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Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency.
J Clin Invest. 1981 Dec; 68(6):1491-5.JCI

Abstract

Biotin-responsive multiple carboxylase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme A (CoA), 3-methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthetase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. Fibroblasts from the initial patient with the infantile form of biotin-responsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40% of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

6798072

Citation

Burri, B J., et al. "Mutant Holocarboxylase Synthetase: Evidence for the Enzyme Defect in Early Infantile Biotin-responsive Multiple Carboxylase Deficiency." The Journal of Clinical Investigation, vol. 68, no. 6, 1981, pp. 1491-5.
Burri BJ, Sweetman L, Nyhan WL. Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency. J Clin Invest. 1981;68(6):1491-5.
Burri, B. J., Sweetman, L., & Nyhan, W. L. (1981). Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency. The Journal of Clinical Investigation, 68(6), 1491-5.
Burri BJ, Sweetman L, Nyhan WL. Mutant Holocarboxylase Synthetase: Evidence for the Enzyme Defect in Early Infantile Biotin-responsive Multiple Carboxylase Deficiency. J Clin Invest. 1981;68(6):1491-5. PubMed PMID: 6798072.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency. AU - Burri,B J, AU - Sweetman,L, AU - Nyhan,W L, PY - 1981/12/1/pubmed PY - 1981/12/1/medline PY - 1981/12/1/entrez SP - 1491 EP - 5 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 68 IS - 6 N2 - Biotin-responsive multiple carboxylase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme A (CoA), 3-methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthetase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. Fibroblasts from the initial patient with the infantile form of biotin-responsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40% of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/6798072/Mutant_holocarboxylase_synthetase:_evidence_for_the_enzyme_defect_in_early_infantile_biotin_responsive_multiple_carboxylase_deficiency_ L2 - https://doi.org/10.1172/jci110402 DB - PRIME DP - Unbound Medicine ER -