RARE DISEASE
Adenylosuccinate lyase deficiency
Adenylosuccinate lyase deficiency
Adenylosuccinate lyase deficiency
Synonyms: ADSL deficiency, Adenylosuccinase deficiency
Synonyms: ADSL deficiency, Adenylosuccinase deficiency
Synonyms: ADSL deficiency, Adenylosuccinase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Adenylosuccinate lyase deficiency (ADSL deficiency) is a rare autosomal recessive disorder of purine metabolism caused by ADSL gene mutations, leading to toxic accumulation of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). It manifests as encephalopathy with psychomotor delay, seizures, microcephaly, and autistic features. Severity ranges from fatal neonatal forms to milder childhood-onset subtypes. Diagnosis involves detecting SAICAr/S-Ado in bodily fluids and genetic testing. No curative therapies exist [1][2][6][17].
Therapies
Supportive care: Anticonvulsants (valproate, levetiracetam) for seizure management, though drug resistance is common [6][13][15]
Experimental approaches: Ketogenic diet (limited efficacy), D-ribose/uridine supplementation (no proven benefit) [3][12][13]
Emerging research: Preclinical gene therapy targeting ADSL enzyme restoration [8]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
41 drug discovery papers about Adenylosuccinate lyase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
41 drug discovery papers about Adenylosuccinate lyase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | A novel homozygous variant causing fatal neonatal adenylosuccinate lyase (ADSL) deficiency presenting with respiratory failure and encephalopathy.
Neonatal adenylosuccinate lyase (ADSL) deficiency is a rare neurodegenerative disorder that is associated with epileptic encephalopathy, diffuse hypotonia, and respiratory failure. Loss of enzymatic function of ADSL leads to toxic buildup of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). We describe a female term neonate who presented with respiratory failure and encephalopathy. Neuroimaging revealed microencephaly, a simplified gyral pattern, and diffuse white matter edema. Genetic testing showed novel homozygous loss of function mutations of ADSL, the adenylosuccinate lyase gene, consistent with fatal neonatal ADSL deficiency. We find this to be one of less than a dozen cases reported of the fatal neonatal phenotype of ADSL deficiency. The case highlights ADSL deficiency as a rare cause of neonatal encephalopathy and respiratory failure. Clinical recognition of epileptic encephalopathy, pertinent findings on MRI, and testing for S-Ado can confirm the diagnosis and support discussions about goals of care.
2026-07-10 | Severe adenylosuccinate lyase deficiency with early autonomic dysfunction: functional characterization of a novel ADSL variant and exploratory treatment with disulfiram.
Adenylosuccinate lyase (ADSL) deficiency (MIM# 103050) is a rare inherited disorder of purine metabolism characterized by neurodevelopmental impairment, epilepsy, and accumulation of succinylpurines. The clinical spectrum ranges from severe prenatal manifestations with congenital anomalies to mild intellectual disability. We report a child with a severe form of ADSL deficiency presenting with early autonomic dysfunction, including recurrent apnea and bradycardia beginning in the neonatal period, followed by pharmacoresistant epilepsy and profound developmental delay. Exome sequencing identified compound heterozygous variants in the ADSL gene: a known variant (NM_000026.4): c.340 T > C (p.Tyr114His), and a novel variant, c.363G > T (p.Leu121Phe). Urinary metabolite analysis showed highly elevated levels of succinylaminoimidazolecarboxamide riboside (SAICAr) and succinyladenosine (SAdo). Functional studies in patient fibroblasts demonstrated severely reduced ADSL activity (1 to 4% of control values) and absence of purinosome assembly. Enzymatic activity in parental fibroblasts was reduced to less than 30% of control values, while purinosome formation remained preserved. Recombinant ADSL proteins carrying the p.(Tyr114His) and p.(Leu121Phe) variants retained less than 6% and 17% of wild-type catalytic activity, respectively, supporting the pathogenicity of the novel variant. In the absence of disease-specific therapy, off-label treatment with disulfiram was initiated to reduce succinylpurine accumulation. Disulfiram treatment was associated with a decrease in SAICAr and an increase in the upstream metabolite aminoimidazole ribotide (Air), suggesting a possible effect on de novo purine synthesis. This study expands the clinical spectrum of ADSL deficiency, functionally validates a novel ADSL variant, and illustrates a potential metabolic intervention targeting succinylpurine accumulation.
