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1.
J Inherit Metab Dis ; 42(4): 647-654, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30746739

RESUMEN

Biotin is a water-soluble vitamin that belongs to the vitamin B complex and which is an essential nutrient of all living organisms from bacteria to man. In eukaryotic cells biotin functions as a prosthetic group of enzymes, collectively known as biotin-dependent carboxylases that catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Enzyme-bound biotin acts as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In recent years, evidence has mounted that biotin also regulates gene expression through a mechanism beyond its role as a prosthetic group of carboxylases. These activities may offer a mechanistic background to a developing literature on the action of biotin in neurological disorders. This review summarizes the role of biotin in activating carboxylases and proposed mechanisms associated with a role in gene expression and in ameliorating neurological disease.


Asunto(s)
Biotina/metabolismo , Deficiencia de Biotinidasa/enzimología , Biotinidasa/metabolismo , Ligasas de Carbono-Carbono/metabolismo , Aminoácidos/metabolismo , Biotina/deficiencia , Deficiencia de Biotinidasa/genética , Regulación de la Expresión Génica , Humanos , Recién Nacido , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Deficiencia Múltiple de Carboxilasa/genética , Deficiencia Múltiple de Carboxilasa/metabolismo
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 26(5): 504-10, 2009 Oct.
Artículo en Chino | MEDLINE | ID: mdl-19806568

RESUMEN

OBJECTIVE: To confirm the diagnosis of multiple carboxylase deficiency (MCD) on the gene level and explore the mutations in Chinese children with MCD. METHODS: Biotinidase (BT) and holocarboxylase synthetase (HLCS) genes were analyzed by PCR and direct sequencing for the 4 BT deficiency patients and 8 HLCS deficiency patients, respectively. The identified mutations in the parents of the patients and 50 normal controls were screened by PCR-restriction fragment length polymorphism and direct DNA sequencing. RESULTS: Total detection rate of gene mutation is 100% in the 12 children with MCD. Six mutations were detected in the 4 children with BT deficiency, they were c. 98-104del7ins3, c. 1369G>A (V457M), c. 1157G>A(W386X), c. 1284C>A(Y428X), c. 1384delA and c. 1493_1494insT. The last four were novel mutations. Four mutations were found in the 8 children with HLCS deficiency. They were c. 126G>T (E42D), c. 1994G>C (R665P), c. 1088T>A (V363D) and c. 1522C>T (R508W). The last two were hot-spot mutations [75%(12/16)], and c. 1994G>C (R665P) was a novel mutation. CONCLUSION: This study confirmed the diagnosis of 12 patients with MCD on the gene level. Six mutations were found in the BT gene and 4 in the HLCS gene, including 5 novel mutations. Two mutations of the HLCS gene are probably hot-spot mutations in Chinese children with HLCS deficiency.


Asunto(s)
Pueblo Asiatico/genética , Biotinidasa/genética , Ligasas de Carbono-Nitrógeno/genética , Deficiencia Múltiple de Carboxilasa/genética , Mutación , Secuencia de Bases , Deficiencia de Biotinidasa , Ligasas de Carbono-Nitrógeno/deficiencia , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Deficiencia Múltiple de Carboxilasa/metabolismo
3.
Mol Genet Metab ; 87(3): 194-7, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16359899

RESUMEN

This article summarizes some findings of a research that I have pursued for the past 25 years, whose roots are immersed in the field of inherited metabolic disorders, and deal with different aspects of the vitamin biotin, starting with a patient with multiple carboxylase deficiency (MCD). Several of MCD clinical manifestations resemble those of infant malnutrition; we demonstrated that about one-third of infants with this common nutritional disorder were indeed biotin-deficient, and that this deficiency is metabolically significant, by studying urine instead of blood, studying urinary organic acids by gas chromatography-mass spectrometry. Remarkably, the metabolic abnormalities became apparent only after protein feeding was started, suggesting that this phenomenon may contribute to the worsening of malnourished individuals when they are abruptly fed. Afterwards, we studied biotin deficiency at the tissue level. Carboxylase activities and masses were significantly reduced in liver, kidney, muscle, adipose tissue, intestine, and spleen, but brain and heart were spared; their mRNAs remained unchanged. On the other hand, holocarboxylase synthetase (HCS) mRNA levels were markedly low in the deficient animals, and increased upon biotin injection. Over 2000 human genes have been identified that depend on biotin for expression. To probe into the "logic" of this enigma, we have started comparative studies among evolutionarily distant organisms, such as mouse and Saccharomyces cerevisiae, and we are now looking for biotin effects on specific genes and proteins, such as HCS and hexokinases, and on their proteomes.


