RARE DISEASE
Hyperlysinemia
Hyperlysinemia
Hyperlysinemia
Synonyms: Hyperlysinemia type I, Lysine alpha-ketoglutarate reductase deficiency
Synonyms: Hyperlysinemia type I, Lysine alpha-ketoglutarate reductase deficiency
Synonyms: Hyperlysinemia type I, Lysine alpha-ketoglutarate reductase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Hyperlysinemia is an autosomal recessive disorder caused by biallelic AASS gene mutations, impairing lysine metabolism and leading to elevated blood lysine levels. Most cases are asymptomatic, though historical associations with intellectual disability or behavioral issues lack clear causal evidence. Incidence is estimated at ~1:300,000–500,000, with newborn screening programs aiding detection [1][2][6][9][10].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
24 drug discovery papers about Hyperlysinemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
24 drug discovery papers about Hyperlysinemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2023-02-22 | Mitochondrial NAD kinase in health and disease.
Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.
2022-01-14 | High lysine and high protein‐containing salinity‐tolerant rice grains ( Oryza sativa cv IR64)
Abstract Lysine cannot be synthesized by the human body, and it is, therefore, an indispensable amino acid in the human that must be consumed in adequate amounts to prevent disease. Unfortunately, lysine is not abundant in many important food sources such as rice grains. Efforts to fortify rice and other monocotyledonous crops with high lysine have proved to be challenging because of their effects on plant growth. The present study was designed to avoid the problems that are often encountered in engineering lysine metabolism. We generated different over‐expression constructs for the key anabolic enzyme, dihydrodipicolinate synthase (DHDPS and cdapA) and knockdown (KD) constructs for the catabolic enzyme—lysine ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH), with expression under the control of either the CaMV35S promoter or the endosperm‐specific glutelinD1 promoter. The use of the endosperm‐specific promoter together with the lysine feedback‐insensitive cdapA for over‐expression provides distinct advantages, as does silencing of LKR/SDH under the control of this promoter. Rice plants produced by over‐expressing cdapA together with silencing of LKR/SDH showed a 58% increase in grain lysine content, as well as higher amounts of total seed protein levels. Moreover, the transgenic seedlings were more tolerant to salinity. These results demonstrate that it is possible to generate high lysine stress‐tolerant rice varieties, which have the potential to reduce the need for dietary supplementation.
2014-05-08 | Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia
Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.
1970-03-05 | Effects of supersuppressor genes on enzymes controlling lysine biosynthesis in Saccharomyces.
Yeast supersuppressor genes capable of masking the effects of several lysine mutant genes (ly(1-1), ly(9-1), ly(2-1)) were studied with respect to their effects on the respective enzymes (saccharopine dehydrogenase, saccharopine reductase, and alpha-amino-adipic acid reductase). In all strains tested, the supersuppressors functioned by allowing enzyme synthesis not found in the unsuppressed mutant. Studies by optical methods of saccharopine dehydrogenase and saccharopine reductase extracted from suppressed ly(1-1) and ly(9-1) cells, respectively, revealed that the K(m) values for these enzymes were significantly greater than those found in wild type. Saccharopine dehydrogenase from suppressed ly(9-1) cells was found to have K(m) values similar to wild type. These findings are consistent with the inference that a supersuppressor may act by enabling nonsense codons to be read, producing altered enzyme protein. Recent findings that lysine degradation in mammals may involve saccharopine and that the human diseases, hyperlysinemia and saccharopinuria, may be due to metabolic blocks in this route of lysine degradation suggest the ly(1-1) and ly(9-1) yeast mutants as models for the human condition and its possible euphenic treatment.
small molecules
2026-02-11 | The neuropathological mechanisms underlying the inborn errors of lysine metabolism.
Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy-ALDH7A1, and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients.
