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Molecular Pharmacology

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Research ArticleArticle

Pteridine Regulation of Inhibition of Hepatic Uroporphyrinogen I Synthetase Activity by Lead Chloride

WALTER N. PIPER and ROBERT B. L. VAN LIER
Molecular Pharmacology November 1977, 13 (6) 1126-1135;
WALTER N. PIPER
Department of Pharmacology, School of Medicine, University of California, San Francisco, California 94143
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ROBERT B. L. VAN LIER
Department of Pharmacology, School of Medicine, University of California, San Francisco, California 94143
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Abstract

A dialyzable factor has been purified from rat hepatic cytosol that protects against PbCl2-mediated inhibition of uroporphyrinogen I synthetase (EC 4.3.1.8), an enzyme of the heme biosynthetic pathway. This factor also stimulated enzymatic activity which was antagonized by folic acid. The factor also produced growth of the folate-requiring microorganisms Lactobacillus casei (ATCC 7469) and Streptococcus faecalis (ATCC 8043), and antagonized binding of [3H]folic acid to a specific folate-binding protein. These results suggested that the factor was a pteridine derivative. The protective effect against inhibition of uroporphyrinogen I synthetase activity by PbCl2 was abolished by prior treatment of factor with γ-glutamyl carboxypeptidase (EC 3.4.12.10), indicating that the factor is a polyglutamated pteridine derivative. The estimated concentrations of factor (as pteroylglutamate) protecting against inhibition of enzyme activity by PbC12 (10 µM) were 3.3 pM (competitive protein binding radioassay) and 16 pM (microbiological assays), which indicates that the glutamate portion of the pteroylpoly-glutamate factor does not merely chelate lead. Additional evidence ruling out chelation as a mechanism is the finding that concentrations of the factor in excess of those protecting against inhibition of uroporphyrinogen I synthetase activity by PbCl2 failed to protect against inhibition of another lead-sensitive enzyme, δ-aminolevulinic acid dehydratase (EC 4.2.1.24). Pteroylhexaglutamate was found to protect against inhibition of uroporphyrinogen I synthetase activity by PbCl2 at 1-10 µM concentrations. Pteroyltriglutamate and pteroylmonoglutamate were unable to protect against inhibition of enzymatic activity by PbCl2. It is suggested that pteroylpolyglutamate derivatives may be regulators of uroporphyrinogen I synthetase activity, and may serve as coenzymes for this enzyme.

ACKNOWLEDGMENTS The authors express their gratitude for the technical assistance of Ms. V. Pascucci.

  • Copyright © 1977 by Academic Press, Inc.

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Molecular Pharmacology
Vol. 13, Issue 6
1 Nov 1977
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Research ArticleArticle

Pteridine Regulation of Inhibition of Hepatic Uroporphyrinogen I Synthetase Activity by Lead Chloride

WALTER N. PIPER and ROBERT B. L. VAN LIER
Molecular Pharmacology November 1, 1977, 13 (6) 1126-1135;

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Research ArticleArticle

Pteridine Regulation of Inhibition of Hepatic Uroporphyrinogen I Synthetase Activity by Lead Chloride

WALTER N. PIPER and ROBERT B. L. VAN LIER
Molecular Pharmacology November 1, 1977, 13 (6) 1126-1135;
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