{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:21:28Z","timestamp":1791148888708,"version":"4.1.0"},"reference-count":0,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,8,15]]},"abstract":"<jats:p>The relationship between a complete deficiency of the purine enzyme hypoxanthine-guanine phosphoribosyltransferase and the neurobehavioural abnormalities in Lesch\u2014Nyhan 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\u2014Nyhan 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\u2014Nyhan 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\u2014 adenine dinucleotide by Lesch\u2014Nyhan 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\u2014Nyhan 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\u2014Nyhan disease.<\/jats:p>","DOI":"10.1042\/bj20020148","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T09:27:52Z","timestamp":1027675672000},"page":"265-272","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Severe pyridine nucleotide depletion in fibroblasts from Lesch\u2013Nyhan patients"],"prefix":"10.1042","volume":"366","author":[{"given":"Lynette D.","family":"FAIRBANKS","sequence":"first","affiliation":[{"name":"Purine Research Unit, Department of Chemical Pathology, GKT, Guy's Hospital, London SE1 9RT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"JACOMELLI","sequence":"additional","affiliation":[{"name":"Dipartimento di Biologia Moleculare, Universit\u00e0 di Siena, 5310 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanna","family":"MICHELI","sequence":"additional","affiliation":[{"name":"Dipartimento di Biologia Moleculare, Universit\u00e0 di Siena, 5310 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"SLADE","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, GKT, Guy's Hospital, London SE1 9RT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Anne","family":"SIMMONDS","sequence":"additional","affiliation":[{"name":"Purine Research Unit, Department of Chemical Pathology, GKT, Guy's Hospital, London SE1 9RT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/366\/1\/265\/710341\/bj3660265.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/366\/1\/265\/710341\/bj3660265.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T12:14:30Z","timestamp":1637583270000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/366\/1\/265\/40198\/Severe-pyridine-nucleotide-depletion-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,8,15]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2002,8,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20020148","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,8,15]]}}}