Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.1.12 (biotinidase)
 392 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biotinidase is the enzyme responsible for the recycling of the vitamin biotin. Biotinidase acts as a hydrolase by cleaving biocytin and biotinyl-peptides, thereby liberating biotin for reutilization. Biotinidase is also important for making biotin bioavailable from bound dietary sources. The interest in this enzyme has been increased by the discovery of biotinidase deficiency, an inherited biotin-responsive disorder that can result in neurological and cutaneous abnormalities, but can be treated effectively with biotin supplementation. Biotinidase has recently been shown to be biotinylated in the presence of biocytin, but not biotin, at neutral and alkaline pH. This raises the possibility that biotinidase acts as a biotin-binding or biotin-carrier protein. Biotinidase has also been shown to have biotinyl-transferase activity resulting in the transfer of biotin from biocytin to nucleophilic acceptors, such as histones. Transferase activity occurs at physiological pH and at physiological concentrations of biocytin and, therefore, may be the main function of the enzyme in serum and other tissues. These novel functions of the enzyme may indicate that biotinidase plays a critical role in the metabolism of biotin in nuclei, particularly of neuronal cells. The role of biotinidase in biotin metabolism may be a paradigm for better understanding the metabolism of other vitamins.
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PMID:Biotinidase and its roles in biotin metabolism. 893 Apr 9

Twenty-four-hour urine specimens from 21 juvenile insulin-dependent diabetics and 10 healthy controls were compared with respect to biotinidase activity and alanine content. Urinary biotinidase activity was analysed by a newly developed high-performance liquid chromatography (HPLC) method. It was found that the excretion of biotinidase in urine was elevated in diabetics (7.02 mU/d; p < 0.005) as compared with controls (not detectable). Alanine excretion was also found to increase (p < 0.01) in diabetics. Biotinidase excretion in diabetics was correlated with alanine excretion (rS = 0.667; p < 0.01), but not with protein, albumin or N-acetyl-beta-glucosaminidase excretion. The simultaneous elevation of urinary biotinidase and alanine excretion in juvenile diabetics suggests that changes in kidney metabolism arise in the early stages of diabetes.
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PMID:Urinary biotinidase and alanine excretion in patients with insulin-dependent diabetes mellitus. 915 61

Biotinidase recycles the vitamin biotin from biocytin upon the degradation of the biotin-dependent carboxylases. We have identified a novel point mutation within the biotinidase gene that encodes the signal peptide in two unrelated individuals with profound biotinidase deficiency. Sequence analysis of genomic DNA from these individuals revealed a G to A transition (G100-->A) located 57 bases downstream of the authentic splice acceptor site in exon B. Although this mutation predicts a G34S substitution, it also generates a 3' splice acceptor site. Sequence of the PCR-amplified cDNA from the homozygous child revealed that all the product was shorter than that of normal individuals and was the result of aberrant splicing. The aberrantly spliced transcript lacked 57 bases, including a second in-frame ATG, that encode most of the putative signal peptide and results in an in-frame deletion of 19 amino acids. The mutation results in failure to secrete the aberrant protein into the blood. This is the first reported example in which a point mutation creates a cryptic 3' splice acceptor site motif that is used preferentially over the upstream authentic splice site. The preferential usage of the downstream splice site is not consistent with the 5'-3' scanning model, but is consistent with the exon definition model of RNA splicing.
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PMID:Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3' splice acceptor site within an exon of the human biotinidase gene. 915 48

Biotinidase deficiency is characterized by neurological and cutaneous abnormalities that can be prevented or ameliorated by oral biotin therapy. A child with biotinidase deficiency went undiagnosed for a long period and has irreversible neurological deficits despite biotin treatment. This child is homozygous for the most common mutation (G98:d7i3) found in symptomatic children with the disorder. The parents insisted on having prenatal diagnosis in a subsequent pregnancy to alleviate their anxiety about having another affected child. Mutation analysis of DNA obtained directly from amniotic fluid and from cultured amniocytes revealed that the fetus was heterozygous for the mutation. Maternal cell contamination of the amniocytes was excluded by genotype analysis. Biotinidase activity in extracts of cultured amniocytes revealed 40 per cent of mean normal activity. At birth, the infant was confirmed to be heterozygous by serum enzyme analysis. This is the first report of the use of molecular analysis for the prenatal diagnosis for biotinidase deficiency.
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PMID:Prenatal diagnosis of heterozygosity for biotinidase deficiency by enzymatic and molecular analyses. 951 11

