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JIMD Reports 2013Sarcosinemia is a rare inborn error of metabolism that is characterised by an increased level of sarcosine (N-methylglycine) in the plasma and urine. The enzymatic block...
Sarcosinemia is a rare inborn error of metabolism that is characterised by an increased level of sarcosine (N-methylglycine) in the plasma and urine. The enzymatic block results from a deficiency of sarcosine dehydrogenase (SarDH), a liver mitochondrial matrix enzyme that converts sarcosine into glycine. Although this condition may remain inapparent until later life, it has been reported in rare cases to lead to neurodevelopmental disability. A 19-year-old male with sarcosinemia presented with dystonia, developmental delay and cognitive impairment. Magnetic resonance imaging revealed vermian hypotrophy. A 2-year pharmacological treatment with memantine was negative on the clinical signs. In this case, it was concluded that the metabolic block leading to sarcosinemia was responsible of a pathologic condition with mental deficiency and complex neurological signs. A maternal isodisomy discovered in the vicinity of SarDH gene could contribute to this pathology. Deficit of SarDH may be considered as a differential diagnosis of growth failure during prenatal stages and respiratory failure at birth following a slowly progressive developmental delay.
PubMed: 23430553
DOI: 10.1007/8904_2012_185 -
Scientific Reports Feb 2023Suppressor of mek1 (Dictyostelium) homolog 2 (Smek2), was identified as one of the responsible genes for diet-induced hypercholesterolemia (DIHC) of exogenously...
Suppressor of mek1 (Dictyostelium) homolog 2 (Smek2), was identified as one of the responsible genes for diet-induced hypercholesterolemia (DIHC) of exogenously hypercholesterolemic (ExHC) rats. A deletion mutation in Smek2 leads to DIHC via impaired glycolysis in the livers of ExHC rats. The intracellular role of Smek2 remains obscure. We used microarrays to investigate Smek2 functions with ExHC and ExHC.BN-Dihc2 congenic rats that harbor a non-pathological Smek2 allele from Brown-Norway rats on an ExHC background. Microarray analysis revealed that Smek2 dysfunction leads to extremely low sarcosine dehydrogenase (Sardh) expression in the liver of ExHC rats. Sarcosine dehydrogenase demethylates sarcosine, a byproduct of homocysteine metabolism. The ExHC rats with dysfunctional Sardh developed hypersarcosinemia and homocysteinemia, a risk factor for atherosclerosis, with or without dietary cholesterol. The mRNA expression of Bhmt, a homocysteine metabolic enzyme and the hepatic content of betaine (trimethylglycine), a methyl donor for homocysteine methylation were low in ExHC rats. Results suggest that homocysteine metabolism rendered fragile by a shortage of betaine results in homocysteinemia, and that Smek2 dysfunction causes abnormalities in sarcosine and homocysteine metabolism.
Topics: Animals; Rats; Betaine; Glucose; Homocysteine; Hypercholesterolemia; Hyperhomocysteinemia; Liver; Mutation; Rats, Inbred BN; Sarcosine; Sarcosine Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Phosphoprotein Phosphatases
PubMed: 36810603
DOI: 10.1038/s41598-022-26115-z -
International Journal of Molecular... Nov 2018Sarcosine is an amino acid that is formed by methylation of glycine and is present in trace amounts in the body. Increased sarcosine concentrations in blood plasma and...