2026-04-28 | Creatine-ribose combination therapy for cellular energy restoration
Creatine enhances phosphocreatine-mediated ATP buffering while D-ribose provides substrate for enhanced PRPP synthesis via ribokinase, creating dual pathway support for energy metabolism disrupted by ADSL deficiency
2026-04-28 | Folate pathway modulation targeting ATIC enzyme enhancement
High-dose folinic acid increases 10-formyl-THF availability to enhance ATIC enzyme activity in the final step of de novo purine synthesis, potentially compensating for upstream disruptions caused by ADSL deficiency
2026-04-28 | Ayurvedic Rasayana compounds for purine salvage pathway enhancement in ADSL deficiency
Ashwagandha (Withania somnifera) withanolides and Brahmi (Bacopa monnieri) bacosides upregulate HPRT1 and APRT expression through Nrf2-mediated transcriptional activation, enhancing alternative purine salvage pathways to compensate for deficient ADSL activity
proteins
2025-09-07 | ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.
2014-04-24 | Modulation of de novo purine biosynthesis leads to activation of AMPK and results in improved glucose handling and insulin sensitivity
AMP activated protein kinase (AMPK) regulates key metabolic reactions and plays a major role in glucose homeostasis. Activating the AMPK is considered as one of the potential therapeutic strategies in treating type-2 diabetes. However, targeting AMPK by small molecule mediated approach can be challenging owing to diverse isoforms of the enzyme and their varied combination in different tissues. In the current study we employ a novel strategy of achieving AMPK activation through increasing the levels of cellular AMP (an allosteric activator of AMPK) levels by activating the enzyme involved in AMP biosynthesis namely Adenylosuccinate lyase (ADSL).Rat primary hepatocytes were cultured under metabolic overload conditions (500 μM palmitate) to induce insulin resistance. ADSL was overexpressed in these hepatocytes and its effect on hepatic glucose output, and triglyceride accumulation was checked. In addition to this, ADSL was overexpressed in high fat diet induced obese mice by hydrodynamic tail vein injection and its effect on fasting glucose, glucose tolerance and pyruvate tolerance were checked.Rat primary hepatocytes when cultured under metabolic overload conditions developed insulin resistance as measured in terms of failure of insulin to suppress the glucose output. Overexpressing the ADSL in these hepatocytes resulted in increased AMPK phosporylation and improved the insulin sensitivity and also resulted in reduced triglyceride accumulation and inflammatory cytokine levels. In addition to this, when ADSL was overexpressed in high fat diet induced obese mice, it resulted in reduced the fasting hyperglycemia (20% reduction), and increased glucose and pyruvate tolerance.This study indicates that activating ADSL can be a potential mechanism to achieve the activation of AMPK in the cells. This leads to a novel idea of exploring the purine nucleotide metabolic pathway as a promising therapeutic target for diabetes and metabolic syndrome.
2004-05-21 | Gln212, Asn270, and Arg301 Are Critical for Catalysis by Adenylosuccinate Lyase from Bacillus subtilis
In adenylosuccinate lyase from Bacillus subtilis, Gln(212), Asn(270), and Arg(301) are conserved and located close to the succinyl moiety of docked adenylosuccinate. We constructed mutant enzymes with Gln(212) replaced by Glu and Met, Asn(270) by Asp and Leu, and Arg(301) by Gln or Lys. The wild-type and mutant enzymes were expressed in Escherichia coli and purified to homogeneity. The specific activities of the Q212M and the 270 and 301 mutant enzymes were decreased more than 3000-fold as compared to the wild type. Only Q212E retained sufficient activity for determination of its kinetic parameters: V(max) was decreased approximately 1000-fold, and K(m) was increased 6-fold, as compared to the wild-type enzyme. Adenylosuccinate binding studies of the other mutants revealed greatly weakened affinities that contributed to, but did not account entirely for, the loss of activity. These mutant enzymes did not differ greatly from the wild-type enzyme in secondary structure or subunit association state, as shown by circular dichroism spectroscopy and light-scattering photometry. Incubation of pairs of inactive mutant enzymes led to reconstitution of some functional sites by subunit complementation, with recovery of up to 25% of the specific activity of the wild-type enzyme. Subunit complementation occurs only if the two mutations are contributed to the active site by different subunits. Thus, mixing Q212E with N270L enzyme yielded a specific activity of approximately 20% of the wild-type enzyme, while mixing Q212M with R301K enzyme did not restore activity. As supported by computer modeling, the studies presented here indicate that Gln(212), Asn(270), and Arg(301) are indispensable to catalysis by adenylosuccinate lyase and probably interact noncovalently with the carboxylate anions of the substrates 5-aminoimidazole-4(N-succinylocarboxamide)ribonucleotide and adenylosuccinate, optimizing their bound orientations.
