Inborn Errors of Purine Salvage and Catabolism

Abstract

Cellular purine nucleotides derive mainly from de novo synthesis or nucleic acid turnover and, only marginally, from dietary intake. They are subjected to catabolism, eventually forming uric acid in humans, while bases and nucleosides may be converted back to nucleotides through the salvage pathways. Inborn errors of the purine salvage pathway and catabolism have been described by several researchers and are usually referred to as rare diseases. Since purine compounds play a fundamental role, it is not surprising that their dysmetabolism is accompanied by devastating symptoms. Nevertheless, some of these manifestations are unexpected and, so far, have no explanation or therapy. Herein, we describe several known inborn errors of purine metabolism, highlighting their unexplained pathological aspects. Our intent is to offer new points of view on this topic and suggest diagnostic tools that may possibly indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all.

Keywords: inborn errors; metabolism; metabolites; neurological disorders; neurological syndromes; purine catabolism; purine salvage; uric acid.

Figure 1

The metabolic scheme depicts the pathways involved in the catabolism and salvage of purine nucleotides. Inosine 5′-monophosphate (IMP) represents the branching point from which both guanylate and adenylate pools are generated. IMP dehydrogenase (4) converts IMP into xanthosine monophosphate (XMP), and adenylosuccinate lyase (3) converts succinyl-adenosine 5-monophosphate (S-AMP) into AMP. Purine nucleotides are converted to the corresponding nucleosides by 5′-nucleotidases (cytosolic 5′-nucleotidase I, 5, and cytosolic 5′-nucleotidase II, 6). Guanosine (Guo) and Inosine (Ino) are phosphorolytically cleaved into the bases guanine (Gua) and hypoxanthine (Hyp), through purine nucleoside phosphorylase (11). Adenosine (Ado) is deaminated to Ino by adenosine deaminase (9). Gua, Hyp, and Adenine (Ade) can be salvaged to the corresponding nucleotides by phosphoribosyltransferases (hypoxanthine-guanine phosphoribosyltransferase, 2, and adenine phosphoribosyltransferase, 12). Phosphoribosylpyrophospate (PRPP), necessary for the salvage of purine bases, is generated by phosphoribosylpyrophosphate synthetase (1), starting from ATP and ribose-5-phosphate (Rib-5-P). Ado can be generated from S-adenosylmethionine (SAM), through methyltransferases (13) and S-adenosylhomocysteine (SAH) hydrolase (10). Ado can be converted into AMP by adenosine kinase (8). Ade can be generated from SAM, through the polyamine synthesis pathway (14) and methylthioAdo phosphorylase (15). AMP is deaminated to IMP by AMP deaminase (7) and Gua is converted to xanthine (Xan) by guanase (16). Eventually, purine bases are converted to uric acid (UA) through xanthine oxidoreductase (17).

Figure 2

Adenylosuccinate lyase (ADSL) is involved both in the de novo purine synthesis (yellow box) and the purine nucleotide cycle (green box). The deficiency of ADSL causes an accumulation of its substrates, succinyl aminoimidazole carboxamide ribotide (SAICAR) and succinyl-AMP (S-AMP), which are both dephosphorylated and converted to SAICA-riboside (SAICAr) and succinyl-Ado (S-Ado), respectively. The formation of the purinosome complex (blue box) is impaired in cases of ADSL deficiency. Phosphoribosylpyrophosphate (PRPP) is synthesized from ribose-5-phosphate (Rib-5-P) by PRPP synthetase (PRPS). Six enzymes can form the purinosome and catalyze the ten steps required to convert PRPP into IMP: PRPP amidotransferase (PPAT), trifunctional phosphoribosyl glicinamide synthetase/phosphoribosyl glycinamide transformylase/phophoribosyl aminoimidazole synthetase (GART), phosphoribosyl glycinamidine synthase (FGAMS), bifunctional phosphoribosyl aminoimidazole carboxylase/phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), ADSL, and bifunctional 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase (ATIC). IMP enters the purine nucleotide cycle composed of adenylosuccinate synthase (ASS), ADSL, and AMP deaminase (AMPD). Asp: Aspartate.

Figure 3

Hypothesis of a common mechanism between equilibrative nucleoside transporter 1 (ENT1) and ectosolic 5′-nucleotidase (eN) deficiency. Panel (A) Ado, formed by eN, whose activity depends on the oscillatory levels of ATP, and nonspecific alkaline phosphatase (AP), can cross the cell membrane through ENT1: Panel (B) ENT1 deficiency is accompanied by an increase in extracellular Ado. Panel (C) In case of eN deficiency, the level of Ado is no more subjected to the oscillatory concentration of ATP, and the activity of AP is up-regulated, thus possibly leading to a paradoxical increase in extracellular Ado.

Figure 4

Transmethylation pathway. S-Adenosylhomocysteine hydrolase (SAHH) catalyzes the reversible reaction which converts S-adenosylhomocysteine (SAH) to homocysteine and adenosine (Ado). Ado can be phosphorylated to AMP by adenosine kinase (ADK). Methionine synthase (MetS) converts homocysteine into methionine. Methionine adenosyl transferase (MetAT) catalyzes the formation of S-adenosylmethionine (SAM). SAM is the donor of the methyl group in the transmethylation reactions catalyzed by methyltransferases (MethylT). X: acceptor of the methyl group. SAH is an inhibitor of MethylT (dashed line). THF: tetrahydrofolate; PPi: inorganic pyrophosphate; Pi: inorganic phosphate.

Figure 5

Proposed mechanisms of vascular inflammation in deficiency of ADA2. In the absence of ADA2 activity, there is a decrease in macrophages M2 and an increase in proinflammatory macrophages M1 that release cytokines such as tumor necrosis factor-α (TNF-α). Adenosine (Ado) cannot be converted to inosine (Ino) and binds to its receptors in neutrophils, leading to neutrophil extracellular trap formation, which induces TNF-α release from M1 macrophages. When ADA2 activity decreases, deoxyadenosine (dAdo) concentration increases. dAdo can enter the cell, and is converted to dIno by ADA1, thereby inhibiting the synthesis of SAM and the transmethylation reactions. The reduction in the activity of DNA methyltransferases (DNAMT) leads to the expression of endogenous retroviral elements that result in increased transcription of IFN-β (interferon β). ENT1: equilibrative nucleoside transporter 1. Parts of the figure were drawn by using pictures from Medical gallery of Blausen Medical [257]. Medical gallery of Blausen Medical is licensed under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/ accessed on 23 May 2023).

Figure 6

Immunological outcomes of purine nucleoside phosphorylase (PNP) inhibition. The lack of PNP causes accumulation of both ribo and deoxyribo guanosine [(d)Guo]. Panel (A), upper: Deoxyguanosine (dGuo) is phosphorylated by deoxycytidine kinase (dCK) to deoxyGMP (dGMP), then converted to deoxyGTP (dGTP), which accumulates in sterile alpha motif and HD domain containing protein 1 (SAMHD1)-deficient cells (namely, T-cell progenitors). Panel (A), lower: In SAMDH1-proficient cells (namely, B lymphoblastic cells), dGTP does not accumulate because it is efficiently converted to dGuo and triphosphate. Panel (B): Elevated endolysosomal guanosine nucleoside levels trigger Toll-like receptor 7 (TLR 7) activation, through a dual binding of single-stranded ribonucleic acid (ssRNA) and guanosine, which causes transcription of the gene encoding for interleukin-6 (IL-6). Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ accessed on 23 May 2023).