Immunological Observations on Patents With Lesch-Nyhan Syndrome, and on the Role of De-Novo Purine Synthesis in Lymphocyte Transformation

Allison, A. C.; Watts, R. W. E.; Hovi, Tapani; Webster, A. D. B.

doi:10.1016/s0140-6736(75)92661-6

Cited by 133 publications

(48 citation statements)

References 23 publications

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“…Fibroblasts from these patients showed a normal PRPP concentration and nucleotide pools were compensated by an increased de novo synthesis (30). Also, the proliferation of T lymphocytes from the patients in response to mitogenic and antigenic stimulation was normal (33). In the leukocytes from two gouty patients affected with a partial deficiency of HPRT, de novo synthesis was accelerated to more than 13 times that of normal controls (34).…”

Section: Discussionmentioning

confidence: 94%

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Yamaoka

Kondo

Honda

et al. 1997

Journal of Biological Chemistry

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Factors controlling relative flux rates of the de novo and salvage pathways of purine nucleotide biosynthesis during animal cell growth are not fully understood. To examine the relative role of each pathway for cell growth, three cell lines including CHO K1 (a wild-type Chinese hamster ovary fibroblast cell line), CHO ade ؊ A (an auxotrophic cell line deficient of amidophosphoribosyltransferase (ATase), a presumed rate-limiting enzyme of the de novo pathway), and CHO ade ؊ A transfected with human ATase cDNA ( ؊ A؉hATase) resulting in 30 -350% of the ATase activity of CHO K1, were cultured in purine-rich or purine-free media. Based on the enzyme activities of ATase and hypoxanthine phosphoribosyltransferase, the metabolic rate of the de novo and salvage pathways, the rate of cell growth (growth rate) in three cell lines under various culture conditions, and the effect of hypoxanthine infusion on the metabolic rate of the de novo pathway in rat liver, we concluded the following. 1) In ؊ A؉hATase transfectants, ATase activity limits the rate of the de novo pathway, which is closely linked with the growth rate. 2) Purine nucleotides are synthesized preferentially by the salvage pathway as long as hypoxanthine, the most essential source of purine salvage, can be utilized, which was confirmed in rat liver in vivo by hypoxanthine infusion. The preferential usage of the salvage pathway results in sparing the energy expenditure required for de novo synthesis.3) The regulatory capacity of the de novo pathway (about 200%) was larger than that of the salvage pathway (about 20%) with constant hypoxanthine phosphoribosyltransferase activity.Purine nucleotides synthesized via de novo and salvage pathways are indispensable for cell growth through DNA and RNA syntheses and for the ATP energy supply. Interference of purine metabolism has thus been the target of antineoplastic drugs. However, it is unclear which of the two pathways is more important for the supply of purine nucleotides during cell growth. Purine nucleotide synthesis catalyzed by HPRT, 1 the key enzyme of the purine salvage pathway, was reported to be more active than that catalyzed by ATase, the presumed ratelimiting enzyme of the de novo pathway, in many tissues and malignant cells (1, 2). The increased metabolic rate via the de novo pathway and ATase activity are, however, more strongly linked with cell growth and malignant transformation than the metabolic rate via the salvage pathway and HPRT activity (1, 3-7). To interpret this enigma, we investigated the mutual regulation of purine biosynthesis between the de novo and salvage pathways. The cDNA cloning of rat and human ATase (hATase) in our laboratory (8, 9), an ATase-deficient auxotrophic Chinese hamster ovary fibroblast cell line of CHO ade Ϫ A, and CHO ade Ϫ A transfected with hATase cDNA driven by the cytomegalovirus promoter ( Ϫ AϩhATase) enabled us to explore the rate-limiting property of ATase and to study the relationship between the two pathways in three cell lines in two purine-free or two purine-...

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Section: Discussionmentioning

confidence: 94%

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Yamaoka

Kondo

Honda

et al. 1997

Journal of Biological Chemistry

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“…Unlike B and T lymphocytes, most other cell types express the IMPDHindependent salvage pathway, which allows purine production despite inhibition of IMPDH by MPA. This explains why MPA has found excellent use as an immunosuppressive pharmaceutical (2).…”

mentioning

confidence: 98%

Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum

Regueira

Kildegaard

Hansen

et al. 2011

Appl Environ Microbiol

144

123

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Mycophenolic acid (MPA) is the active ingredient in the increasingly important immunosuppressive pharmaceuticals CellCept (Roche) and Myfortic (Novartis). Despite the long history of MPA, the molecular basis for its biosynthesis has remained enigmatic. Here we report the discovery of a polyketide synthase (PKS), MpaC, which we successfully characterized and identified as responsible for MPA production in Penicillium brevicompactum. mpaC resides in what most likely is a 25-kb gene cluster in the genome of Penicillium brevicompactum. The gene cluster was successfully localized by targeting putative resistance genes, in this case an additional copy of the gene encoding IMP dehydrogenase (IMPDH). We report the cloning, sequencing, and the functional characterization of the MPA biosynthesis gene cluster by deletion of the polyketide synthase gene mpaC of P. brevicompactum and bioinformatic analyses. As expected, the gene deletion completely abolished MPA production as well as production of several other metabolites derived from the MPA biosynthesis pathway of P. brevicompactum. Our work sets the stage for engineering the production of MPA and analogues through metabolic engineering.

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“…In contrast to these observations, we found that children with inherited deficiencies in the major purine salvage pathway, mediated by hypoxanthine-guanine phosphoribosyltransferase, have essentially normal immune functions, although they have neurological deficits [12]. Our conclusion was that de novo synthesis of guanosine nucleotides is required for human lymphocytes to respond to antigenic stimulation.…”

Section: Biochemical Studies On Inherited Defects In Immunitymentioning

confidence: 79%

Observational, Hypothesis-Driven and Genomics Research Strategies for Analyzing Inherited Differences in Responses to Infectious Diseases

Allison¹

2008

Public Health Genomics

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The first phase of research on genetic factors influencing susceptibility to infectious diseases was observational and descriptive. It began with the identification of children and adults with selective and non-selective immunodeficiencies. The types of infections to which these patients are susceptible provided evidence for the roles of T-cells, B-cells, leukocytes, and complement in controlling infectious diseases. Later the biochemical bases for these deficiencies were characterized. For example, an abnormal tyrosine kinase is associated with X-linked agammaglobulinemia, and lack of adenosine deaminase results in severe combined immunodeficiency. The second strategy for analyzing inherited resistance to disease was hypothesis-driven. Observations on the distribution of the sickle-cell gene suggested that heterozygotes might be resistant to P. falciparum malaria. That proposal has been confirmed repeatedly. Persons heterozygous for other hemoglobin mutations and those with glucose-6-phosphate dehydrogenase deficiency also have some degree of resistance to malaria. The third, modern phase of research on susceptibility to infectious diseases is genomic. This powerful approach facilitated characterization of the mutations responsible for most of the above-mentioned defects. Moreover, genomics strategies make analyses of susceptibility to infections possible even when these are under multifactorial genetic control, as exemplified by malaria. This is likely to be true for most infectious diseases, so the genomic approach is an important way forward.

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Immunological Observations on Patents With Lesch-Nyhan Syndrome, and on the Role of De-Novo Purine Synthesis in Lymphocyte Transformation

Cited by 133 publications

References 23 publications

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis

Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum

Observational, Hypothesis-Driven and Genomics Research Strategies for Analyzing Inherited Differences in Responses to Infectious Diseases

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