Lipoic acid biosynthesis defects.

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.

• Authors: Johannes A Mayr, René G Feichtinger, Frederic Tort, Antonia Ribes, Wolfgang Sperl
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 37 Issue 4 Pg. 553-63 (Jul 2014) ISSN: 1573-2665 [Electronic] United States
• PMID: 24777537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Carrier Proteins
• Multienzyme Complexes
• glycine cleavage system
• Thioctic Acid
• 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
• Amino Acid Oxidoreductases
• Dihydrolipoamide Dehydrogenase
• Transferases
• Acyltransferases
• lipoyltransferase I
• lipoyltransferase II
• Sulfurtransferases
• lipoic acid synthase

Topics

• 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) (genetics)
• Acyltransferases (genetics)
• Amino Acid Oxidoreductases (genetics)
• Animals
• Carrier Proteins (genetics)
• Dihydrolipoamide Dehydrogenase (genetics)
• Disease Models, Animal
• Humans
• Lipid Metabolism, Inborn Errors (enzymology, genetics)
• Multienzyme Complexes (genetics)
• Sulfurtransferases (genetics)
• Thioctic Acid (biosynthesis, deficiency)
• Transferases (genetics)