2003-08-01 | The characterization of mutant Bacillus subtilis adenylosuccinate lyases corresponding to severe human adenylosuccinate lyase deficiencies.
Abstract Adenylosuccinate lyase is a homotetramer that catalyzes two discrete reactions in the de novo synthesis of purines: the cleavage of adenylosuccinate and succinylaminoimidazole carboxamide ribotide (SAICAR). Several point mutations in the gene encoding the enzyme have been implicated in human disease. Bacillus subtilis adenylosuccinate lyase was used as a model system in which mutations were constructed corresponding to those mutations associated with severe human adenylosuccinate lyase deficiency. Site‐directed mutagenesis was utilized to construct amino acid substitutions in B. subtilis adenylosuccinate lyase; Met 10 , Ile 123 , and Thr 367 were replaced by Leu, Trp, and Arg, respectively, and the altered enzymes were expressed in Escherichia coli . These purified enzymes containing amino acid substitutions were found to have substantial catalytic activity and exhibit relatively small changes in their kinetic parameters. The major deviations from the wild‐type‐like behavior were observed upon biophysical characterization. All of these enzymes with amino acid replacements are associated with marked thermal instability. I123W adenylosuccinate lyase exhibits notable changes in the circular dichroism spectra, and a native gel electrophoresis pattern indicative of some protein aggregation. T367R also exhibits alterations at the quarternary level, as reflected in native gel electrophoresis. Experimental results, combined with homology modeling, suggest that the altered enzymes are primarily structurally impaired. The enzyme instability was found to be lessened by subunit complementation with the wild‐type enzyme, under mild conditions; these studies may have implications for the in vivo behavior of adenylosuccinate lyase in heterozygous patients. Residues Met 10 , Ile 123 , and Thr 367 appear to be located in regions of the enzyme important for maintaining the structural integrity required for a stable, functional enzyme.
small molecules
2026-08-11 | A novel homozygous variant causing fatal neonatal adenylosuccinate lyase (ADSL) deficiency presenting with respiratory failure and encephalopathy.
Neonatal adenylosuccinate lyase (ADSL) deficiency is a rare neurodegenerative disorder that is associated with epileptic encephalopathy, diffuse hypotonia, and respiratory failure. Loss of enzymatic function of ADSL leads to toxic buildup of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). We describe a female term neonate who presented with respiratory failure and encephalopathy. Neuroimaging revealed microencephaly, a simplified gyral pattern, and diffuse white matter edema. Genetic testing showed novel homozygous loss of function mutations of ADSL, the adenylosuccinate lyase gene, consistent with fatal neonatal ADSL deficiency. We find this to be one of less than a dozen cases reported of the fatal neonatal phenotype of ADSL deficiency. The case highlights ADSL deficiency as a rare cause of neonatal encephalopathy and respiratory failure. Clinical recognition of epileptic encephalopathy, pertinent findings on MRI, and testing for S-Ado can confirm the diagnosis and support discussions about goals of care.
2026-07-10 | Severe adenylosuccinate lyase deficiency with early autonomic dysfunction: functional characterization of a novel ADSL variant and exploratory treatment with disulfiram.
