RARE DISEASE
Disorder of lysine and hydroxylysine metabolism
Disorder of lysine and hydroxylysine metabolism
Disorder of lysine and hydroxylysine metabolism
Drug discovery
0
drugs
With orphan designations
Overview
Disorders of lysine and hydroxylysine metabolism encompass rare inherited defects in amino acid catabolism, primarily involving the saccharopine pathway. Key conditions include glutaric acidemia type I (GA-I, GCDH gene mutations), hyperlysinemia (AASS gene mutations), and 2-aminoadipic/2-oxoadipic aciduria (DHTKD1 gene mutations). GA-I, the most severe, causes neurotoxic accumulation of glutaric acid and 3-hydroxyglutaric acid, leading to irreversible striatal damage and dystonia if untreated. Hyperlysinemia is typically asymptomatic, while 2-aminoadipic aciduria may rarely present with neurodevelopmental issues. Early diagnosis via newborn screening enables pre-symptomatic intervention for GA-I [1][3][9][13].
Burden
Untreated GA-I leads to severe motor disability (dystonia, dyskinesia), intellectual impairment, and mortality from metabolic crises [1][9][10].
Lifelong dietary adherence, frequent monitoring, and risk of irreversible neurological damage despite treatment [11][13].
Asymptomatic hyperlysinemia and 2-aminoadipic aciduria pose minimal clinical burden [1][2].
Therapies
GA-I: Low lysine/tryptophan diet with lysine-free amino acid supplements, L-carnitine (100 mg/kg/day), and emergency protocols (glucose infusion, reduced protein intake) during illness to prevent catabolic crises [3][5][11][13].
Symptomatic management of dystonia and multidisciplinary care for neurological complications [9][10].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
28 drug discovery papers about Disorder of lysine and hydroxylysine metabolism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
28 drug discovery papers about Disorder of lysine and hydroxylysine metabolism, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-05 | Case report: Adult presentation of glutaric aciduria type I.
Introduction - Glutaric aciduria (or glutaric acidemia) type 1 (GA1) is a rare autosomal recessive neurometabolic disorder caused by mutations in the GCDH gene that results in a deficiency of the glutaryl-CoA dehydrogenase enzyme. It plays a vital role in the degradation of L-lysine, L-hydroxylysine, and L-tryptophan. Accumulating toxic metabolites (namely glutaric acid/GA and 3-hydroxyglutaric acid/3-OH-GA) leads to progressive neurological deterioration. GA1 is one of the limited neurometabolic disorders, where we can stop the progression of the disease with a diet and aggressive emergency treatment during excessive catabolism. If undiagnosed through newborn screening, symptoms start to present in childhood between 3-36 months, with neurological symptoms related to sepsis or fever. However, 10-20% of cases start insidiously.Case report - We report the case of a 53-year-old male with GA1, who presented progressive spastic tetraparesis, dysarthria, and focal seizures. His initial symptoms, misattributed to cerebral palsy and previous ischemic strokes, had gradually worsened in recent years, leaving him bedridden. Specific metabolic laboratory testing and radiological evaluations revealed the characteristic features of the disease. Genetic testing identified a known pathogenic homozygous mutation in the GCDH gene, which confirms the diagnosis of GA1. Low-lysine diet and supplementation with carnitine and riboflavin were started. After the initiation of treatment, no further progression was observable.Conclusion - This case underscores the importance of considering hereditary neurometabolic disorders like GA1 - taking into account the available metabolic screening - not only in pediatric patients but also in adult patients with progressive neurological decline. This case contributes to the limited literature available on GA1 cases in adults and highlights the need for early detection strategies to avoid irreversible neurological damage.
2025-09-04 | Acute Flaccid Paralysis in Infancy: A Rare Presentation of Glutaric Aciduria Type I
Glutaric aciduria type I (GA1) is a rare autosomal recessive disorder caused by deficiency of glutaryl-CoA dehydrogenase, disturbing lysine, hydroxylysine, and tryptophan metabolism [1].Although typical presentations include dystonia and developmental delay, acute flaccid paralysis (AFP) is a seldom recognized manifestation [2].We describe a 10-month-old girl, evaluated at Wadia Children's Hospital, Mumbai in June 2023, presenting with AFP and neuroregression post-febrile illness.MRI revealed striatal injury and subdural collections.Diagnosis was confirmed by elevated glutarylcarnitine (C5DC) and pathogenic GCDH mutation.Early lysinerestricted diet and carnitine supplementation stabilized her course.This report emphasizes the need to consider GA1 in AFP, especially with macrocephaly and suggestive neuroimaging, and highlights that prompt management is crucial for improved outcomes [3].
