The relationship between a complete deficiency of the purine enzyme hypoxanthine-guanine phosphoribosyltransferase and the neurobehavioural abnormalities in Lesch—Nyhan disease remains an enigma. In vitro studies using lymphoblasts or fibroblasts have evaluated purine and pyrimidine metabolism with conflicting results. This study focused on pyridine nucleotide metabolism in control and Lesch—Nyhan fibroblasts using radiolabelled salvage precursors to couple the extent of uptake with endocellular nucleotide concentrations. The novel finding, highlighted by specific culture conditions, was a marked NAD depletion in Lesch—Nyhan fibroblasts. ATP and GTP were also 50% of the control, as reported in lymphoblasts. A 6-fold greater incorporation of [14C]nicotinic acid into nicotinic acid— adenine dinucleotide by Lesch—Nyhan fibroblasts, with no unmetabolized substrate (20% in controls), supported disturbed pyridine metabolism, NAD depletion being related to utilization by poly(ADP-ribose) polymerase in DNA repair. Although pyrimidine nucleotide concentrations were similar to controls, Lesch—Nyhan cells showed reduced [14C]cytidine/uridine salvage into UDP sugars. Incorporation of [14C]uridine into CTP by both was minimal, with more than 50% [14C]cytidine metabolized to UTP, indicating that fibroblasts, unlike lymphoblasts, lack active CTP synthetase, but possess cytidine deaminase. Restricted culture conditions may be neccesary to mimic the situation in human brain cells at an early developmental stage. Cell type may be equally important. NAD plus ATP depletion in developing brain could restrict DNA repair, leading to neuronal damage/loss by apoptosis, and, with GTP depletion, affect neurotransmitter synthesis and basal ganglia dopaminergic neuronal systems. Thus aberrant pyridine nucleotide metabolism could play a vital role in the pathophysiology of Lesch—Nyhan disease.
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August 2002
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Research Article|
August 15 2002
Severe pyridine nucleotide depletion in fibroblasts from Lesch–Nyhan patients
Lynette D. FAIRBANKS;
Lynette D. FAIRBANKS
1
∗Purine Research Unit, Department of Chemical Pathology, GKT, Guy's Hospital, London SE1 9RT, U.K.
1To whom correspondence should be addressed (e-mail lynette.fairbanks@kcl.ac.uk).
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Gabriella JACOMELLI;
Gabriella JACOMELLI
†Dipartimento di Biologia Moleculare, Università di Siena, 5310 Siena, Italy
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Vanna MICHELI;
Vanna MICHELI
†Dipartimento di Biologia Moleculare, Università di Siena, 5310 Siena, Italy
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Tina SLADE;
Tina SLADE
‡Department of Medical and Molecular Genetics, GKT, Guy's Hospital, London SE1 9RT, U.K.
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H. Anne SIMMONDS
H. Anne SIMMONDS
∗Purine Research Unit, Department of Chemical Pathology, GKT, Guy's Hospital, London SE1 9RT, U.K.
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Publisher: Portland Press Ltd
Received:
January 23 2002
Revision Received:
April 23 2002
Accepted:
May 08 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 265–272.
Article history
Received:
January 23 2002
Revision Received:
April 23 2002
Accepted:
May 08 2002
Citation
Lynette D. FAIRBANKS, Gabriella JACOMELLI, Vanna MICHELI, Tina SLADE, H. Anne SIMMONDS; Severe pyridine nucleotide depletion in fibroblasts from Lesch–Nyhan patients. Biochem J 15 August 2002; 366 (1): 265–272. doi: https://doi.org/10.1042/bj20020148
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