Adenylosuccinate lyase (ADSL) deficiency (MIM# 103050) is a rare inherited disorder of purine metabolism characterized by neurodevelopmental impairment, epilepsy, and accumulation of succinylpurines. The clinical spectrum ranges from severe prenatal manifestations with congenital anomalies to mild intellectual disability. We report a child with a severe form of ADSL deficiency presenting with early autonomic dysfunction, including recurrent apnea and bradycardia beginning in the neonatal period, followed by pharmacoresistant epilepsy and profound developmental delay. Exome sequencing identified compound heterozygous variants in the ADSL gene: a known variant (NM_000026.4): c.340 T > C (p.Tyr114His), and a novel variant, c.363G > T (p.Leu121Phe). Urinary metabolite analysis showed highly elevated levels of succinylaminoimidazolecarboxamide riboside (SAICAr) and succinyladenosine (SAdo). Functional studies in patient fibroblasts demonstrated severely reduced ADSL activity (1 to 4% of control values) and absence of purinosome assembly. Enzymatic activity in parental fibroblasts was reduced to less than 30% of control values, while purinosome formation remained preserved. Recombinant ADSL proteins carrying the p.(Tyr114His) and p.(Leu121Phe) variants retained less than 6% and 17% of wild-type catalytic activity, respectively, supporting the pathogenicity of the novel variant. In the absence of disease-specific therapy, off-label treatment with disulfiram was initiated to reduce succinylpurine accumulation. Disulfiram treatment was associated with a decrease in SAICAr and an increase in the upstream metabolite aminoimidazole ribotide (Air), suggesting a possible effect on de novo purine synthesis. This study expands the clinical spectrum of ADSL deficiency, functionally validates a novel ADSL variant, and illustrates a potential metabolic intervention targeting succinylpurine accumulation.
2026-04-28 | Creatine-ribose combination therapy for cellular energy restoration
Creatine enhances phosphocreatine-mediated ATP buffering while D-ribose provides substrate for enhanced PRPP synthesis via ribokinase, creating dual pathway support for energy metabolism disrupted by ADSL deficiency
2026-04-28 | Folate pathway modulation targeting ATIC enzyme enhancement
High-dose folinic acid increases 10-formyl-THF availability to enhance ATIC enzyme activity in the final step of de novo purine synthesis, potentially compensating for upstream disruptions caused by ADSL deficiency
2026-04-28 | Ayurvedic Rasayana compounds for purine salvage pathway enhancement in ADSL deficiency
Ashwagandha (Withania somnifera) withanolides and Brahmi (Bacopa monnieri) bacosides upregulate HPRT1 and APRT expression through Nrf2-mediated transcriptional activation, enhancing alternative purine salvage pathways to compensate for deficient ADSL activity
proteins
2025-09-07 | ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.
2014-04-24 | Modulation of de novo purine biosynthesis leads to activation of AMPK and results in improved glucose handling and insulin sensitivity
AMP activated protein kinase (AMPK) regulates key metabolic reactions and plays a major role in glucose homeostasis. Activating the AMPK is considered as one of the potential therapeutic strategies in treating type-2 diabetes. However, targeting AMPK by small molecule mediated approach can be challenging owing to diverse isoforms of the enzyme and their varied combination in different tissues. In the current study we employ a novel strategy of achieving AMPK activation through increasing the levels of cellular AMP (an allosteric activator of AMPK) levels by activating the enzyme involved in AMP biosynthesis namely Adenylosuccinate lyase (ADSL).Rat primary hepatocytes were cultured under metabolic overload conditions (500 μM palmitate) to induce insulin resistance. ADSL was overexpressed in these hepatocytes and its effect on hepatic glucose output, and triglyceride accumulation was checked. In addition to this, ADSL was overexpressed in high fat diet induced obese mice by hydrodynamic tail vein injection and its effect on fasting glucose, glucose tolerance and pyruvate tolerance were checked.Rat primary hepatocytes when cultured under metabolic overload conditions developed insulin resistance as measured in terms of failure of insulin to suppress the glucose output. Overexpressing the ADSL in these hepatocytes resulted in increased AMPK phosporylation and improved the insulin sensitivity and also resulted in reduced triglyceride accumulation and inflammatory cytokine levels. In addition to this, when ADSL was overexpressed in high fat diet induced obese mice, it resulted in reduced the fasting hyperglycemia (20% reduction), and increased glucose and pyruvate tolerance.This study indicates that activating ADSL can be a potential mechanism to achieve the activation of AMPK in the cells. This leads to a novel idea of exploring the purine nucleotide metabolic pathway as a promising therapeutic target for diabetes and metabolic syndrome.