Sarcosine is an amino acid that is formed by methylation of glycine and is present in trace amounts in the body. Increased sarcosine concentrations in blood plasma and urine are manifested in sarcosinemia and in some other diseases such as prostate cancer. For this purpose, sarcosine detection using the nanomedicine approach was proposed. In this study, we have prepared superparamagnetic iron oxide nanoparticles (SPIONs) with different modified surface area. Nanoparticles (NPs) were modified by chitosan (CS), and sarcosine oxidase (SOX). SPIONs without any modification were taken as controls. The obtained NPs were characterized by physicochemical methods. The size of the NPs determined by the dynamic light scattering method was as follows: SPIONs/Au/NPs (100⁻300 nm), SPIONs/Au/CS/NPs (300⁻700 nm), and SPIONs/Au/CS/SOX/NPs (600⁻1500 nm). The amount of CS deposited on the NP surface was found to be 48 mg/mL for SPIONs/Au/CS/NPs and 39 mg/mL for SPIONs/Au/CS/SOX/NPs, and repeatability varied around 10%. Pseudo-peroxidase activity of NPs was verified using sarcosine, horseradish peroxidase (HRP) and 3,3',5,5'-tetramethylbenzidine (TMB) as a substrate. For TMB, all NPs tested evinced substantial pseudo-peroxidase activity at 650 nm. The concentration of SPIONs/Au/CS/SOX/NPs in the reaction mixture was optimized to 0⁻40 mg/mL. Trinder reaction for sarcosine detection was set up at 510 nm at an optimal reaction temperature of 37 °C and pH 8.0. The course of the reaction was linear for 150 min. The smallest amount of NPs that was able to detect sarcosine was 0.2 mg/well (200 µL of total volume) with the linear dependence y = 0.0011x - 0.0001 and the correlation coefficient = 0.9992, relative standard deviation (RSD) 6.35%, limit of detection (LOD) 5 µM. The suggested method was further validated for artificial urine analysis ( = 0.99, RSD 21.35%, LOD 18 µM). The calculation between the detected and applied concentrations showed a high correlation coefficient ( = 0.99). NPs were tested for toxicity and no significant growth inhibition was observed in any model system (, , ). The hemolytic activity of the prepared NPs was similar to that of the phosphate buffered saline (PBS) control. The reaction system was further tested on real urine specimens. The proposed detection system allows the analysis of sarcosine at micromolar concentrations and to monitor changes in its levels as a potential prostate cancer marker. The whole system is suitable for low-cost miniaturization and point-of-care testing technology and diagnostic systems. This system is simple, inexpensive, and convenient for screening tests and telemedicine applications.
Topics: Biomarkers, Tumor; Chitosan; Escherichia coli; Ferric Compounds; Gold; Hemolysis; Horseradish Peroxidase; Humans; Hydrogen-Ion Concentration; Limit of Detection; Magnetite Nanoparticles; Male; Oxidation-Reduction; Particle Size; Precision Medicine; Prostatic Neoplasms; Reproducibility of Results; Saccharomyces cerevisiae; Sarcosine; Sarcosine Oxidase; Staphylococcus aureus
PubMed: 30467297
DOI: 10.3390/ijms19123722 -
Proceedings of the National Academy of... Apr 1992A mouse mutant with sarcosinemia was found by screening the progeny of ethylnitrosourea-mutagenized mice for aminoacidurias. Paper chromatography, column chromatography,...
A mouse mutant with sarcosinemia was found by screening the progeny of ethylnitrosourea-mutagenized mice for aminoacidurias. Paper chromatography, column chromatography, and gas chromatography-mass spectrometry identified high levels of sarcosine in the urine of the mutant mice. While sarcosine cannot be detected in the urine of plasma of normal mice, the urinary sarcosine level of 102 +/- 58 mmol per g of creatinine in the mutant mice was at the upper range of the urinary levels (1.5-4.5 mmol of sarcosine per g of creatinine) observed in humans with sarcosinemia. Similarly, the plasma sarcosine level of 785 +/- 153 mumol/liter in the sarcosinemic mice was at the upper range of the plasma sarcosine levels (53-760 mumol/liter) observed in affected humans. Sarcosine dehydrogenase [sarcosine:(acceptor) oxidoreductase (demethylating), EC 1.5.99.1] activity was deficient in sarcosinemic mice. The sarcosinuria phenotype in these mice was inherited as an autosomal recessive trait. This mouse mutant provides a useful genetic model for human sarcosinemia and for development of therapeutic approaches for genetic disease.
Topics: Amino Acid Metabolism, Inborn Errors; Animals; Ethylnitrosourea; Gas Chromatography-Mass Spectrometry; Mice; Mice, Mutant Strains; Mutagenesis; Oxidoreductases, N-Demethylating; Phenotype; Sarcosine; Sarcosine Dehydrogenase
PubMed: 1372986
DOI: 10.1073/pnas.89.7.2644 -
European Journal of Biochemistry Nov 1998Sarcosine dehydrogenase (SarDH) is a mitochondrial flavoenzyme involved in the oxidative degradation of choline to glycine. The absence of SarDH activity in humans is...
