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Angel L. Pey 《Amino acids》2013,45(6):1331-1341
Many inborn errors of amino acids metabolism are caused by single point mutations affecting the ability of proteins to fold properly (i.e., protein homeostasis), thus leading to enzyme loss-of-function. Mutations may affect protein homeostasis by altering intrinsic physical properties of the polypeptide (folding thermodynamics, and rates of folding/unfolding/misfolding) as well as the interaction of partially folded states with elements of the protein homeostasis network (such as molecular chaperones and proteolytic machineries). Understanding these mutational effects on protein homeostasis is required to develop new therapeutic strategies aimed to target specific features of the mutant polypeptide. Here, I review recent work in three different diseases of protein homeostasis associated to inborn errors of amino acids metabolism: phenylketonuria, inherited homocystinuria and primary hyperoxaluria type I. These three different genetic disorders involve proteins operating in different cell organelles and displaying different structural complexities. Mutations often decrease protein kinetic stability of the native state (i.e., its half-life for irreversible denaturation), which can be studied using simple kinetic models amenable to biophysical and biochemical characterization. Natural ligands and pharmacological chaperones are shown to stabilize mutant enzymes, thus supporting their therapeutic application to overcome protein kinetic destabilization. The role of molecular chaperones in protein folding and misfolding is also discussed as well as their potential pharmacological modulation as promising new therapeutic approaches. Since current available treatments for these diseases are either burdening or only successful in a fraction of patients, alternative treatments must be considered covering studies from protein structure and biophysics to studies in animal models and patients.  相似文献   

3.
Metabolic mayhem caused by 2-ketoacid imbalances   总被引:6,自引:0,他引:6  
A variety of herbicides act by inhibiting the branched chain amino-acid biosynthetic enzyme, acetolactate synthase (EC 4.1.3.18). The initial consequences of this event are 2-ketoacid accumulation and amino-acid starvation. Recent studies demonstrate that 2-ketoacid imbalances play a significant role in the action of these herbicides; such imbalances may also be important in certain inborn errors of human metabolism.  相似文献   

4.
Glycosphingolipid storage disorders are inborn errors of metabolism caused by the defective activity of degradative enzymes in lysosomes. In this review, we summarize studies performed over the past few years attempting to define the secondary and down-stream biochemical and cellular pathways affected in GSL storage disorders that are responsible for neuronal dysfunction, a characteristic of most of these disorders. We focus mainly on the regulation of intracellular calcium homeostasis and phospholipid biosynthesis. These studies may help unravel new roles for glycosphingolipids in the regulation of normal cell physiology, as well as suggest potential new therapeutic options in the glycosphingolipid and other lysosomal storage disorders.  相似文献   

5.
Thirty years ago, a number of human inborn errors in carbohydrate metabolism were explored with specific enzymatic tests on blood samples (hemolysates). Hereditary galactosemia was the first example. When the inoperative step in galactose metabolism was specified, the basis for the diet therapy used on the galactosemic infants, namely galactose-free diet, could be shown to be securely founded. As far as galactose metabolism is concerned, the cells of the infant are faced with two problems: (i) the conversion of dietary lactose (galactosyl glucose) to glucose and its catabolites involved in energy metabolism, and (ii) the conversion of dietary glucose or lactose to galactosyl units of glycolipids and glycoprotein cell structures. Subsequent studies on microorganisms revealed several types of hereditary defect in galactose metabolism. One type which permits the bacteria to develop a normal carbohydrate pattern in their cell walls includes an enzyme defect, like that described in the cells of the galactosemic infant. Two other types, with the inability to synthesize UDPGlc or UDPGal from glucose, do not permit the bacteria to build the fabric of the normal bacterial cell wall. This is the subject for discussion.  相似文献   

6.
Amniocentesis is a valuable and standard procedure for prenatal diagnosis of genetic or inborn errors of metabolism. Amnion cells are cultivated and chromosomes or proteins can be examined to provide molecular diagnosis. Mainly individual proteins are searched for based upon pedigrees and/or anamnesis. As inborn errors of metabolism involve a vast diversity of metabolic enzymes, we aimed to find a screening method for a large series of metabolic enzymes. Amnion cells were obtained from amniocentesis and subjected to proteomic analysis. We used two-dimensional gel electrophoresis with in-gel digestion followed by matrix-assisted laser desorption/ionization-time of flight analysis, to identify metabolic enzymes. Furthermore, we compared metabolic proteins in amnion cells from controls with those from Down Syndrome (DS). Enzymes involved in carbohydrate handling, amino acid handling, -purine metabolism and intermediary metabolism as well as miscellaneous metabolic pathways were detected. Protein levels of several enzymes were significantly deranged in samples obtained from patients with DS. This approach, with the advantage of the concomitant determination of many enzyme proteins, may form the basis for future metabolic screens when amniocentesis is carried out.  相似文献   