Biotinidase cleaves biotin from biocytin, thereby recycling the vitamin. We have determined the structure of the human biotinidase gene. A genomic clone, containing three exons that code for the mature enzyme, was obtained by screening a human genomic bacteriophage library with the biotinidase cDNA by plaque hybridization. To obtain a clone containing the most 5' exon of the biotinidase cDNA, a human PAC library by PCR was screened. The human biotinidase gene is organized into four exons and spans at least 23 kb. The 5'-flanking region of exon 1 contains a CCAAT element, three initiator sequences, an octamer sequence, three methylation consensus sites, two GC boxes, and one HNF-5 site, but has no TATA element. The region from nt -600 to +400 has features of a CpG island and resembles a housekeeping gene promoter. The structure and sequence of this gene are useful for identifying and characterizing mutations that cause biotinidase deficiency.
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PMID:Structure of the human biotinidase gene. 953 Jun 34

Biotinidase deficiency is an autosomal recessive disorder of biotin recycling. Biotinidase cleaves the biotin from biocytin or short biotinyl-peptides to replenish the free biotin pool, or it can transfer the vitamin to specific proteins. The cDNA for human serum biotinidase has two in-frame start codons, potentially allowing for the synthesis of an enzyme with a signal peptide (SP) consisting of either 21 or 41 amino acids. In order to examine the requirements of the signal peptide region for the production and secretion of biotinidase, three different forms of the normal human serum biotinidase gene were constructed that encode either the 21-amino-acid SP (SP21-NL) or the 41-amino-acid SP (SP41-NL) or without a SP (NoSP-NL). These constructs were expressed in insect cells via a baculovirus expression system. Biotinidase from cells with SP41-NL and SP21-NL had immunoreactive and biotinyl-hydrolase-active enzyme in lysates and expression media. Cells with NoSP-NL had about 3% of the immunoreactive material and no enzyme activity in lysates and no immunoreactive protein or enzymatic activity in the expression medium. Lack of biotinidase from cells with NoSP-NL may be due to translation inefficiency or increased susceptibility of this species to protease degradation than the secreted forms. We have demonstrated that the 21-amino-acid signal peptide is sufficient to result in glycosylated, secreted biotinidase, but we cannot determine if the glycosylated biotinidase in the lysates or secreted in the medium of cells with SP41-NL use the first, second, or both ATGs in the SP region. Because this particular expression system has no mechanism for timing the movement of newly translated biotinidase protein, we cannot draw conclusions about the relative efficiency of SP41-NL versus SP21-NL, but it is possible that either is used in vivo depending on particular cellular conditions.
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PMID:Examination of the signal peptide region of human biotinidase using a baculovirus expression system. 1065 58

A miniaturized quantitative biotinidase assay has been developed using biotin 6-amidoquinoline as substrate and the 100-fold enhanced fluorescence of 6-amidoquinoline measured using apolar solvents. Amidoquinoline is measured after deproteinization by ethanol/acetone using individual standardisation and solvent resistant microtiter plates. The assay was optimized for end point determinations of biotinidase activities in serum and for newborn screening using dried blood spots. Serum activities obtained are closely correlated with values obtained using a quantitative validation method (r=0.96). Analytical sensitivity is around 2% of the mean activity (7.01+/-1.92 nmol/min/ml, mean+/-SD) of a healthy control population. With dried blood spots, a close correlation with values obtained using the Wallac-test kit (r=0.92) was found. Biotinidase activities of a healthy population of 651 newborns amount to 0.2429+/-0.07 nmol/min/ml blood. The analytical sensitivity is close to 1% of the mean activity.
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PMID:Biotinidase determination in serum and dried blood spots--high sensitivity fluorimetric ultramicro-assay. 1171 93