2023-10-22 | A case of hyperlysinemia identified by urine newborn screening
Abstract Hyperlysinemia is a rare autosomal recessive deficiency of 2‐aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarce. The description of additional cases, in particular, those identified without ascertainment bias, may help counseling of new cases in the future. It may also help to establish the risks associated with pharmacological inhibition of AASS, a potential therapeutic strategy that is under investigation for other inborn errors of lysine degradation. We describe the identification of a hyperlysinemia case identified in the Provincial Neonatal Urine Screening Program in Sherbrooke, Quebec. This case presented with a profile of cystinuria but with a very high increase in urinary lysine. A diagnosis of hyperlysinemia was confirmed through biochemical testing and the identification of biallelic variants in AASS . The p.R146W and p.T371I variants are novel and affect the folding of the lysine‐2‐oxoglutarate domain of AASS. The 11‐month‐old boy is currently doing well without any therapeutic interventions. The identification of this case through newborn urine screening further establishes that hyperlysinemia is a biochemical abnormality with limited clinical consequences and may not require any intervention.
2018-12-20 | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis
Amino acid catabolism is frequently executed in mitochondria; however, it is largely unknown how aberrant amino acid metabolism affects mitochondria. Here we report the requirement for mitochondrial saccharopine degradation in mitochondrial homeostasis and animal development. In Caenorhbditis elegans, mutations in the saccharopine dehydrogenase (SDH) domain of the bi-functional enzyme α-aminoadipic semialdehyde synthase AASS-1 greatly elevate the lysine catabolic intermediate saccharopine, which causes mitochondrial damage by disrupting mitochondrial dynamics, leading to reduced adult animal growth. In mice, failure of mitochondrial saccharopine oxidation causes lethal mitochondrial damage in the liver, leading to postnatal developmental retardation and death. Importantly, genetic inactivation of genes that raise the mitochondrial saccharopine precursors lysine and α-ketoglutarate strongly suppresses SDH mutation-induced saccharopine accumulation and mitochondrial abnormalities in C. elegans. Thus, adequate saccharopine catabolism is essential for mitochondrial homeostasis. Our study provides mechanistic and therapeutic insights for understanding and treating hyperlysinemia II (saccharopinuria), an aminoacidopathy with severe developmental defects.
2017-06-20 | Effect of moderate alterations of dietary protein or lysine on indices of lysine metabolism in liver, kidney and heart of growing pigs
Lysine addition to swine diets via either feed-grade lysine or protein sources costs producers. To better understand how diet affects lysine oxidation (LOX), weanling pigs were fed a control (C), high protein (HP), low protein (LP), high lysine (HL), or low lysine (LL) diets. No diet-induced alterations in lysine catabolism were detected in heart or kidney (P > 0.05). Liver lysine α-ketoglutarate reductase (LKR) (P < 0.05), saccharopine dehydrogenase (P < 0.05) activities, and α-aminoadipate δ-semialdehyde synthase abundance (P < 0.01) were reduced by 30%, 35%, and 52%, respectively, in pigs consuming LL compared with pigs consuming C. Expression of ornithine carrier-1 (ORC-1) mRNA in pigs fed HL was 170% greater (P < 0.05) than that in pigs fed C, whereas expression of the ORC-1 mRNA in pigs fed LL was 50% lower (P < 0.05) than that in pigs fed C. Expression of ORC-2 mRNA in pigs fed HL was 88% higher (P < 0.05) than that in pigs fed LL. The ORC transporters and LKR phosphorylation are likely points of regulation of LOX and, interventions aimed at these targets may be the best opportunity to decrease LOX and thus the requirement, subsequently decreasing feed costs.
2015-06-02 | Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid.
Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects.
proteins
2022-04-01 | The Metabolite Saccharopine Impairs Neuronal Development by Inhibiting the Neurotrophic Function of Glucose-6-Phosphate Isomerase.
Mutations in the Aminoadipate-Semialdehyde Synthase (AASS) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurologic disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here, we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). While extracellular supplementation of GPI restores defective neuronal development caused by G498E mutation in SDH of Aass. Altogether, our findings not only unravel the requirement for saccharopine degradation in neuronal development, but also provide the mechanistic insights for understanding the neurometabolic disorder of hyperlysinemia-II.SIGNIFICANCE STATEMENT The association between neurologic disorder and a pronounced biochemical abnormality in hyperlysinemia remains a challenging clinical question. Here, we report that mice carrying the R65Q mutation in lysine α-ketoglutarate reductase (LKR) domain of aminoadipate-semialdehyde synthase (AASS) have an elevated cerebral lysine levels and a normal brain development, whereas those carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain of AASS exhibit an elevation of both cerebral lysine and saccharopine and a small brain with defective neuronal development. Furthermore, saccharopine impairs neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). These findings demonstrate saccharopine degradation is essential for neuronal development.