Asunto(s)
Biotina/metabolismo , Errores Innatos del Metabolismo/historia , Animales , Biotina/deficiencia , Historia del Siglo XX , Humanos , Lactante , Errores Innatos del Metabolismo/enzimología , Errores Innatos del Metabolismo/genética , Deficiencia Múltiple de Carboxilasa/enzimología , Deficiencia Múltiple de Carboxilasa/genética , Deficiencia Múltiple de Carboxilasa/historia , Deficiencia Múltiple de Carboxilasa/metabolismo , Ratas , Saccharomyces cerevisiae
4.
J Biol Chem ; 279(50): 52312-8, 2004 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-15456772

RESUMEN

Holocarboxylase synthetase (HCS) catalyzes the biotinylation of five carboxylases in human cells, and mutations of HCS cause multiple carboxylase deficiency (MCD). Although HCS also participates in the regulation of its own mRNA levels, the relevance of this mechanism to normal metabolism or to the MCD phenotype is not known. In this study, we show that mRNA levels of enzymes involved in biotin utilization, including HCS, are down-regulated during biotin deficiency in liver while remaining constitutively expressed in brain. We propose that this mechanism of regulation is aimed at sparing the essential function of biotin in the brain at the expense of organs such as liver and kidney during biotin deprivation. In MCD, it is possible that some of the manifestations of the disease may be associated with down-regulation of biotin utilization in liver because of the impaired activity of HCS and that high dose biotin therapy may in part be important to overcoming the adverse regulatory impact in such organs.


Asunto(s)
Biotina/metabolismo , Encéfalo/metabolismo , Hígado/metabolismo , Deficiencia Múltiple de Carboxilasa/genética , Deficiencia Múltiple de Carboxilasa/metabolismo , Animales , Secuencia de Bases , Biotina/deficiencia , Ligasas de Carbono-Nitrógeno/genética , Ligasas de Carbono-Nitrógeno/metabolismo , Línea Celular , ADN Complementario/genética , Deficiencia de Holocarboxilasa Sintetasa/genética , Deficiencia de Holocarboxilasa Sintetasa/metabolismo , Humanos , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Distribución Tisular
5.
Hum Mol Genet ; 13(1): 15-23, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14613969

RESUMEN

The attachment of biotin to apocarboxylases is catalyzed by holocarboxylase synthetase (HCS). An inherited deficiency of HCS results in the disorder 'multiple carboxylase deficiency', which is characterized by reduced activity of all biotin-dependent carboxylases. Here we show that the majority of HCS localizes to the nucleus rather than the cytoplasm based on immunofluorescence studies with antibodies to peptides and full length HCS and on the expression of recombinant HCS. Subnuclear fractionations indicate that HCS is associated with chromatin and the nuclear lamina, the latter in a discontinuous distribution in high salt-extracted nuclear membranes. During mitosis, HCS resolves into ring-like particles which co-localize with lamin B. Nuclear HCS retains its biotinylating activity and was shown to biotinylate purified histones in vitro. Significantly, fibroblasts from patients with HCS deficiency are severely deficient in histone biotinylation in addition to the deficiency of carboxylase activities. We propose that the role of HCS in histone modification may be linked to the participation of biotin in the regulation of gene expression or cell division and that affected patients may have additional disease beyond that due to the effect on carboxylases.


Asunto(s)
Biotinilación , Ligasas de Carbono-Nitrógeno/metabolismo , Núcleo Celular/metabolismo , Regulación Enzimológica de la Expresión Génica , Histonas/metabolismo , Deficiencia Múltiple de Carboxilasa/metabolismo , Anticuerpos/metabolismo , Cromatina/metabolismo , ADN Complementario/genética , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Matriz Nuclear/metabolismo , Plásmidos/genética , Pruebas de Precipitina , Células Tumorales Cultivadas
6.
Rev Invest Clin ; 52(2): 194-9, 2000.
Artículo en Español | MEDLINE | ID: mdl-10846444

RESUMEN

Biotin is a water soluble enzyme cofactor that belongs to the vitamin B complex. In humans, biotin is involved in important metabolic pathways such as gluconeogenesis, fatty acid synthesis, and amino acid catabolism by acting a as prosthetic group for pyruvate carboxylase, propionyl-CoA carboxylase, beta-methylcrotinyl-CoA carboxylase, and acetyl-CoA carboxylase. Carboxylases are synthesized as apo-carboxylases without biotin and the active form is produced by their covalent binding of biotin to the epsilon-amino group of a lysine residue of the apocarboxylases. This reaction is catalyzed by the holo-carboxylase synthetase. The last step in the degradation of carboxylases, the cleavage of the biotinyl moiety from the epsilon-amino group lysine residues, is catalyzed by biotinidase and results in the release of free biotin, which can be recycled. Biotin regulates the catabolic enzyme propionyl-CoA carboxylase at the posttranscriptional level whereas the holo-carboxylase synthetase is regulated at the transcriptional level. Aside from its role in the regulation of gene expression of carboxylases, biotin has been implicated in the induction of the receptor for the asialoglycoprotein, glycolytic enzymes and of egg yolk biotin binding proteins. Biotin deficiency in humans is extremely rare and is generally associated with prolonged parenteral nutrition, the consumption of large quantities of avidin, usually in the form of raw eggs, severe malnutrition and, inherited metabolic disorders. In humans, there are autosomal recessive disorders of biotin metabolism that result from the disruption of the activity of biotinidase or holo-carboxylase synthetase.


