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Lipoic acid biosynthesis defects

  • ICIEM Symposium 2013
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Lipoate is a covalently bound cofactor essential for five redox reactions in humans: in four 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). Two enzymes are from the energy metabolism, α-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the GCS. All these enzymes consist of multiple subunits and share a similar architecture. Lipoate synthesis in mitochondria involves mitochondrial fatty acid synthesis up to octanoyl-acyl-carrier protein; and three lipoate-specific steps, including octanoic acid transfer to glycine cleavage H protein by lipoyl(octanoyl) transferase 2 (putative) (LIPT2), lipoate synthesis by lipoic acid synthetase (LIAS), and lipoate transfer by lipoyltransferase 1 (LIPT1), which is necessary to lipoylate the E2 subunits of the 2-oxoacid dehydrogenases. The reduced form dihydrolipoate is reactivated by dihydrolipoyl dehydrogenase (DLD). Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy. LIPT1 deficiency spares the GCS, and resulted in a combined 2-oxoacid dehydrogenase deficiency and early death in one patient and in a less severely affected individual with a Leigh-like phenotype. As LIAS is an iron–sulphur-cluster-dependent enzyme, a number of recently identified defects in mitochondrial iron–sulphur cluster synthesis, including NFU1, BOLA3, IBA57, GLRX5 presented with deficiency of LIAS and a LIAS-like phenotype. As in DLD deficiency, a broader clinical spectrum can be anticipated for lipoate synthesis defects depending on which of the affected enzymes is most rate limiting.

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Acknowledgments

Supported by the E-Rare project GENOMIT FWF I 920-B13, the Vereinigung zur Förderung Pädiatrischer Forschung und Fortbildung Salzburg, and the grant of the Fondo de Investigación Sanitaria (FIS) PI12/01138.

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This article does not contain any studies on human subjects or on animals performed by any of the authors.

The first author designed the article; all authors contributed essentially to the final version.

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Authors and Affiliations

  1. Department of Paediatrics, Paracelsus Medical University Salzburg, Salzburg, 5020, Austria

    Johannes A. Mayr, René G. Feichtinger & Wolfgang Sperl

  2. Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS, CIBERER, C/Mejía Lequerica s/n, Barcelona, 08028, Spain

    Frederic Tort & Antonia Ribes

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  1. Johannes A. Mayr
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Correspondence to Johannes A. Mayr.

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Communicated by: Garry Brown

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Mayr, J.A., Feichtinger, R.G., Tort, F. et al. Lipoic acid biosynthesis defects. J Inherit Metab Dis 37, 553–563 (2014). https://doi.org/10.1007/s10545-014-9705-8

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