2020-11-17 | Fungal Enzyme l-Lysine α-Oxidase Affects the Amino Acid Metabolism in the Brain and Decreases the Polyamine Level
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to be depletion of the essential amino acid l-lys and action of reactive oxidative species produced by the reaction. Here, we report that LO penetrates into the brain and is retained there for up to 48 h after intravenous injection, which might be explained by specific pharmacokinetics. LO actively intervenes in amino acid metabolism in the brain. The most significant impact of LO was towards amino acids, which are directly exposed to its action (l-lys, l-orn, l-arg). In addition, the enzyme significantly affected the redistribution of amino acids directly associated with the tricarboxylic acid (TCA) cycle (l-asp and l-glu). We discovered that the depletion of l-orn, the precursor of polyamines (PA), led to a significant and long-term decrease in the concentration of polyamines, which are responsible for regulation of many processes including cell proliferation. Thus, LO may be used to reduce levels of l-lys and PA in the brain.
cell therapies
2026-01-12 | Rapid Phenotypic Screening of Lysine-Degrading Probiotics via FTIR Spectroscopy: Toward Precision Therapy for Hyperlysinemia.
Hyperlysinemia is a life-threatening metabolic disorder that requires the continuous clearance of lysine. Engineered probiotics capable of degrading lysine in the gut represent a promising therapeutic strategy. However, the introduction of heterologous metabolic pathways can impose a substantial fitness burden on the bacterial host, potentially compromising the therapeutic efficacy. Current screening methods fail to adequately assess this pathway-induced stress. Therefore, optimizing methods to evaluate bacterial fitness after pathway modification is essential for developing effective bacterial therapies. Here, we present a label-free phenotypic screening approach using Fourier transform infrared (FTIR) spectroscopy to evaluate the physiological burden imposed by two distinct lysine catabolism pathways engineered Escherichia coli Nissle 1917 (EcN): the plant-derived bifunctional enzyme LKR-SDR and the yeast-derived two-enzyme cascade Lys2-Lys5. Employing FTIR under lysine stress mimicking pathological concentrations, decoded pathway-specific stress signatures, and molecular resilience. Probiotics expressing LKR-SDR exhibited severe multisystem damage, including proteotoxicity, lipid peroxidation, and significant nucleic acid stress. In contrast, the Lys2-Lys5 strain demonstrated superior resilience, maintained structural integrity, and exhibited adaptive metabolic changes, primarily through lipid membrane remodeling. This study establishes FTIR spectroscopy as a rapid screening platform that identifies the Lys2-Lys5 pathway as optimal for probiotic therapies. By directly linking spectroscopic signatures to cellular fitness, FTIR spectroscopy accelerates the rational development of durable microbial therapeutics for inborn metabolic disorders.
2024-06-14 | Engineered probiotic cocktail with two cascade metabolic Escherichia coli for the treatment of hyperlysinemia.
Engineering probiotics have emerged as a potential strategy for the treatment of metabolic diseases. However, due to the exceptional complexity of these metabolic disorders and the intricate relationship between gut microbes, it is difficult to achieve an ideal therapeutic effect in a specific metabolic disorder using only a single engineered strain. In this work, we proposed a probiotic cocktail strategy by engineering two cascade metabolic bacteria to treat hyperlysinemia, an inherited lysine metabolic disorder with loss of α-aminoadipate semialdehyde synthase (AASS) activity. A probiotic E. coli Nissle 1917 strain EcNT (pTLS) with a heterologous enzyme pathway in Saccharomyces cerevisiae was engineered to metabolize the excess lysine. Another one EcNT (pK25) was engineered to consume the products of lysine metabolism. The bacterial cocktail enables the maintenance of a metabolic cascade with AASS-like functional activity to maintain the blood lysine concentrations and downstream metabolites. In vitro experimental results showed that the cocktail bacteria had a better metabolic capacity and metabolites balance at a ratio of EcNT (pTLS) and EcNT (pK25) of 1:2. Feeding of the cocktail bacteria to the mouse model effectively reduced the concentration of lysine and balanced saccharopine in the plasma of hyperlysinemia-like mice. These findings not only provide a promising strategy of probiotic stains for the treatment of hyperlysinemia but also highlight the potential of engineered cascade cocktails to intervene and even cure other inherited metabolic diseases.
gene therapies
2023-02-22 | Mitochondrial NAD kinase in health and disease.
Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.
2022-01-14 | High lysine and high protein‐containing salinity‐tolerant rice grains ( Oryza sativa cv IR64)
Abstract Lysine cannot be synthesized by the human body, and it is, therefore, an indispensable amino acid in the human that must be consumed in adequate amounts to prevent disease. Unfortunately, lysine is not abundant in many important food sources such as rice grains. Efforts to fortify rice and other monocotyledonous crops with high lysine have proved to be challenging because of their effects on plant growth. The present study was designed to avoid the problems that are often encountered in engineering lysine metabolism. We generated different over‐expression constructs for the key anabolic enzyme, dihydrodipicolinate synthase (DHDPS and cdapA) and knockdown (KD) constructs for the catabolic enzyme—lysine ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH), with expression under the control of either the CaMV35S promoter or the endosperm‐specific glutelinD1 promoter. The use of the endosperm‐specific promoter together with the lysine feedback‐insensitive cdapA for over‐expression provides distinct advantages, as does silencing of LKR/SDH under the control of this promoter. Rice plants produced by over‐expressing cdapA together with silencing of LKR/SDH showed a 58% increase in grain lysine content, as well as higher amounts of total seed protein levels. Moreover, the transgenic seedlings were more tolerant to salinity. These results demonstrate that it is possible to generate high lysine stress‐tolerant rice varieties, which have the potential to reduce the need for dietary supplementation.
2014-05-08 | Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia
Dienoyl-CoA reductase (DECR) deficiency with hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.
1970-03-05 | Effects of supersuppressor genes on enzymes controlling lysine biosynthesis in Saccharomyces.
Yeast supersuppressor genes capable of masking the effects of several lysine mutant genes (ly(1-1), ly(9-1), ly(2-1)) were studied with respect to their effects on the respective enzymes (saccharopine dehydrogenase, saccharopine reductase, and alpha-amino-adipic acid reductase). In all strains tested, the supersuppressors functioned by allowing enzyme synthesis not found in the unsuppressed mutant. Studies by optical methods of saccharopine dehydrogenase and saccharopine reductase extracted from suppressed ly(1-1) and ly(9-1) cells, respectively, revealed that the K(m) values for these enzymes were significantly greater than those found in wild type. Saccharopine dehydrogenase from suppressed ly(9-1) cells was found to have K(m) values similar to wild type. These findings are consistent with the inference that a supersuppressor may act by enabling nonsense codons to be read, producing altered enzyme protein. Recent findings that lysine degradation in mammals may involve saccharopine and that the human diseases, hyperlysinemia and saccharopinuria, may be due to metabolic blocks in this route of lysine degradation suggest the ly(1-1) and ly(9-1) yeast mutants as models for the human condition and its possible euphenic treatment.
small molecules
2026-02-11 | The neuropathological mechanisms underlying the inborn errors of lysine metabolism.
Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy-ALDH7A1, and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients.
2023-10-22 | A case of hyperlysinemia identified by urine newborn screening
Abstract Hyperlysinemia is a rare autosomal recessive deficiency of 2‐aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarce. The description of additional cases, in particular, those identified without ascertainment bias, may help counseling of new cases in the future. It may also help to establish the risks associated with pharmacological inhibition of AASS, a potential therapeutic strategy that is under investigation for other inborn errors of lysine degradation. We describe the identification of a hyperlysinemia case identified in the Provincial Neonatal Urine Screening Program in Sherbrooke, Quebec. This case presented with a profile of cystinuria but with a very high increase in urinary lysine. A diagnosis of hyperlysinemia was confirmed through biochemical testing and the identification of biallelic variants in AASS . The p.R146W and p.T371I variants are novel and affect the folding of the lysine‐2‐oxoglutarate domain of AASS. The 11‐month‐old boy is currently doing well without any therapeutic interventions. The identification of this case through newborn urine screening further establishes that hyperlysinemia is a biochemical abnormality with limited clinical consequences and may not require any intervention.
