Regulation of nicotinamide-adenine dinucleotide synthesis in erythrocytes of patients with hypoxanthine-guanine phosphoribosyltransferase deficiency and a patient with phosphoribosylpyrophosphate synthetase superactivity

Clin Sci (Lond). 1990 Feb;78(2):239-45. doi: 10.1042/cs0780239.

Abstract

1. The synthesis of nicotinamide-adenine dinucleotide from nicotinamide and nicotinic acid was compared over different time scales at both physiological (0.7 mumol/l) and high (0.2-3 mmol/l) substrate concentrations in erythrocytes from three patients with hypoxanthine-guanine phosphoribosyltransferase (hypoxanthine phosphoribosyltransferase, EC 2.4.2.8) deficiency (including one Lesch-Nyhan patient) and from one patient with phosphoribosylpyrophosphate synthetase superactivity. The above disorders are associated with grossly altered erythrocyte nicotinamide-adenine dinucleotide levels. 2. At the physiological substrate concentration and incubation times up to 2 h, nicotinamide proved the most efficient nicotinamide-adenine dinucleotide precursor for erythrocytes from both patients and control subjects. The conversion of nicotinamide to its mononucleotide, but not further metabolism, was impaired in phosphoribosylpyrophosphate synthetase-mutant cells. The Lesch-Nyhan and phosphoribosylpyrophosphate synthetase-mutant cells were unusual in that both showed no further stimulation of nucleotide synthesis at 18 mmol/l Pi compared with 1 mmol/l. 3. At the high substrate concentrations, using 18 mmol/l Pi, nicotinamide was a poor precursor in all instances. Using nicotinic acid, nucleotide formation was 30-fold that from nicotinamide, reaching its maximum at 0.2 mmol/l. Conversion of nicotinic acid to nicotinamide-adenine dinucleotide in the phosphoribosylpyrophosphate synthetase-mutant cells was again grossly impaired. 4. There was no evidence for increased nicotinamide-adenine dinucleotide breakdown in the phosphoribosylpyrophosphate synthetase-mutant cells under any of the above conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • Child
  • Chromatography, High Pressure Liquid
  • Erythrocytes / metabolism*
  • Female
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / deficiency*
  • Lesch-Nyhan Syndrome / metabolism
  • Male
  • Metabolism, Inborn Errors / metabolism*
  • NAD / biosynthesis*
  • Niacinamide / metabolism
  • Nicotinic Acids / metabolism
  • Phosphotransferases / metabolism*
  • Ribose-Phosphate Pyrophosphokinase / metabolism*

Substances

  • Nicotinic Acids
  • NAD
  • Niacinamide
  • Hypoxanthine Phosphoribosyltransferase
  • Phosphotransferases
  • Ribose-Phosphate Pyrophosphokinase