ArticleJournal of molecular medicine (Berlin, Germany)2012
A novel molecular mechanism to explain biotin-unresponsive holocarboxylase synthetase deficiency.
Article in Journal of molecular medicine (Berlin, Germany), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 33 citations in OpenAlex.
- Holocarboxylase synthetase deficiency: pathogenesis, clinical features, diagnosis, treatment, and research prospects.European journal of pediatrics · 2026Review
- Hydrogen-Deuterium Exchange Defines Ligand-Induced Conformational Changes to the Class III Biotin Protein Ligase from Saccharomyces cerevisiae.Chembiochem : a European journal of chemical biology · 2025Article
- Clinical diagnosis, treatment, and genetic analysis of adolescent onset holocarboxylase synthetase deficiency and cobalamin C deficiency: A case report and literature review.Metabolism open · 2025Article
- Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis.Molecular genetics and metabolism reports · 2024Article
- Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review.Frontiers in genetics · 2024Article
- Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2022Article
- The Biotin Biosynthetic Pathway in Mycobacterium tuberculosis is a Validated Target for the Development of Antibacterial Agents.Current medicinal chemistry · 2020Review
- Inborn errors of metabolism.Handbook of clinical neurology · 2019Review
- Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency.JIMD reports · 2017Article
- Biotin Protein Ligase Is a Target for New Antibacterials.Antibiotics (Basel, Switzerland) · 2016Review
- Mechanisms of biotin-regulated gene expression in microbes.Synthetic and systems biotechnology · 2016Review
- Article
- Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation.JIMD reports · 2014Article
- Structural characterization of Staphylococcus aureus biotin protein ligase and interaction partners: an antibiotic target.Protein science : a publication of the Protein Society · 2013Article
- The influence of micronutrients in cell culture: a reflection on viability and genomic stability.BioMed research international · 2013Review
- Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase.ACS medicinal chemistry letters · 2012Article
- Selective inhibition of biotin protein ligase from Staphylococcus aureus.The Journal of biological chemistry · 2012Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Biotin (vitamins H and B7) is an important micronutrient as defects in its availability, metabolism or adsorption can cause serious illnesses, especially in the young. A key molecule in the biotin cycle is holocarboxylase synthetase (HLCS), which attaches biotin onto the biotin-dependent enzymes. Patients with congenital HLCS deficiency are prescribed oral biotin supplements that, in most cases, reverse the clinical symptoms. However, some patients respond poorly to biotin therapy and have an extremely poor long-term prognosis. Whilst a small number of mutations in the HLCS gene have been implicated, the molecular mechanisms that lead to the biotin-unresponsive phenotype are not understood. To improve our understanding of HLCS, limited proteolysis was performed together with yeast two-hybrid analysis. A structured domain within the N-terminal region that contained two missense mutations was identified in patients who were refractory to biotin therapy, namely p.L216R and p.L237P. Genetic studies demonstrated that the interaction between the enzyme and the protein substrate was disrupted by mutation. Further dissection of the binding mechanism using surface plasmon resonance demonstrated that the mutations reduced affinity for the substrate through a >15-fold increase in dissociation rate. Together, these data provide the first molecular explanation for HLCS-deficient patients that do not respond to biotin therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.