2018-12-20 | The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis
Amino acid catabolism is frequently executed in mitochondria; however, it is largely unknown how aberrant amino acid metabolism affects mitochondria. Here we report the requirement for mitochondrial saccharopine degradation in mitochondrial homeostasis and animal development. In Caenorhbditis elegans, mutations in the saccharopine dehydrogenase (SDH) domain of the bi-functional enzyme α-aminoadipic semialdehyde synthase AASS-1 greatly elevate the lysine catabolic intermediate saccharopine, which causes mitochondrial damage by disrupting mitochondrial dynamics, leading to reduced adult animal growth. In mice, failure of mitochondrial saccharopine oxidation causes lethal mitochondrial damage in the liver, leading to postnatal developmental retardation and death. Importantly, genetic inactivation of genes that raise the mitochondrial saccharopine precursors lysine and α-ketoglutarate strongly suppresses SDH mutation-induced saccharopine accumulation and mitochondrial abnormalities in C. elegans. Thus, adequate saccharopine catabolism is essential for mitochondrial homeostasis. Our study provides mechanistic and therapeutic insights for understanding and treating hyperlysinemia II (saccharopinuria), an aminoacidopathy with severe developmental defects.
2017-06-20 | Effect of moderate alterations of dietary protein or lysine on indices of lysine metabolism in liver, kidney and heart of growing pigs
Lysine addition to swine diets via either feed-grade lysine or protein sources costs producers. To better understand how diet affects lysine oxidation (LOX), weanling pigs were fed a control (C), high protein (HP), low protein (LP), high lysine (HL), or low lysine (LL) diets. No diet-induced alterations in lysine catabolism were detected in heart or kidney (P > 0.05). Liver lysine α-ketoglutarate reductase (LKR) (P < 0.05), saccharopine dehydrogenase (P < 0.05) activities, and α-aminoadipate δ-semialdehyde synthase abundance (P < 0.01) were reduced by 30%, 35%, and 52%, respectively, in pigs consuming LL compared with pigs consuming C. Expression of ornithine carrier-1 (ORC-1) mRNA in pigs fed HL was 170% greater (P < 0.05) than that in pigs fed C, whereas expression of the ORC-1 mRNA in pigs fed LL was 50% lower (P < 0.05) than that in pigs fed C. Expression of ORC-2 mRNA in pigs fed HL was 88% higher (P < 0.05) than that in pigs fed LL. The ORC transporters and LKR phosphorylation are likely points of regulation of LOX and, interventions aimed at these targets may be the best opportunity to decrease LOX and thus the requirement, subsequently decreasing feed costs.
2015-06-02 | Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid.
Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects.
proteins
2022-04-01 | The Metabolite Saccharopine Impairs Neuronal Development by Inhibiting the Neurotrophic Function of Glucose-6-Phosphate Isomerase.
Mutations in the Aminoadipate-Semialdehyde Synthase (AASS) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurologic disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here, we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). While extracellular supplementation of GPI restores defective neuronal development caused by G498E mutation in SDH of Aass. Altogether, our findings not only unravel the requirement for saccharopine degradation in neuronal development, but also provide the mechanistic insights for understanding the neurometabolic disorder of hyperlysinemia-II.SIGNIFICANCE STATEMENT The association between neurologic disorder and a pronounced biochemical abnormality in hyperlysinemia remains a challenging clinical question. Here, we report that mice carrying the R65Q mutation in lysine α-ketoglutarate reductase (LKR) domain of aminoadipate-semialdehyde synthase (AASS) have an elevated cerebral lysine levels and a normal brain development, whereas those carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain of AASS exhibit an elevation of both cerebral lysine and saccharopine and a small brain with defective neuronal development. Furthermore, saccharopine impairs neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). These findings demonstrate saccharopine degradation is essential for neuronal development.
