Abstract:
:Holocarboxylase synthetase (HCS) catalyses the biotinylation of the four biotin-dependent carboxylases found in humans. A deficiency in HCS results in biotin-responsive multiple carboxylase deficiency. We have evaluated the biotin responsiveness associated with six missense mutations previously identified in affected patients by expression of plasmids containing the mutated HCS in an Escherichia coli strain mutated in the corresponding BirA gene. We demonstrate that the mutations identified in the MCD patients are indeed responsible for their reduced HCS activity. Four of the mutations, clustering in the putative biotin binding domain as deduced from the structure of the E. coli enzyme, are consistent with an explanation for biotin responsiveness based on altered affinity for biotin. The remaining mutations, located outside the biotin binding region, were associated with a more limited biotin responsiveness that may be explained by the degree of residual enzyme activity present. The data suggest that the concentration of circulating biotin is as low as 100 times below the Km of the enzyme, so that any increase in biotin concentration through dietary supplementation would result in saturation of the available mutant enzyme. We suggest that these alternative explanations are sufficient to account for the apparent universality of biotin responsiveness in biotin responsive multiple carboxylase deficiency.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Dupuis L,Campeau E,Leclerc D,Gravel RAdoi
10.1006/mgme.1998.2785subject
Has Abstractpub_date
1999-02-01 00:00:00pages
80-90issue
2eissn
1096-7192issn
1096-7206pii
S1096-7192(98)92785-8journal_volume
66pub_type
杂志文章abstract:OBJECTIVE:To assess whether or not pyrimethamine (PMT) can be used to enhance β-hexosaminidase A activity (HexA) in subjects with Late Onset Tay Sachs (LOTS), we studied the effect of incremental doses of PMT in vivo in 9 LOTS patients carrying the αG269S/c.1278insTACT mutations. METHODS:PMT treatment was initiated at...
journal_title:Molecular genetics and metabolism
pub_type: 临床试验,杂志文章
doi:10.1016/j.ymgme.2010.11.163
更新日期:2011-03-01 00:00:00
abstract::Mechanisms producing the divergent phenotypes, Wolman disease (WD) and cholesterol ester storage disease (CESD), associated with the genetic deficiency of human lysosomal acid lipase/cholesterol ester hydrolase (hLAL) function were investigated with the determination of HLAL activity levels, mRNA and protein expressio...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
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doi:10.1006/mgme.2000.3130
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.10.002
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2009.09.003
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pub_type: 杂志文章
doi:10.1006/mgme.1999.2872
更新日期:1999-08-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
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更新日期:2005-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.05.013
更新日期:2012-08-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2021.01.005
更新日期:2021-01-14 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2935
更新日期:1999-12-01 00:00:00
abstract::Classic phenylketonuria (PKU) is characterized by severe mental retardation in untreated individuals and mild neurocognitive abnormalities in some early treated adults. The exact biochemical mechanisms underlying this neurotoxicity remain undetermined. Several theories implicate abnormal cerebral energy utilization an...
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2005.06.010
更新日期:2006-03-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2007.10.002
更新日期:2008-03-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2017.03.007
更新日期:2017-05-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.05.004
更新日期:2004-08-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章,评审
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更新日期:2007-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s1096-7192(02)00026-4
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pub_type: 杂志文章
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更新日期:2012-02-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.02.002
更新日期:2012-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.ymgme.2017.12.428
更新日期:2018-02-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2000.3005
更新日期:2000-07-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2007.03.009
更新日期:2007-08-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.04.003
更新日期:2016-06-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.11.197
更新日期:2012-03-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1998.2795
更新日期:1999-03-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.03.006
更新日期:2011-07-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2950
更新日期:2000-01-01 00:00:00