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S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin.

Publication ,  Journal Article
Kredich, NM; Hershfield, MS
Published in: Proc Natl Acad Sci U S A
May 1979

The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and adenosine. Although adenosine-induced pyrimidine starvation appears to contribute to this effect, uridine only partially reverses adenosine toxicity in WI-L2 and not at all in strain 107, an adenosine kinase-(ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) deficient derivative of WI-L2. Treatment of both cell lines with EHNA and adenosine leads to striking elevations in intracellular S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methylation reactions. The methylation in vivo of both DNA and RNA is inhibited by concentrations of EHNA and adenosine that elevate intracellular AdoHcy. Addition of 100 muM L-homocysteine thiolactone to cells treated with EHNA and adenosine enhances adenosine toxicity and further elevates AdoHcy to levels approximately 60-fold higher than those obtained in the absence of this amino acid, presumably by combining with adenosine to form AdoHcy in a reaction catalyzed by S-adenosylhomocysteine hydrolase (EC 3.3.1.1). In the adenosine kinase-deficient strain 107, a combination of ADA inhibition and L-homocysteine thiolactone markedly increases intracellular AdoHcy and inhibits growth even in the absence of exogenous adenosine. These results demonstrate a form of toxicity from endogenously produced adenosine and support the view that AdoHcy, by inhibiting methylation, is a mediator of uridine-resistant adenosine toxicity in these human lymphoblast lines. Furthermore, they suggest that AdoHcy may play a role in the pathogenesis of the severe combined immunodeficiency disease found in most children with heritable ADA deficiency.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 1979

Volume

76

Issue

5

Start / End Page

2450 / 2454

Location

United States

Related Subject Headings

  • S-Adenosylhomocysteine
  • Phosphotransferases
  • Methylation
  • Lymphocytes
  • Lactones
  • Humans
  • Homocysteine
  • Cell Line
  • Cell Division
  • Adenosine Kinase
 

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Kredich, N. M., & Hershfield, M. S. (1979). S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A, 76(5), 2450–2454. https://doi.org/10.1073/pnas.76.5.2450
Kredich, N. M., and M. S. Hershfield. “S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin.Proc Natl Acad Sci U S A 76, no. 5 (May 1979): 2450–54. https://doi.org/10.1073/pnas.76.5.2450.
Kredich NM, Hershfield MS. S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A. 1979 May;76(5):2450–4.
Kredich, N. M., and M. S. Hershfield. “S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin.Proc Natl Acad Sci U S A, vol. 76, no. 5, May 1979, pp. 2450–54. Pubmed, doi:10.1073/pnas.76.5.2450.
Kredich NM, Hershfield MS. S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A. 1979 May;76(5):2450–2454.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 1979

Volume

76

Issue

5

Start / End Page

2450 / 2454

Location

United States

Related Subject Headings

  • S-Adenosylhomocysteine
  • Phosphotransferases
  • Methylation
  • Lymphocytes
  • Lactones
  • Humans
  • Homocysteine
  • Cell Line
  • Cell Division
  • Adenosine Kinase