Sarcosine dehydrogenase (SarDH) is a mitochondrial flavoenzyme involved in the oxidative degradation of choline to glycine. The absence of SarDH activity in humans is genetically transmitted and is the cause of an amino acid metabolism disorder called sarcosinemia. Tryptic fragments of the purified enzyme from rat liver were subjected to Edman degradation and the sequences obtained were used to clone the cDNA encoding the full length protein. The deduced amino acid sequence of SarDH shares an overall similarity of 47% with dimethylglycine dehydrogenase (Me2GlyDH), another flavoenzyme involved in the mitochondrial choline catabolism with a similar FAD-binding domain. Covalent binding of FAD to SarDH was demonstrated by the observation of strong fluorescence at 530 nm under excitation at 450 nm of the enzyme immunoprecipitated under denaturing conditions from liver extracts. The localization of SarDH immunoreactivity in the mitochondrial matrix was confirmed by Western-blot analysis of purified mitochondrial fractions. Finally, the tissue distribution of SarDH was investigated by Northern-blot analysis of total RNA and Western-blot analysis of total protein from several rat tissues. A strong expression in the liver, but also in the lung, pancreas, kidney, thymus, and oviduct was observed. We therefore suggest that the enzymes of the choline catabolism pathway are important also for metabolism in nonhepatic tissues.
Topics: Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Cell Line; Cloning, Molecular; DNA Primers; DNA, Complementary; Humans; Male; Mitochondria, Liver; Molecular Sequence Data; Oxidoreductases, N-Demethylating; RNA, Messenger; Rats; Rats, Wistar; Sarcosine Dehydrogenase; Sequence Homology, Amino Acid
PubMed: 9839943
DOI: 10.1046/j.1432-1327.1998.2570556.x -
Communications Biology 2019Gaseous formaldehyde is an organic small molecule formed in the early stages of earth's evolution. Although toxic in high concentrations, formaldehyde plays an important...
Gaseous formaldehyde is an organic small molecule formed in the early stages of earth's evolution. Although toxic in high concentrations, formaldehyde plays an important role in cellular metabolism and, unexpectedly, is found even in the healthy brain. However, its pathophysiological functions in the brain are unknown. Here, we report that under physiological conditions, spatial learning activity elicits rapid formaldehyde generation from mitochondrial sarcosine dehydrogenase (SARDH). We find that elevated formaldehyde levels facilitate spatial memory formation by enhancing N-methyl-D-aspartate (NMDA) currents, but that high formaldehyde concentrations gradually inactivate the NMDA receptor by cross-linking NR1 subunits to NR2B via the C232 residue. We also report that in mice with aldehyde dehydrogenase-2 () knockout, formaldehyde accumulation due to hypofunctional ALDH2 impairs memory, consistent with observations of Alzheimer's disease patients. We also find that formaldehyde deficiency caused by mutation of the mitochondrial gene in children with sarcosinemia or in mice with deletion leads to cognitive deficits. Hence, we conclude that endogenous formaldehyde regulates learning and memory via the NMDA receptor.
PubMed: 31815201
DOI: 10.1038/s42003-019-0694-x -
Cell Death & Disease Dec 2014Cervical cancer is one of the most common carcinomas in the genital system. In the present study, we report that SBF-1, a synthetic steroidal glycoside, has a strong...
SBF-1 exerts strong anticervical cancer effect through inducing endoplasmic reticulum stress-associated cell death via targeting sarco/endoplasmic reticulum Ca(2+)-ATPase 2.
Cervical cancer is one of the most common carcinomas in the genital system. In the present study, we report that SBF-1, a synthetic steroidal glycoside, has a strong antigrowth activity against human cervical cancer cells in vitro and in vivo. SBF-1 suppressed the growth, migration and colony formation of HeLa cells. In addition, severe endoplasmic reticulum (ER) stress was triggered by SBF-1, and 4-phenyl-butyric acid, a chemical chaperone, partially reversed SBF-1-induced cell death. To uncover the target protein of SBF-1, the compound was labeled with biotin. The biotin-labeled SBF-1 bound to sarco/ER Ca(2+)-ATPase 2 (SERCA2) and colocalized with SERCA2 in HeLa cells. Moreover, SBF-1 inhibited SERCA activity, depleted ER Ca2+ and increased cytosolic Ca2+ levels. 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, a chelator of Ca2+, partially blocked SBF-1-induced ER stress and growth inhibition. Importantly, knockdown of SERCA2 increased the sensitivity of HeLa cells to SBF-1-induced ER stress and cell death, whereas overexpression of SERCA2 decreased this sensitivity. Furthermore, SBF-1 induced growth suppression and apoptosis in HeLa xenografts, which is closely related to the induction of ER stress and inhibition of SERCA activity. Finally, SERCA2 expression was elevated in human cervical cancer tissues (n=299) and lymph node metastasis (n=8), as compared with normal cervix tissues (n=23), with a positive correlation with clinical stages. In all, these results suggest that SBF-1 disrupts Ca2+ homeostasis and causes ER stress-associated cell death through directly binding to SERCA2 and inhibiting SERCA activity. Our findings also indicate that SERCA2 is a potential therapeutic target for human cervical cancer.