2021-03-05 | Neutrophil Adhesion and the Release of the Free Amino Acid Hydroxylysine
During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
2020-12-28 | Structure-function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism.
2-Oxoadipate dehydrogenase (E1a, also known as DHTKD1, dehydrogenase E1, and transketolase domain-containing protein 1) is a thiamin diphosphate-dependent enzyme and part of the 2-oxoadipate dehydrogenase complex (OADHc) in l-lysine catabolism. Genetic findings have linked mutations in the DHTKD1 gene to several metabolic disorders. These include α-aminoadipic and α-ketoadipic aciduria (AMOXAD), a rare disorder of l-lysine, l-hydroxylysine, and l-tryptophan catabolism, associated with clinical presentations such as developmental delay, mild-to-severe intellectual disability, ataxia, epilepsy, and behavioral disorders that cannot currently be managed by available treatments. A heterozygous missense mutation, c.2185G→A (p.G729R), in DHTKD1 has been identified in most AMOXAD cases. Here, we report that the G729R E1a variant when assembled into OADHc in vitro displays a 50-fold decrease in catalytic efficiency for NADH production and a significantly reduced rate of glutaryl-CoA production by dihydrolipoamide succinyl-transferase (E2o). However, the G729R E1a substitution did not affect any of the three side-reactions associated solely with G729R E1a, prompting us to determine the structure-function effects of this mutation. A multipronged systematic analysis of the reaction rates in the OADHc pathway, supplemented with results from chemical cross-linking and hydrogen-deuterium exchange MS, revealed that the c.2185G→A DHTKD1 mutation affects E1a-E2o assembly, leading to impaired channeling of OADHc intermediates. Cross-linking between the C-terminal region of both E1a and G729R E1a with the E2o lipoyl and core domains suggested that correct positioning of the C-terminal E1a region is essential for the intermediate channeling. These findings may inform the development of interventions to counter the effects of pathogenic DHTKD1 mutations.
2020-04-03 | Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model.
Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3-hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh-/-) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood-brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.
gene therapies
2024-01-16 | Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.
Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.
2012-11-29 | The Activities of Lysyl Hydroxylase 3 (LH3) Regulate the Amount and Oligomerization Status of Adiponectin
Lysyl hydroxylase 3 (LH3) has lysyl hydroxylase, galactosyltransferase, and glucosyltransferase activities, which are sequentially required for the formation of glucosylgalactosyl hydroxylysines in collagens. Here we demonstrate for the first time that LH3 also modifies the lysine residues in the collagenous domain of adiponectin, which has important roles in glucose and lipid metabolism and inflammation. Hydroxylation and, especially, glycosylation of the lysine residues of adiponectin have been shown to be essential for the formation of the more active high molecular weight adiponectin oligomers and thus for its function. In cells that totally lack LH3 enzyme, the galactosylhydroxylysine residues of adiponectin were not glucosylated to glucosylgalactosylhydroxylysine residues and the formation of high and middle molecular weight adiponectin oligomers was impaired. Circulating adiponectin levels in mutant mice lacking the lysyl hydroxylase activity of LH3 were significantly reduced, which indicates that LH3 is required for complete modification of lysine residues in adiponectin and the loss of some of the glycosylated hydroxylysine residues severely affects the secretion of adiponectin. LH mutant mice with reduced adiponectin level showed a high fat diet-induced increase in glucose, triglyceride, and LDL-cholesterol levels, hallmarks of the metabolic syndrome in humans. Our results reveal the first indication that LH3 is an important regulator of adiponectin biosynthesis, secretion and activity and thus might be a potential candidate for therapeutic applications in diseases associated with obesity and insulin resistance.
