tissue xenograft model. Immucillins are capable of providing complete control of in vivo PNP levels and hold promise for treatment of proliferative T-cell disorders.
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PMID:Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents. 1208 52

We report two siblings with purine nucleoside phosphorylase deficiency revealed by isolated spastic paraplegia, whereas symptoms of immune deficiency did not become apparent until 3 years of age. As the concurrence of immunodeficiency and neurologic problems strongly suggests the diagnosis of purine nucleoside phosphorylase deficiency, special attention should be paid to counts of lymphocytes in any infant with spastic paraplegia.
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PMID:Familial spastic paraplegia as the presenting manifestation in patients with purine nucleoside phosphorylase deficiency. 1269 83

Genetic deficiency of human purine nucleoside phosphorylase (PNP) causes T-cell immunodeficiency. The enzyme is therefore a target for autoimmunity disorders, tissue transplant rejection and T-cell malignancies. Transition state analysis of bovine PNP led to the development of immucillin-H (ImmH), a powerful inhibitor of bovine PNP but less effective for human PNP. The transition state of human PNP differs from that of the bovine enzyme and transition state analogues specific for the human enzyme were synthesized. Three first generation transition state analogues, ImmG (Kd = 42 pM), ImmH (Kd = 56 pM), and 8-aza-ImmH (Kd = 180 pM), are compared with three second generation DADMe compounds (4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)-immucillins) tailored to the transition state of human PNP. The second generation compounds, DADMe-ImmG (Kd = 7pM), DADMe-ImmH (Kd = 16 pM), and 8-aza-DADMe-ImmH (Kd = 2.0 nM), are superior for inhibition of human PNP by binding up to 6-fold tighter. The DADMe-immucillins are the most powerful PNP inhibitors yet described, with Km/Kd ratios up to 5,400,000. ImmH and DADMe-ImmH are orally available in mice; DADMe-ImmH is more efficient than ImmH. DADMe-ImmH achieves the ultimate goal in transition state inhibitor design in mice. A single oral dose causes inhibition of the target enzyme for the approximate lifetime of circulating erythrocytes.
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PMID:Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. 1284 89

The disorders of purine and pyrimidine metabolism are unusual in their variety of clinical presentations and in the mechanisms by which these presentations result from the fundamental mutations. In the most common of the hyperuricemic metabolic disorders, deficiency of hypoxanthine phosphoribosyl transferase, the fundamental deficiency in the activity of an enzyme of purine salvage leads to enormous overactivity of de novo pathway of purine synthesis and purine overproduction. In the other hyperuricemic disorder, that of phosphoribosylpyrophosphate synthetase, mutation leads not to deficient activity, but superactivity of the enzyme in an early stage of the synthetic pathway leading to overproduction. A number of disorders of purine metabolism lead to immunodeficiency; these include adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. Marked susceptibility to infection is also seen in disorders of pyrimidine metabolism, classically in orotic aciduria, but also in pyrimidine nucleotide depletion syndrome. Orotic aciduria is a disorder of pyrimidine nucleotide synthesis, UMP synthetase deficiency, in which a single gene mutation can cause deficiency of two enzyme activities, orotic phosphoribosyltransferase and orotidine monophosphate decarboxylase which reside in a single protein. Pyrimidine degradation defects, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies leading to developmental delay are detected by analysis of the urine for pyrimidines and dihydropyrimidines. The recent discovery of aminoimidazolecarboxamideriboside deficiency points up the utility of simple colorimetric tests in bringing to light disorders of metabolism. Adenylosuccinatelyase deficiency and molybdenum cofactor deficiency illustrate the same point.
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PMID:Disorders of purine and pyrimidine metabolism. 1617 80

Defects in purine nucleoside phosphorylase (PNP) enzyme activity result in abnormal nucleoside homeostasis, severe T cell immunodeficiency, neurological dysfunction, and early death. Protein transduction domain (PTD) can transfer molecules into cells and may help restore PNP activity in cases of PNP deficiency. However, long-term use of PTD to replace enzymes in animal models or patients has not previously been described. We fused human PNP to the HIV-TAT PTD and found that the fusion with TAT changed the retention and distribution of PNP in PNP-deficient mice. TAT induced rapid intracellular delivery of PNP into tissues, including the brain, prevented urinary excretion of PNP, and protected PNP from neutralizing antibodies, resulting in significant extension of the enzyme's biological activity in vivo. Frequent TAT-PNP injections in PNP-deficient mice corrected the metabolic disorder and immune defects with no apparent toxicity. TAT-PNP remained effective over 24 weeks of treatment, resulting in continued improvement in immune function and extended survival. Our data demonstrate that TAT changes the properties of PNP in vivo and that long-term intracellular delivery of PNP by TAT corrects PNP deficiency in mice. We provide evidence to promote further use of PTD to treat diseases that require repeated intracellular enzyme or protein delivery.
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PMID:TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice. 1696 10

After receiving BS and MS degrees from the University of Washington in Seattle, I entered its new medical school in 1947, receiving an MD degree in 1951. After internship and residency, I obtained a 2-year postdoctoral fellowship in hematology under the guidance of Dr Clement Finch. The last 6 months of the fellowship were spent in London, England, at Dr Patrick Mollison's Blood Transfusion Research Unit. There I met and worked with Marie Cutbush (later Crookston) who has been a long-term friend. On returning to Seattle, I joined the faculty of the medical school and became the associate director of the Puget Sound Blood Center. There, I supervised the blood typing and cross-matching laboratory, introducing methods I had learned in London and measuring the effectiveness of various cross-matching procedures. My own research was largely directed toward human genetic polymorphism, and I wrote a textbook published in 1969, describing the biochemical structure, function, inheritance, and geographic distribution of the genetic markers. Subsequently, I discovered that 2 forms of inherited immunodeficiency disease were due to deficiencies of the enzymes adenosine deaminase and purine nucleoside phosphorylase. In 1979, I became the director of the blood center and was shortly afterwards elected to the National Academy of Sciences. I retired in 1987 and have spent most of the intervening years relearning to play the violin and exploring the wonders of chamber music.
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PMID:Back to the beginnings: an autobiography. 1706 74


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