Topics: Amino Acid Metabolism, Inborn Errors; Animals; Antineoplastic Agents; Calcium; Cell Death; Cholestenones; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Female; Humans; Mice, Inbred C57BL; Mice, Nude; Mitochondrial Diseases; Saponins; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sarcosine Dehydrogenase; Uterine Cervical Neoplasms
PubMed: 25522275
DOI: 10.1038/cddis.2014.538 -
CMAJ : Canadian Medical Association... Jul 1991To compare the prevalence of hereditary metabolic diseases in the native and non-native populations of Manitoba and northwestern Ontario.
OBJECTIVE
To compare the prevalence of hereditary metabolic diseases in the native and non-native populations of Manitoba and northwestern Ontario.
DESIGN
Retrospective analysis.
SETTING
Children's Hospital, Winnipeg.
PATIENTS
Patients were selected by three methods: laboratory tests designed to screen patients suspected of having a metabolic disease, laboratory investigation of newborn infants with abnormalities detected through screening, and investigation of near relatives of probands with disease.
RESULTS
A total of 138 patients with organic acid, amino acid and carbohydrate disorders were seen from 1960 to 1990. Of these, 49 (36%) were native Indians (Algonkian linguistic group). This was in sharp contrast to the proportion of native Indians in the total study population (5.8%). Congenital lactic acidosis due to pyruvate carboxylase deficiency (13 patients), glutaric aciduria type I (14 patients) and primary hyperoxaluria type II (8 patients) were the most common disorders detected. Other rare disorders included glutaric aciduria type II (one patient), 2-hydroxyglutaric aciduria (one patient) and sarcosinemia (one patient). Underreporting, especially of glutaric aciduria type I and hyperoxaluria type II, was likely in the native population.
CONCLUSIONS
Hereditary metabolic diseases are greatly overrepresented in the native population of Manitoba and northwestern Ontario. We recommend that native children who present with illnesses involving disturbances of acid-base balance or with neurologic, renal or liver disease of unknown cause by investigated for a possible metabolic disorder.
Topics: Acidosis, Lactic; Adolescent; Amino Acid Metabolism, Inborn Errors; Carbohydrate Metabolism, Inborn Errors; Child; Female; Glucose-6-Phosphatase; Humans; Indians, North American; Infant; Infant, Newborn; Male; Manitoba; Ontario; Prevalence
PubMed: 1650287
DOI: No ID Found -
Annals of the Academy of Medicine,... Aug 2006Sarcosinaemia is a rare metabolic disorder which has not been reported in Asia.
INTRODUCTION
Sarcosinaemia is a rare metabolic disorder which has not been reported in Asia.
CLINICAL PICTURE
The urine samples of 2 patients were screened as a routine metabolic screening offered for patients with mental retardation in our hospital. We used gas chromatography-mass spectrometry (GC-MS) which is capable of detecting abnormal pattern in amino acids and organic acids. Plasma sarcosine level was further quantified by GC-MS. The same methods were used in the investigations of asymptomatic family members. Urine examination by GC-MS revealed excessive amount of sarcosine in urine (normally undetectable) and their plasma sarcosine levels were raised. The 2 differential diagnoses of presence of sarcosine in urine--glutaric aciduria type II and folate deficiency--were ruled out by the absence of abnormal organic acids in the initial urine screen and by normal serum folate level respectively. Screening of the 2 families identified excessive sarcosine in urine in 2 siblings, one from each family. However, these 2 siblings of indexed patients thus identified have no neurological or developmental problem.
CONCLUSION
Our finding was consistent with the notion that sarcosinaemia is a benign condition picked up coincidentally during screening for mental retardation.
Topics: Amino Acid Metabolism, Inborn Errors; Child; Child, Preschool; China; Family Health; Female; Gas Chromatography-Mass Spectrometry; Hong Kong; Humans; India; Intellectual Disability; Sarcosine; Sarcosine Dehydrogenase
PubMed: 17006587
DOI: No ID Found