2002-11-01 | The third activity for lysyl hydroxylase 3: galactosylation of hydroxylysyl residues in collagens in vitro
Lysyl hydroxylase (LH, EC 1.14.11.4), galactosyltransferase (EC 2.4.1.50) and glucosyltransferase (EC 2.4.1.66) are enzymes involved in posttranslational modifications of collagens. They sequentially modify lysyl residues in specific positions to hydroxylysyl, galactosylhydroxylysyl and glucosylgalactosyl hydroxylysyl residues. These structures are unique to collagens and essential for their functional activity. Lysines and hydroxylysines form collagen cross-links. Hydroxylysine derived cross-links, usually as glycosylated forms, occur especially in weight-bearing and mineralized tissues. The detailed functions of the hydroxylysyl and hydroxylysyl linked carbohydrate structures are not known, however. Hydroxylysine linked carbohydrates are found mainly in collagens, but recent reports indicate that these structures are also present and probably have an important function in other proteins. Earlier we have shown that human LH3, but not isoforms LH1, LH2a and LH2b, possesses both LH and glucosyltransferase activity (J. Biol. Chem. 275 (2000) 36158). In this paper we demonstrate that galactosyltransferase activity is also associated with the same gene product, thus indicating that one gene product can catalyze all three consecutive steps in hydroxylysine linked carbohydrate formation. In vitro mutagenesis experiments indicate that Cys144 and aspartates in positions 187–191 of LH3 are important for the galactosyltransferase activity. Our results suggest that manipulation of the gene for LH3 can be used to selectively alter the glycosylation and hydroxylation reactions, and provides a new tool to clarify the functions of the unique hydroxylysine linked carbohydrates in collagens and other proteins.
2001-05-10 | Adenoviral gene transfer restores lysyl hydroxylase activity in type VI Ehlers-Danlos syndrome.
Type VI Ehlers-Danlos syndrome is a disease characterized by disturbed lysine hydroxylation of collagen. The disease is caused by mutations in lysyl hydroxylase 1 gene and it affects several organs including the cardiovascular system, the joint and musculoskeletal system, and the skin. The skin of type VI Ehlers-Danlos syndrome patients is hyperelastic, scars easily, and heals slowly and poorly. We hypothesized that providing functional lysyl hydroxylase 1 gene to the fibroblasts in and around wounds in these patients would improve healing. In this study we tested the feasibility of transfer of the lysyl hydroxylase 1 gene into fibroblasts derived from rats and a type VI Ehlers-Danlos syndrome patient (in vitro) and into rat skin (in vivo). We first cloned human lysyl hydroxylase 1 cDNA into a recombinant adenoviral vector (Ad5RSV-LH). Transfection of human type VI Ehlers-Danlos syndrome fibroblasts (about 20% of normal lysyl hydroxylase 1 activity) with the vector increased lysyl hydroxylase 1 activity in these cells to near or greater levels than that of wild type, unaffected fibroblasts. The adenoviral vector successfully transfected rat fibroblasts producing both beta-galactosidase and lysyl hydroxylase 1 gene activity. We next expanded our studies to a rodent model. Intradermal injections of the vector to the abdominal skin of rats produced lysyl hydroxylase 1 mRNA and elevated lysyl hydroxylase 1 activity, in vivo. These data suggest the feasibility of gene replacement therapy to modify skin wound healing in type VI Ehlers-Danlos syndrome patients.
small molecules
2026-08-05 | Case report: Adult presentation of glutaric aciduria type I.
Introduction - Glutaric aciduria (or glutaric acidemia) type 1 (GA1) is a rare autosomal recessive neurometabolic disorder caused by mutations in the GCDH gene that results in a deficiency of the glutaryl-CoA dehydrogenase enzyme. It plays a vital role in the degradation of L-lysine, L-hydroxylysine, and L-tryptophan. Accumulating toxic metabolites (namely glutaric acid/GA and 3-hydroxyglutaric acid/3-OH-GA) leads to progressive neurological deterioration. GA1 is one of the limited neurometabolic disorders, where we can stop the progression of the disease with a diet and aggressive emergency treatment during excessive catabolism. If undiagnosed through newborn screening, symptoms start to present in childhood between 3-36 months, with neurological symptoms related to sepsis or fever. However, 10-20% of cases start insidiously.Case report - We report the case of a 53-year-old male with GA1, who presented progressive spastic tetraparesis, dysarthria, and focal seizures. His initial symptoms, misattributed to cerebral palsy and previous ischemic strokes, had gradually worsened in recent years, leaving him bedridden. Specific metabolic laboratory testing and radiological evaluations revealed the characteristic features of the disease. Genetic testing identified a known pathogenic homozygous mutation in the GCDH gene, which confirms the diagnosis of GA1. Low-lysine diet and supplementation with carnitine and riboflavin were started. After the initiation of treatment, no further progression was observable.Conclusion - This case underscores the importance of considering hereditary neurometabolic disorders like GA1 - taking into account the available metabolic screening - not only in pediatric patients but also in adult patients with progressive neurological decline. This case contributes to the limited literature available on GA1 cases in adults and highlights the need for early detection strategies to avoid irreversible neurological damage.