Asunto(s)
Biotina/metabolismo , Ligasas de Carbono-Carbono/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Aminoácidos/metabolismo , Apoenzimas/metabolismo , Biotina/deficiencia , Biotinidasa , Biotinilación , Niño , Coenzimas/metabolismo , Ácidos Grasos/metabolismo , Regulación de la Expresión Génica , Gluconeogénesis , Humanos , Recién Nacido , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Deficiencia Múltiple de Carboxilasa/genética , Deficiencia Múltiple de Carboxilasa/metabolismo
7.
Ugeskr Laeger ; 160(8): 1151-7, 1998 Feb 16.
Artículo en Danés | MEDLINE | ID: mdl-9492625

RESUMEN

Biotinidase deficiency and holocarboxylase synthetase deficiency are two autosomal recessively inherited disorders of biotin metabolism affecting children below the age of two years. Both cause multiple carboxylase deficiency resulting in defects of fatty acid synthesis, gluconeogenesis and amino acid catabolism. The clinical picture involves the nervous system, the skin, the respiratory system, the digestive system and the immune system, but great individual variations often makes the clinical diagnosis difficult. Early diagnosis and treatment with biotin are essential in order to prevent death from metabolic acidosis or irreversible damage to the central nervous system. Two patients with biotinidase deficiency, two patients with holocarboxylase synthetase deficiency and a review of the literature are presented. Neonatal screening for biotinidase deficiency or a higher degree of metabolic screening of the urine in children below the age of one year with seizures and unexplained clinical course are discussed.


Asunto(s)
Deficiencia Múltiple de Carboxilasa , Biotina/administración & dosificación , Diagnóstico Diferencial , Humanos , Lactante , Recién Nacido , Deficiencia Múltiple de Carboxilasa/diagnóstico , Deficiencia Múltiple de Carboxilasa/tratamiento farmacológico , Deficiencia Múltiple de Carboxilasa/metabolismo
10.
Neuropediatrics ; 24(2): 98-102, 1993 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8352834

RESUMEN

A 15-year-old boy suffered from progressive bilateral optic neuropathy of acute onset at the age of 10 years. Subsequently he developed spastic paraparesis and a predominantly motor type neuro-axonal neuropathy in all limbs. The basic error has been elucidated to be due to an unusual biotinidase Km variant with biphasic enzyme kinetics causing systemic biotin depletion and consequent multiple biotin-dependent carboxylase deficiency. After daily oral substitution with 10 mg biotin metabolic derangements subsided rapidly. Follow-up studies over one year after substitution with biotin demonstrated remarkable recovery from part of the previously present neuro-ophthalmological, motor and cognitive deficits. The previously extinguished flash-evoked visual potentials now showed clear responses after six months of substitution with biotin. In contrast with reports in literature, these findings indicated that neurological damage associated with biotinidase deficiency, rather than being permanent, is to some extent reversible.


Asunto(s)
Amidohidrolasas/deficiencia , Biotina/uso terapéutico , Administración Oral , Adolescente , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Biotina/administración & dosificación , Biotinidasa , Análisis Químico de la Sangre , Cognición , Colorimetría , Potenciales Evocados Visuales/efectos de los fármacos , Estudios de Seguimiento , Humanos , Masculino , Deficiencia Múltiple de Carboxilasa/sangre , Deficiencia Múltiple de Carboxilasa/metabolismo , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/tratamiento farmacológico , Atrofia Óptica/diagnóstico , Atrofia Óptica/tratamiento farmacológico , Parálisis/diagnóstico , Parálisis/tratamiento farmacológico , Trastornos de la Visión/diagnóstico , Agudeza Visual
12.
J Inherit Metab Dis ; 13(1): 76-92, 1990.
Artículo en Inglés | MEDLINE | ID: mdl-2109151

