The PRPP synthetase spectrum: What does it demonstrate about nucleotide syndromes?

Duley, John A., Christodoulou, John and de Brouwer, Arjan P. M. (2011) The PRPP synthetase spectrum: What does it demonstrate about nucleotide syndromes?. Nucleosides, Nucleotides and Nucleic Acids, 30 12: 1129-1139. doi:10.1080/15257770.2011.591747

Author Duley, John A.
Christodoulou, John
de Brouwer, Arjan P. M.
Title The PRPP synthetase spectrum: What does it demonstrate about nucleotide syndromes?
Journal name Nucleosides, Nucleotides and Nucleic Acids   Check publisher's open access policy
ISSN 1525-7770
Publication date 2011
Sub-type Article (original research)
DOI 10.1080/15257770.2011.591747
Volume 30
Issue 12
Start page 1129
End page 1139
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher Taylor & Francis
Collection year 2012
Language eng
Formatted abstract
Defects in X-linked phosphoribosylpyrophosphate synthetase 1 (PRPS1) manifest as follows: (1) PRS-I enzyme “superactivity” (gain-of-function mutations affecting allosteric regions); (2) PRS-I overexpression (which may be linked to miRNA mutation); (3) severe PRS-I deficiency/ Arts syndrome (missense mutations producing loss-of-function); (4) moderate PRS-I deficiency/Charcot–Marie–Tooth disease-5 (less severe loss-of-function mutations); and (5) mild PRS-I deficiency/Deafness-2 (mutations producing slight destabilization). Similar to Lesch–Nyhan disease, PRPS1-related disorders arise from phosphoribosyl-pyrophosphate (PRPP)-dependent nucleotide “depletion” of purine nucleotides (e.g., ATP, GTP). S-adenosylmethionine (SAMe) appears to partially alleviate purine depletion via a PRPP-independent path. Synthesis of pyrimidine nucleotides is PRPP dependent, with uridine monophosphate synthase deficiency producing pyrimidine nucleotide depletion. But pyrimidine salvage from uridine does not require PRPP, and this nucleoside is transported freely to pyrimidine-depleted tissues. Regulation of nicotinamide nucleotides is less clear; synthesis from pyridine nucleobases is PRPP dependent. Nucleotide “depletion” contrasts with nucleotide “toxicity,” exemplified by the purine disorders adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies or by pyrimidine nucleotidase deficiency. These are characterized by the accumulation of one or more abnormal nucleotides such as succinyl- or deoxy-nucleotides or their metabolites, which interrupt other nucleotide or related pathways or are toxic to specific cell types. Theoretically, purine toxicity disorders would not be ameliorated by SAMe therapy, and this was confirmed for one adenylosuccinate lyase-deficient child. Nucleotide defects may also be seen as an aspect of mitochondrial disease, with SAMe-based mitochondrial therapy perhaps meriting further investigation.
Keyword Nucleotides
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
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Created: Thu, 15 Dec 2011, 11:24:55 EST by Charna Kovacevic on behalf of School of Pharmacy