Biotinidase deficiency is an autosomal recessive genetic disorder which is not uncommon in the Saudi population. Biotinidase is responsible for biotin recycling and biotin is an essential cofactor for activation of the carboxylase enzymes. Absence of biotinidase leads to infantile or early childhood encephalopathy, seizure disorder, dermatitis, alopecia, neural deafness and optic atrophy. The disease can be diagnosed by simple fluorometric enzyme assay. Treatment with biotin is both cheap and simple, resulting in rewarding clinical recovery and normalization of the biochemical, neuroradiological and neurophysiological parameters. If neglected, however, a patient may die of acute metabolic acidosis or may suffer from permanent neural deafness and optic atrophy, with mental and motor handicap. We describe the detection and treatment of 20 cases of biotinidase deficiency in our hospital and recommend the introduction of a neonatal screening programme for this disorder.
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PMID:Biotinidase deficiency: a treatable genetic disorder in the Saudi population. 1192 14

We describe a 3-year-old boy with biotin dependency not caused by biotinidase, holocarboxylase synthetase, or nutritional biotin deficiency. We sought to define the mechanism of his biotin dependency. The child became acutely encephalopathic at age 18 months. Urinary organic acids indicated deficiency of several biotin-dependent carboxylases. Symptoms improved rapidly following biotin supplementation. Serum biotinidase activity and Biotinidase gene sequence were normal. Activities of biotin-dependent carboxylases in PBMCs and cultured skin fibroblasts were normal, excluding biotin holocarboxylase synthetase deficiency. Despite extracellular biotin sufficiency, biotin withdrawal caused recurrent abnormal organic aciduria, indicating intracellular biotin deficiency. Biotin uptake rates into fresh PBMCs from the child and into his PBMCs transformed with Epstein Barr virus were about 10% of normal fresh and transformed control cells, respectively. For fresh and transformed PBMCs from his parents, biotin uptake rates were consistent with heterozygosity for an autosomal recessive genetic defect. Increased biotin breakdown was ruled out, as were artifacts of biotin supplementation and generalized defects in membrane permeability for biotin. These results provide evidence for a novel genetic defect in biotin transport. This child is the first known with this defect, which should now be included in the identified causes of biotin dependency.
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PMID:Biotin dependency due to a defect in biotin transport. 1207 Mar 9

Biotinidase is essential for recycling the vitamin biotin and for transferring biotin to proteins, such as histones, suggesting that the enzyme localizes to various cellular and extracellular sites. To better understand the functions of the enzyme, we examined its gene structure and subcellular localization. Using RACE-PCR and a BLAST search, we extended the 5' sequence of the biotinidase gene. Three novel, alternatively spliced variants of biotinidase, 1a, 1b, and 1c, were identified in multiple human tissues. Exon 1c is present only in testes. The sequence of the 5' splice variants, 1a and 1b, suggest that biotinidase localizes to the mitochondria and/or ER, respectively. Using indirect immunofluorescence studies, biotinidase localizes to organelles in the cytoplasm, but not nucleus, of human fibroblasts and Hep G2 cells. Endogenous expression was examined by isopycnic gradient centrifugation of rat liver organelles, which identified an 85kDa biotinidase protein with biotinyl-hydrolase and transferase activities in microsomes and possibly lysosomes. A 48kDa protein, which also reacts with anti-biotinidase, localizes to mitochondria. The 48kDa protein is not N-glycosylated but is biotinylated, is in the inner mitochondrial matrix, but has no biotinyl-hydrolase or transferase activities. The function and validation of the mitochondrial species remains to be determined. The 5' splice variants and organelle fractionation studies indicate that biotinidase is directed to the secretory pathway and perhaps mitochondria.
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PMID:Identification of alternatively spliced human biotinidase mRNAs and putative localization of endogenous biotinidase. 1505 18


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