Abstract
Extremely low erythrocyte NAD levels (14μM-control mean 7μM) were a repeated finding in a patient with PPRPs superactivity and neurological abnormalities, including inherited nerve deafness. The biochemical basis for this was studied using (14-C) labelled NAD precursor, Nicotinic acid (NA)+glutamine, or Micotinamide (ilam) and intact erythrocytes as an in vitro model. Various incubation times (1 min-48hrs) and substrate levels (1 μM) were used at physiological phosphate (1mM Pi) and PRP stimulating conditions (18mM Pi). NAD formation was higher from Nam than NA at low substrate levels in controls and patient. The patient showed faster NAD production, but a slower incorporation of Nam and NA into NMN, deNMN, with no stimulation by Pi. NAD was the predominant metabolite from either route after 24 or 48 hrs, with no decomposition in patient or controls. Some NA and deNMN were found at low and high Nam concentrations in the patient, indicating deamination of unmetabolized Nam. At high precursor concentrations 10-fold higher levels of NAD were produced by NA than by Nam. In the patient synthesis was less than 10% of controls from both precursors and although endogenous NAD levels were doubled by NA, the results suggest they could not be normalized by therapy with either NA or Ham. NAD stability was not altered in the patient. Thus, lower substrate utilization for nucleotide synthesis, or alternative metabolism must be implicated in the low erythrocyte NAD level. Higher substrate levels did not increase production rate, suggesting that maximal activity and not substrate affinity of the committed enzymes may be involved.
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Micheli, V., Anne Simmonds, H. 87 NAD SYNTHESIS BY ERYTHROCYTES IN PHOSPHORIBOSYL -PYROPHOSPHATE SYNTHETASE (PPRPs) SUPERACTIVITY. Pediatr Res 24, 125 (1988). https://doi.org/10.1203/00006450-198807000-00111
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DOI: https://doi.org/10.1203/00006450-198807000-00111