Biochemical Bases of Accelerated Purine Biosynthesis de Novo in Human Fibroblasts Lacking Hypoxanthine-Guanine Phosphoribosyltransferase

Rosenbloom, Frederick M.; Henderson, J. Frank; Caldwell, Ian C.; Kelley, William N.; Seegmiller, J. Edwin

doi:10.1016/s0021-9258(19)56968-x

Cited by 239 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…tant strains,16 of the 50 spores isolated germinated, and of these three failed to grow onVOL. 128, 1976 on May 5, 2021 by guest http://jb.asm.org/ Downloaded from…”

mentioning

confidence: 99%

“…In humans, the loss of HPRTase activity has been demonstrated in persons with Lesch-Nyhan disease or gout and results in an increase in IMP catabolism (16). This apparently results in an efflux of hypoxanthine (or a derivative), which contributes to excess uric acid formation in the blood.…”

mentioning

confidence: 99%

“…The heritable disease gouty arthritis in humans is characterized by high levels of hypoxanthine and, consequently, uric acid in the blood stream of afflicted individuals. The primary lesion is thought to be a deficiency of HPRTase (16) or an aberration in the purine synthetic pathway that may lead to the excretion of excess hypoxanthine from cells into the blood stream. The lack of HPRTase activity and the excretion of hypoxanthine (or inosine) by the ad-8 strain suggests the similarity between the ad-8 auxotrophic strains in Neurospora and the phenotype of gouty arthritis in humans.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Regulation of hypoxanthine transport in Neurospora crassa

Sabina¹,

Magill²,

Magill³

1976

J Bacteriol

View full text Add to dashboard Cite

Hypoxanthine uptake and hypoxanthine phosphoribosyltransferase activity (EC 2.4.2.8) were determined in germinated conidia from the adenine auxotrophic strains ad-1 and ad-8 and the double mutant strain ad-1 ad-8. The mutant strain ad-1 appears to lack aminoimidazolecarboximide ribonucleotide formyltransferase (EC 2.1.2.3) or inosine 5'monophosphate cyclohydrolase (EC 3.5.1.10) activities, or both, whereas the ad-8 strain lacks adenylosuccinate synthase activity (EC 6.3.4.4). Normal (or wild-type) hypoxanthine transport capacity was found to the ad-1 conidia, whereas the ad-8 strains failed to take up any hypoxanthine. The double mutant strains showed intermediate transport capacities. Similar results were obtained for hypoxanthine phosphoribosyl-transferase activity assayed in germinated conidia. The ad-1 strain showed greatest activity, the ad-8 strain showed the least activity, and the double mutant strain showed intermediate activity levels. Ion-exchange chromatography of the growth media revealed that in the presence of NH+/4, the ad-8 strain excreted hypoxanthine or inosine, the ad-1 strain did not excrete any purines, and the ad-1 ad-8 double mutant strain excreted uric acid. In the absence of NH+/4, none of the strains excreted any detectable purine compounds.

show abstract

“…tant strains,16 of the 50 spores isolated germinated, and of these three failed to grow onVOL. 128, 1976 on May 5, 2021 by guest http://jb.asm.org/ Downloaded from…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of hypoxanthine transport in Neurospora crassa

Sabina¹,

Magill²,

Magill³

1976

J Bacteriol

View full text Add to dashboard Cite

show abstract

“…In humans, deficiencies in the enzymes punne nucleoside phosphorylase (6) or HGPRTase (15) result in marked purine overproduction. The deficiency in HGPRTase is associated with an increased intracellular concentration of PRPP (25), a rate-limiting substrate for de novo purine synthesis, whereas erythrocytes but not fibroblasts from purine nucleoside phosphorylasedeficient children have elevated PRPP (6). Two mechanisms have been attributed to this purine overproduction in purine salvage enzyme deficiency: PRPP sparing, due to the absence of the inosine cycle, and decreased synthesis of nucleotide effectors which feedback-inhibit the early steps of the de novo pathway (25).…”

Section: Discussionmentioning

confidence: 99%

“…The deficiency in HGPRTase is associated with an increased intracellular concentration of PRPP (25), a rate-limiting substrate for de novo purine synthesis, whereas erythrocytes but not fibroblasts from purine nucleoside phosphorylasedeficient children have elevated PRPP (6). Two mechanisms have been attributed to this purine overproduction in purine salvage enzyme deficiency: PRPP sparing, due to the absence of the inosine cycle, and decreased synthesis of nucleotide effectors which feedback-inhibit the early steps of the de novo pathway (25). The characterization of the nucleoside transport-deficient AU-100-fdUrd4 cell line allowed us to examine the contribution of PRPP sparing to purine biosynthetic rates in a homologous cell culture system.…”

Section: Discussionmentioning

confidence: 99%

Genetic Studies on the Role of the Nucleoside Transport Function in Nucleoside Efflux, the Inosine Cycle, and Purine Biosynthesis

Ullman

Kaur

Watts

1983

Molecular and Cellular Biology

View full text Add to dashboard Cite

A mutant clone (AU-100) which is 90% deficient in adenylosuccinate synthetase activity was characterized from wild-type murine S49 T-lymphoma cells. This AU-100 cell line and its hypoxanthine-guanine phosphoribosyltransferase-deficient derivative, AUTG-50B, overproduce purines severalfold and excrete massive amounts of inosine into the culture medium (Ullman et al., Proc. Natl. Acad. Sci. U.S.A. 79:5127-5131, 1982). We introduced a mutation into both of these cell lines which make them incapable of taking up nucleosides from the culture medium. The genetic deficiency in nucleoside transport prevents the adenylosuccinate synthetase-deficient AU-100 cells from excreting inosine. Because of an extremely efficient intracellular inosine salvage system, the nucleoside transport-deficient AU-100 cells also no longer overproduce purines. AUTG-50B cells which have been made genetically deficient in nucleoside transport still overproduce purines but excrete hypoxanthine rather than inosine. These studies demonstrate genetically that nucleoside transport and nucleoside efflux share a common component and that nucleoside transport has an important regulatory function which profoundly affects the rates of purine biosynthesis and purine salvage.

show abstract

Clinical Features of Patients With the "Partial" Deficiency of the X-Linked Uricaciduria Enzyme

Greene¹

1972

Arch Intern Med

View full text Add to dashboard Cite

show abstract

Biochemical Bases of Accelerated Purine Biosynthesis de Novo in Human Fibroblasts Lacking Hypoxanthine-Guanine Phosphoribosyltransferase

Cited by 239 publications

References 35 publications

Regulation of hypoxanthine transport in Neurospora crassa

Regulation of hypoxanthine transport in Neurospora crassa

Genetic Studies on the Role of the Nucleoside Transport Function in Nucleoside Efflux, the Inosine Cycle, and Purine Biosynthesis

Clinical Features of Patients With the "Partial" Deficiency of the X-Linked Uricaciduria Enzyme

Contact Info

Product

Resources

About