Regulation of nicotinamide-adenine dinucleotide synthesis in erythrocytes of patients with hypoxanthine-guanine phosphoribosyltransferase deficiency and a patient with phosphoribosylpyrophosphate synthetase superactivity.
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)
Micheli
V
V
Istituto di Chimica Biologica, Universita' di Siena, Italy.
Simmonds
H A
HA
Ricci
C
C
D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency*; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism; D008297:Male; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D009243:NAD / Q000096:biosynthesis*; D009536:Niacinamide / Q000378:metabolism; D009539:Nicotinic Acids / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism*
D009539:Nicotinic Acids; D009243:NAD; D009536:Niacinamide; D007041:Hypoxanthine Phosphoribosyltransferase; D010770:Phosphotransferases; D012268:Ribose-Phosphate Pyrophosphokinase