7.
Computer simulation of purine metabolism   总被引:1,自引:0,他引:1  
A computer model of purine metabolism, including catabolism, salvage pathways and interconversion among nucleotides, is given. Steady-state rate equations corresponding to metabolic enzymes are written based on information from the literature about their kinetic behaviour. Numerical integration of this set of equations is performed employing selected parameters taken from the literature. After stabilization of purine compound concentrations is reached, simulation of enzyme deficit and enzyme overproduction is carried out. The latter is calculated by varying specified maximum velocities in the numerical integration. A pattern of intermediate metabolite concentrations is found. These results form a basis for the comparison of normal patterns or patterns reflecting the effects of inborn errors of metabolism. The aim of this paper is to demonstrate the usefulness of this computer simulation method in complex metabolism pathways.  相似文献   

8.
Peroxisomes are subcellular organelles and are present in virtually all eukaryotic cells. Characteristic features of these organelles are their inducibility and their functional versatility. Their importance in the intermediary metabolism of cells is exemplified by the discovery of several inborn, fatal peroxisomal errors in man, the so-called peroxisomal disorders. Recent findings in research on peroxisome biogenesis and function have demonstrated that peroxisomal matrix proteins and peroxisomal membrane proteins (PMPs) follow separate pathways to reach their target organelle. This paper addresses the principles of PMP sorting and summarizes the current knowledge of the role of these proteins in organelle biogenesis and function.  相似文献   

9.
Since the aggregate incidence of inborn errors of metabolism is relatively high, a high degree of suspicion is essential to correctly diagnose an inborn error of amino acid metabolism. We report a case of alkaptonuria an autosomal recessive disorder that occurs due to deficiency of homogentisic acid oxidasein a β-thalassemia infant presenting with reddish discoloration of nappies and clothes, breath holding spells, and microcytic hypochromic anemia. Born to consanguineous cousins, to our knowledge, the combination of β-thalassemia and alkaptonuria, which we have described in this baby, has not been reported earlier.  相似文献   

10.
Alkaptonuria (AKU) is one of the first prototypic inborn errors in metabolism and the first human disease found to be transmitted via Mendelian autosomal recessive inheritance. It is caused by HGD mutations, which leads to a deficiency in homogentisate 1,2-dioxygenase (HGD) activity.  相似文献   

11.
The biennial 15th symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.  相似文献   

12.
Using materials from a nationwide screening project on inborn errors of metabolism in Japan, the incidence of histidinemia, phenylketonuria, galactosemia and homocystinuria were found to be 140, 16, 14 and 7 in 1 million live births, respectively. Geographical variations were observed, especially in histidinemia, which are most likely due to chance.  相似文献   

13.
Dysregulation of lipid metabolism underlies many chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Therefore, understanding enzymatic mechanisms controlling lipid synthesis and degradation is imperative for successful drug discovery for these human diseases. Genes encoding α/β hydrolase fold domain (ABHD) proteins are present in virtually all reported genomes, and conserved structural motifs shared by these proteins predict common roles in lipid synthesis and degradation. However, the physiological substrates and products for these lipid metabolizing enzymes and their broader role in metabolic pathways remain largely uncharacterized. Recently, mutations in several members of the ABHD protein family have been implicated in inherited inborn errors of lipid metabolism. Furthermore, studies in cell and animal models have revealed important roles for ABHD proteins in lipid metabolism, lipid signal transduction, and metabolic disease. The purpose of this review is to provide a comprehensive summary surrounding the current state of knowledge regarding mammalian ABHD protein family members. In particular, we will discuss how ABHD proteins are ideally suited to act at the interface of lipid metabolism and signal transduction. Although, the current state of knowledge regarding mammalian ABHD proteins is still in its infancy, this review highlights the potential for the ABHD enzymes as being attractive targets for novel therapies targeting metabolic disease.  相似文献   

14.
Clinical studies were conducted by gas chromatography mass spectrometry selected ion monitoring of urinary dicarboxylic acids as dicyclohexyl esters. The dicyclohexyl esters of the dicarboxylic acids give characteristic electron impact mass spectra suitable for selected ion monitoring. The mass spectra exhibit a prominent acid + 1H ion and an (acid + 1H)-H2O ion for use as quantitating and confirming ions. The cyclohexyl esters are stable for days at room temperature and have excellent chromatographic properties. Dicarboxylic acid quantitation is performed within one hour using only 50 microliter of unpurified urine. A rapid method specifically for methylmalonic acid quantitation is described which has assisted physicians in the diagnosis of pernicious anemia and methylmalonic aciduria. This procedure is applicable for screening urinary organic acids for detection of inborn errors of metabolism. The detection of a child with elevated medium length dicarboxylic acids in the terminal urine specimen is reported. This condition, previously described as an inborn error, is attributed to a terminal event. Finally, an increase in urinary succinic acid paralleling putrescine levels is described during a response to cancer chemotherapy.  相似文献   