2004-05-21 | Gln212, Asn270, and Arg301 Are Critical for Catalysis by Adenylosuccinate Lyase from Bacillus subtilis
In adenylosuccinate lyase from Bacillus subtilis, Gln(212), Asn(270), and Arg(301) are conserved and located close to the succinyl moiety of docked adenylosuccinate. We constructed mutant enzymes with Gln(212) replaced by Glu and Met, Asn(270) by Asp and Leu, and Arg(301) by Gln or Lys. The wild-type and mutant enzymes were expressed in Escherichia coli and purified to homogeneity. The specific activities of the Q212M and the 270 and 301 mutant enzymes were decreased more than 3000-fold as compared to the wild type. Only Q212E retained sufficient activity for determination of its kinetic parameters: V(max) was decreased approximately 1000-fold, and K(m) was increased 6-fold, as compared to the wild-type enzyme. Adenylosuccinate binding studies of the other mutants revealed greatly weakened affinities that contributed to, but did not account entirely for, the loss of activity. These mutant enzymes did not differ greatly from the wild-type enzyme in secondary structure or subunit association state, as shown by circular dichroism spectroscopy and light-scattering photometry. Incubation of pairs of inactive mutant enzymes led to reconstitution of some functional sites by subunit complementation, with recovery of up to 25% of the specific activity of the wild-type enzyme. Subunit complementation occurs only if the two mutations are contributed to the active site by different subunits. Thus, mixing Q212E with N270L enzyme yielded a specific activity of approximately 20% of the wild-type enzyme, while mixing Q212M with R301K enzyme did not restore activity. As supported by computer modeling, the studies presented here indicate that Gln(212), Asn(270), and Arg(301) are indispensable to catalysis by adenylosuccinate lyase and probably interact noncovalently with the carboxylate anions of the substrates 5-aminoimidazole-4(N-succinylocarboxamide)ribonucleotide and adenylosuccinate, optimizing their bound orientations.
2003-08-01 | The characterization of mutant Bacillus subtilis adenylosuccinate lyases corresponding to severe human adenylosuccinate lyase deficiencies.
Abstract Adenylosuccinate lyase is a homotetramer that catalyzes two discrete reactions in the de novo synthesis of purines: the cleavage of adenylosuccinate and succinylaminoimidazole carboxamide ribotide (SAICAR). Several point mutations in the gene encoding the enzyme have been implicated in human disease. Bacillus subtilis adenylosuccinate lyase was used as a model system in which mutations were constructed corresponding to those mutations associated with severe human adenylosuccinate lyase deficiency. Site‐directed mutagenesis was utilized to construct amino acid substitutions in B. subtilis adenylosuccinate lyase; Met 10 , Ile 123 , and Thr 367 were replaced by Leu, Trp, and Arg, respectively, and the altered enzymes were expressed in Escherichia coli . These purified enzymes containing amino acid substitutions were found to have substantial catalytic activity and exhibit relatively small changes in their kinetic parameters. The major deviations from the wild‐type‐like behavior were observed upon biophysical characterization. All of these enzymes with amino acid replacements are associated with marked thermal instability. I123W adenylosuccinate lyase exhibits notable changes in the circular dichroism spectra, and a native gel electrophoresis pattern indicative of some protein aggregation. T367R also exhibits alterations at the quarternary level, as reflected in native gel electrophoresis. Experimental results, combined with homology modeling, suggest that the altered enzymes are primarily structurally impaired. The enzyme instability was found to be lessened by subunit complementation with the wild‐type enzyme, under mild conditions; these studies may have implications for the in vivo behavior of adenylosuccinate lyase in heterozygous patients. Residues Met 10 , Ile 123 , and Thr 367 appear to be located in regions of the enzyme important for maintaining the structural integrity required for a stable, functional enzyme.
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