2025-09-04 | Acute Flaccid Paralysis in Infancy: A Rare Presentation of Glutaric Aciduria Type I
Glutaric aciduria type I (GA1) is a rare autosomal recessive disorder caused by deficiency of glutaryl-CoA dehydrogenase, disturbing lysine, hydroxylysine, and tryptophan metabolism [1].Although typical presentations include dystonia and developmental delay, acute flaccid paralysis (AFP) is a seldom recognized manifestation [2].We describe a 10-month-old girl, evaluated at Wadia Children's Hospital, Mumbai in June 2023, presenting with AFP and neuroregression post-febrile illness.MRI revealed striatal injury and subdural collections.Diagnosis was confirmed by elevated glutarylcarnitine (C5DC) and pathogenic GCDH mutation.Early lysinerestricted diet and carnitine supplementation stabilized her course.This report emphasizes the need to consider GA1 in AFP, especially with macrocephaly and suggestive neuroimaging, and highlights that prompt management is crucial for improved outcomes [3].
2021-03-05 | Neutrophil Adhesion and the Release of the Free Amino Acid Hydroxylysine
During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
2020-12-28 | Structure-function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism.
2-Oxoadipate dehydrogenase (E1a, also known as DHTKD1, dehydrogenase E1, and transketolase domain-containing protein 1) is a thiamin diphosphate-dependent enzyme and part of the 2-oxoadipate dehydrogenase complex (OADHc) in l-lysine catabolism. Genetic findings have linked mutations in the DHTKD1 gene to several metabolic disorders. These include α-aminoadipic and α-ketoadipic aciduria (AMOXAD), a rare disorder of l-lysine, l-hydroxylysine, and l-tryptophan catabolism, associated with clinical presentations such as developmental delay, mild-to-severe intellectual disability, ataxia, epilepsy, and behavioral disorders that cannot currently be managed by available treatments. A heterozygous missense mutation, c.2185G→A (p.G729R), in DHTKD1 has been identified in most AMOXAD cases. Here, we report that the G729R E1a variant when assembled into OADHc in vitro displays a 50-fold decrease in catalytic efficiency for NADH production and a significantly reduced rate of glutaryl-CoA production by dihydrolipoamide succinyl-transferase (E2o). However, the G729R E1a substitution did not affect any of the three side-reactions associated solely with G729R E1a, prompting us to determine the structure-function effects of this mutation. A multipronged systematic analysis of the reaction rates in the OADHc pathway, supplemented with results from chemical cross-linking and hydrogen-deuterium exchange MS, revealed that the c.2185G→A DHTKD1 mutation affects E1a-E2o assembly, leading to impaired channeling of OADHc intermediates. Cross-linking between the C-terminal region of both E1a and G729R E1a with the E2o lipoyl and core domains suggested that correct positioning of the C-terminal E1a region is essential for the intermediate channeling. These findings may inform the development of interventions to counter the effects of pathogenic DHTKD1 mutations.
2020-04-03 | Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model.
Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3-hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh-/-) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood-brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.
gene therapies
2024-01-16 | Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.
Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.