2020-11-17 | Fungal Enzyme l-Lysine α-Oxidase Affects the Amino Acid Metabolism in the Brain and Decreases the Polyamine Level
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to be depletion of the essential amino acid l-lys and action of reactive oxidative species produced by the reaction. Here, we report that LO penetrates into the brain and is retained there for up to 48 h after intravenous injection, which might be explained by specific pharmacokinetics. LO actively intervenes in amino acid metabolism in the brain. The most significant impact of LO was towards amino acids, which are directly exposed to its action (l-lys, l-orn, l-arg). In addition, the enzyme significantly affected the redistribution of amino acids directly associated with the tricarboxylic acid (TCA) cycle (l-asp and l-glu). We discovered that the depletion of l-orn, the precursor of polyamines (PA), led to a significant and long-term decrease in the concentration of polyamines, which are responsible for regulation of many processes including cell proliferation. Thus, LO may be used to reduce levels of l-lys and PA in the brain.
cell therapies
2026-01-12 | Rapid Phenotypic Screening of Lysine-Degrading Probiotics via FTIR Spectroscopy: Toward Precision Therapy for Hyperlysinemia.
Hyperlysinemia is a life-threatening metabolic disorder that requires the continuous clearance of lysine. Engineered probiotics capable of degrading lysine in the gut represent a promising therapeutic strategy. However, the introduction of heterologous metabolic pathways can impose a substantial fitness burden on the bacterial host, potentially compromising the therapeutic efficacy. Current screening methods fail to adequately assess this pathway-induced stress. Therefore, optimizing methods to evaluate bacterial fitness after pathway modification is essential for developing effective bacterial therapies. Here, we present a label-free phenotypic screening approach using Fourier transform infrared (FTIR) spectroscopy to evaluate the physiological burden imposed by two distinct lysine catabolism pathways engineered Escherichia coli Nissle 1917 (EcN): the plant-derived bifunctional enzyme LKR-SDR and the yeast-derived two-enzyme cascade Lys2-Lys5. Employing FTIR under lysine stress mimicking pathological concentrations, decoded pathway-specific stress signatures, and molecular resilience. Probiotics expressing LKR-SDR exhibited severe multisystem damage, including proteotoxicity, lipid peroxidation, and significant nucleic acid stress. In contrast, the Lys2-Lys5 strain demonstrated superior resilience, maintained structural integrity, and exhibited adaptive metabolic changes, primarily through lipid membrane remodeling. This study establishes FTIR spectroscopy as a rapid screening platform that identifies the Lys2-Lys5 pathway as optimal for probiotic therapies. By directly linking spectroscopic signatures to cellular fitness, FTIR spectroscopy accelerates the rational development of durable microbial therapeutics for inborn metabolic disorders.
2024-06-14 | Engineered probiotic cocktail with two cascade metabolic Escherichia coli for the treatment of hyperlysinemia.
Engineering probiotics have emerged as a potential strategy for the treatment of metabolic diseases. However, due to the exceptional complexity of these metabolic disorders and the intricate relationship between gut microbes, it is difficult to achieve an ideal therapeutic effect in a specific metabolic disorder using only a single engineered strain. In this work, we proposed a probiotic cocktail strategy by engineering two cascade metabolic bacteria to treat hyperlysinemia, an inherited lysine metabolic disorder with loss of α-aminoadipate semialdehyde synthase (AASS) activity. A probiotic E. coli Nissle 1917 strain EcNT (pTLS) with a heterologous enzyme pathway in Saccharomyces cerevisiae was engineered to metabolize the excess lysine. Another one EcNT (pK25) was engineered to consume the products of lysine metabolism. The bacterial cocktail enables the maintenance of a metabolic cascade with AASS-like functional activity to maintain the blood lysine concentrations and downstream metabolites. In vitro experimental results showed that the cocktail bacteria had a better metabolic capacity and metabolites balance at a ratio of EcNT (pTLS) and EcNT (pK25) of 1:2. Feeding of the cocktail bacteria to the mouse model effectively reduced the concentration of lysine and balanced saccharopine in the plasma of hyperlysinemia-like mice. These findings not only provide a promising strategy of probiotic stains for the treatment of hyperlysinemia but also highlight the potential of engineered cascade cocktails to intervene and even cure other inherited metabolic diseases.
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