RESUMEN

Seventeen partially biotinidase-deficient patients detected by neonatal screening or family studies were compared with four patients with classical biotinidase deficiency. Using a sensitive HPLC method for biotinidase in plasma (substrate: biocytin) the patients could be divided into two groups: one with residual biotinidase activity, and the second with undetectable biotinidase activity (0-activity). Biocytin excretion, characteristically elevated in 0-activity patients, decreased rapidly with increasing residual biotinidase activity and was almost normal when residual activity exceeded 2-3% of mean normal. In one patient with classical disease (0-activity) biotin deficiency, typical organic aciduria and multiple carboxylase deficiency were found as early as at the second week of life. In contrast, 13 infants with residual activities from 1.2% to 23% had no remarkable clinical or biochemical abnormalities. However, in three 5-, 14- and 15-year-old healthy siblings with residual biotinidase activities between 2.3% and 4.2%, biotin deficiency was proven by decreased activities of the mitochondrial carboxylases in lymphocytes (30-57% of mean normal) and, in the older siblings, also by subnormal plasma biotin concentrations. In biotinidase deficiency, biotin depletion presumably occurs earlier in the brain than in other tissues and may thus first affect the central nervous system. For this reason and because of discrete biochemical abnormalities found in a patient with residual biotinidase activity of 8%, we suggest that at least all patients with residual activities below 10% should be treated with biotin.


Asunto(s)
Amidohidrolasas/deficiencia , Errores Innatos del Metabolismo/metabolismo , Ácidos/metabolismo , Adolescente , Adulto , Amidohidrolasas/sangre , Biotina/sangre , Biotina/uso terapéutico , Biotina/orina , Biotinidasa , Preescolar , Ácidos Grasos/metabolismo , Femenino , Humanos , Lactante , Recién Nacido , Linfocitos/enzimología , Lisina/análogos & derivados , Lisina/sangre , Lisina/orina , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Deficiencia Múltiple de Carboxilasa/metabolismo
14.
J Inherit Metab Dis ; 11(3): 270-6, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3148068

RESUMEN

An 8-year-old boy with late onset multiple carboxylase deficiency is described. Biotinidase deficiency and holocarboxylase-synthetase deficiency have been excluded. A very slow biochemical response to biotin was found. The decrease in urinary organic acid excretion followed first-order kinetics with a half-life of about 50 days. The initially low carboxylase activities in thrombocytes were increased but not normalized after 3 months of treatment.


Asunto(s)
Amidohidrolasas/sangre , Biotina/metabolismo , Ligasas de Carbono-Nitrógeno , Ligasas/metabolismo , Deficiencia Múltiple de Carboxilasa/metabolismo , Biotinidasa , Niño , Fibroblastos/enzimología , Glicina/análogos & derivados , Glicina/orina , Humanos , Cinética , Masculino , Valeratos/orina
15.
Arch Dermatol ; 123(12): 1696-1698a, 1987 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-3318710

RESUMEN

The important role of biotin in human physiology has been highlighted by the recognition of two newly discovered human inborn errors of the metabolism of biotin. The molecular defect in the neonatal-onset disease is in the enzyme holocarboxylase synthetase. The defect in the later infantile-onset disease is in the enzyme biotinidase. Both disorders present with impressive clinical manifestations involving the skin and hair. In the neonatal disease, alopecia totalis is associated with a bright red scaly total body eruption. In biotinidase deficiency, the alopecia is more patchy and the skin lesions resemble acrodermatitis enteropathica. Both disorders are complicated by recurrent episodes of life-threatening acidosis and massive ketosis.


Asunto(s)
Biotina/metabolismo , Ligasas de Carbono-Nitrógeno , Errores Innatos del Metabolismo/diagnóstico , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Biotina/uso terapéutico , Biotinidasa , Humanos , Lactante , Recién Nacido , Ligasas/deficiencia , Ligasas/genética , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/metabolismo , Deficiencia Múltiple de Carboxilasa/complicaciones , Deficiencia Múltiple de Carboxilasa/diagnóstico , Deficiencia Múltiple de Carboxilasa/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/etiología , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiología
16.
Am J Clin Nutr ; 44(4): 475-80, 1986 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-3766434

RESUMEN

The effects of biotin deficiency and supplementation upon saturated fatty acids in serum, liver, cerebrum, and cerebellum of rats were investigated. Serum total fatty acids were reduced in deficient animals to 29% of normal. The percentage composition of some odd-chain fatty acids was increased in the serum and liver of deficient rats. The relative composition of most saturated fatty acids with carbon-chain lengths greater than or equal to 22 were increased in serum and liver of deficient rats. In contrast, there were no differences in the brain saturated fatty acids of deficient animals compared to those of normal and supplemented animals. These results may indicate that alterations in saturated fatty acids do not play a major role in the neurologic abnormalities in human biotin or inherited multiple-carboxylase deficiencies.


Asunto(s)
Biotina/deficiencia , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Animales , Biotina/farmacología , Encéfalo/metabolismo , Ácidos Grasos/sangre , Lípidos/sangre , Hígado/metabolismo , Masculino , Deficiencia Múltiple de Carboxilasa/metabolismo , Ratas , Ratas Endogámicas
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