Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes

Abstract

Three human mitochondrial diseases that directly affect lipoic acid metabolism result from heterozygous missense and nonsense mutations in the LIAS, LIPT1, and LIPT2 genes. However, the functions of the proteins encoded by these genes in lipoic acid metabolism remained uncertain due to a lack of biochemical analysis at the enzyme level. An exception was the LIPT1 protein for which a perplexing property had been reported, a ligase lacking the ability to activate its substrate. This led to several models, some contradictory, to accommodate the role of LIPT1 protein activity in explaining the phenotypes of the afflicted neonatal patients. Recent evidence indicates that this LIPT1 protein activity is a misleading evolutionary artifact and that the physiological role of LIPT1 is in transfer of lipoic acid moieties from one protein to another. This and other new biochemical data now define a straightforward pathway that fully explains each of the human disorders specific to the assembly of lipoic acid on its cognate enzyme proteins.

Keywords: LIAS; LIPT1; LIPT2; glycine cleavage system; lipoate assembly; lipoic acid; pyruvate dehydrogenase; α-ketoglutarate dehydrogenase.

FIGURE 1

The human pathway of assembly of lipoyl moieties on its cognate proteins. LIPT2 utilizes octanoyl-ACP synthesized by the mitochondrial fatty acid synthesis system to modify GCSH. The reaction proceeds via a LIPT2 acyl enzyme intermediate as shown. The octanoyl-GCSH is then converted to lipoyl-GCSH by LIAS catalyzed sulfur insertion. LIPT1 then transfers the lipoyl moiety from GCSH to form an acyl enzyme intermediate. This in turn is attacked by a specific lysine reside of the lipoyl domain (LD) of the N-termini of the E2 subunits of the dehydrogenases or GCSH to give the active modified enzymes.