15.
To diagnose inborn errors of metabolism, it would be desirable to simultaneously analyze and quantify organic acids, purines, pyrimidines, amino acids, sugars, polyols, and other compounds using a single-step fractionation; unfortunately, no such method currently exists. The present article will be concerned primarily with a practical yet comprehensive diagnostic procedure of inborn errors of metabolism (IEM). This procedure involves the use of urine or eluates from urine on filter paper, stable isotope dilution, and gas chromatography-mass spectrometry (GC-MS). This procedure not only offers reliable and quantitative evidence for diagnosing, understanding and monitoring the diseases, but also provides evidence for the diagnosis of new kinds of IEM. In this review, the differential diagnosis for hyperammonemia are described; deficiencies of ornithine carbamoyl transferase, argininosuccinate synthase (citrullinemia), argininosuccinate lyase and arginase, lysinuric protein intolerance, hyperammonemia-hyperornithinemia-homocitrullinemia syndrome, and citrullinemia type II. The diagnosis of IEM of purine and pyrimidine such as deficiencies of hypoxanthine-guanine phosphoribosyl transferase, adenine phosphoribosyl transferase, dihydropyrimidine dehydrogenase, dihydropyrimidinase and beta-ureidopropionase are described. During the pilot study for newborn screening, we found neonates with diseases at a rate of 1 per 1,400 including propionic acidemia, methylmalonic acidemia, orotic aciduria, beta-ureidopropionase deficiency, lactic aciduria and neuroblastoma. A rapid and reliable prenatal diagnosis for propionic acidemia is also described.  相似文献   

16.
Screening tests have been devised to detect the catalytic activities of at least 19 enzymes, primarily of the Emden-Meyerhof pathway, in normal blood specimens collected and dried on filter paper. Since these specimens can be mailed to a laboratory for assay, such screening tests may be useful in detecting individuals with inborn errors of metabolism among large populations or in certain types of genetic studies. Two new screening tests, for argininosuccinic aciduria and orotic aciduria, have been devised. These tests detect the normal enzyme activity in erythrocytes by means of a visible growth response of bacterial auxotrophs when nonutilizable substrates are converted by the enzymes into growth-promoting products. The use of the dried blood specimen in gel electrophoretic and immunoelectrophoretic procedures for genetic studies is also described.This investigation was supported in part by National Institutes of Health Grant No. NB-05290 and by the Children's Bureau Grant No. 435.  相似文献   

17.
The present communciation describes the use of four approaches to the detection of hereditary metabolic disorders: (1) the bacterial inhibition assay, (2) the reduction of nicotinamide adenine dinucleotide phosphate (NADP), (3) the use of paper chromatography, and (4) other specific methods. Using small quantities of capillary blood or urine, practical and simple methods have been devised for the diagnosis of 30 inborn errors of metabolism through screening programs.  相似文献   

18.

Background

Since 1975 cells lines from patients with suspected inborn errors of vitamin B12 metabolism have been referred to our laboratory because of elevations of homocysteine, methylmalonic acid, or both.

Design

Cultured fibroblasts from patients were subjected to a battery of tests: incorporation of labelled propionate and methyltetrahydrofolate into cellular macromolecules, to test the functional integrity of methylmalonyl-CoA mutase and methionine synthase, respectively; uptake of labelled cyanocobalamin and synthesis of adenosylcobalamin and methylcobalamin; and, where applicable, complementation analysis.

Results

This approach has allowed for the discovery of novel steps in the cellular transport and metabolism of vitamin B12, including those involving cellular uptake, the efflux of vitamin B12 from lysosomes, and the synthesis of adenosylcobalamin and methylcobalamin. For all of these disorders, the responsible genes have been discovered.

Conclusion

The study of highly selected patients with suspected inborn errors of metabolism has consistently resulted in the discovery of previously unknown metabolic steps and has provided new lessons in biology.  相似文献   

19.
Cystathionine beta-synthase and gamma-cystathionase, the two major enzymes of the transsulfuration pathway of methionine metabolism, are described. These enzymes are responsible for inborn errors, e.g., homocystinuria and cystathioninuria. The interaction of gamma-cystathionase with the cofactor, substrates and inhibitors of the general formula RONH2 containing structural fragments of substrates has been studied. A non-radioactive avidin-biotin system for the microdetection of gamma-cystathionase in dot blots has been developed. This system was applied for immunoscreening of a rat liver cDNA library in the prokaryotic expression vector lambda gt 11.  相似文献   

20.
A higher incidence of depression has been described in adults with primary oxidative phosphorylation disease. We evaluated the psychological characteristics of eighteen non-retarded pediatric patients diagnosed with a disorder of the oxidative phosphorylation. We found significantly higher rate of withdrawn, depressive behaviour compared to population norm scores, to children with other types of inborn errors of metabolism and also in comparison to patients with Sotos syndrome. The occurrence of depressive behaviour showed no correlation with the degree of mitochondrial dysfunction. These findings support the hypothesis that mood disorders could be associated to abnormal cerebral energy metabolism.  相似文献   

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