2012-11-29 | The Activities of Lysyl Hydroxylase 3 (LH3) Regulate the Amount and Oligomerization Status of Adiponectin
Lysyl hydroxylase 3 (LH3) has lysyl hydroxylase, galactosyltransferase, and glucosyltransferase activities, which are sequentially required for the formation of glucosylgalactosyl hydroxylysines in collagens. Here we demonstrate for the first time that LH3 also modifies the lysine residues in the collagenous domain of adiponectin, which has important roles in glucose and lipid metabolism and inflammation. Hydroxylation and, especially, glycosylation of the lysine residues of adiponectin have been shown to be essential for the formation of the more active high molecular weight adiponectin oligomers and thus for its function. In cells that totally lack LH3 enzyme, the galactosylhydroxylysine residues of adiponectin were not glucosylated to glucosylgalactosylhydroxylysine residues and the formation of high and middle molecular weight adiponectin oligomers was impaired. Circulating adiponectin levels in mutant mice lacking the lysyl hydroxylase activity of LH3 were significantly reduced, which indicates that LH3 is required for complete modification of lysine residues in adiponectin and the loss of some of the glycosylated hydroxylysine residues severely affects the secretion of adiponectin. LH mutant mice with reduced adiponectin level showed a high fat diet-induced increase in glucose, triglyceride, and LDL-cholesterol levels, hallmarks of the metabolic syndrome in humans. Our results reveal the first indication that LH3 is an important regulator of adiponectin biosynthesis, secretion and activity and thus might be a potential candidate for therapeutic applications in diseases associated with obesity and insulin resistance.
2002-11-01 | The third activity for lysyl hydroxylase 3: galactosylation of hydroxylysyl residues in collagens in vitro
Lysyl hydroxylase (LH, EC 1.14.11.4), galactosyltransferase (EC 2.4.1.50) and glucosyltransferase (EC 2.4.1.66) are enzymes involved in posttranslational modifications of collagens. They sequentially modify lysyl residues in specific positions to hydroxylysyl, galactosylhydroxylysyl and glucosylgalactosyl hydroxylysyl residues. These structures are unique to collagens and essential for their functional activity. Lysines and hydroxylysines form collagen cross-links. Hydroxylysine derived cross-links, usually as glycosylated forms, occur especially in weight-bearing and mineralized tissues. The detailed functions of the hydroxylysyl and hydroxylysyl linked carbohydrate structures are not known, however. Hydroxylysine linked carbohydrates are found mainly in collagens, but recent reports indicate that these structures are also present and probably have an important function in other proteins. Earlier we have shown that human LH3, but not isoforms LH1, LH2a and LH2b, possesses both LH and glucosyltransferase activity (J. Biol. Chem. 275 (2000) 36158). In this paper we demonstrate that galactosyltransferase activity is also associated with the same gene product, thus indicating that one gene product can catalyze all three consecutive steps in hydroxylysine linked carbohydrate formation. In vitro mutagenesis experiments indicate that Cys144 and aspartates in positions 187–191 of LH3 are important for the galactosyltransferase activity. Our results suggest that manipulation of the gene for LH3 can be used to selectively alter the glycosylation and hydroxylation reactions, and provides a new tool to clarify the functions of the unique hydroxylysine linked carbohydrates in collagens and other proteins.
2001-05-10 | Adenoviral gene transfer restores lysyl hydroxylase activity in type VI Ehlers-Danlos syndrome.
Type VI Ehlers-Danlos syndrome is a disease characterized by disturbed lysine hydroxylation of collagen. The disease is caused by mutations in lysyl hydroxylase 1 gene and it affects several organs including the cardiovascular system, the joint and musculoskeletal system, and the skin. The skin of type VI Ehlers-Danlos syndrome patients is hyperelastic, scars easily, and heals slowly and poorly. We hypothesized that providing functional lysyl hydroxylase 1 gene to the fibroblasts in and around wounds in these patients would improve healing. In this study we tested the feasibility of transfer of the lysyl hydroxylase 1 gene into fibroblasts derived from rats and a type VI Ehlers-Danlos syndrome patient (in vitro) and into rat skin (in vivo). We first cloned human lysyl hydroxylase 1 cDNA into a recombinant adenoviral vector (Ad5RSV-LH). Transfection of human type VI Ehlers-Danlos syndrome fibroblasts (about 20% of normal lysyl hydroxylase 1 activity) with the vector increased lysyl hydroxylase 1 activity in these cells to near or greater levels than that of wild type, unaffected fibroblasts. The adenoviral vector successfully transfected rat fibroblasts producing both beta-galactosidase and lysyl hydroxylase 1 gene activity. We next expanded our studies to a rodent model. Intradermal injections of the vector to the abdominal skin of rats produced lysyl hydroxylase 1 mRNA and elevated lysyl hydroxylase 1 activity, in vivo. These data suggest the feasibility of gene replacement therapy to modify skin wound healing in type VI Ehlers-Danlos syndrome patients.
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