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.

Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway

“…Mutations are found in two genes, that encoding lipoyl synthase (LIAS) and that encoding the defective lipoate ligase activity (LIPT1). As first seen in dihydrolipoamide dehydrogenase deficiency, the four known LIAS patients are clinically heterogeneous (144,(150)(151)(152). Two died early in life and two survived, albeit with severe neurological problems.…”

Lipoic acid metabolism and mitochondrial redox regulation

“…This enzyme can utilize both the (R)-and (S)-enantiomers of LA and primarily uses GTP to activate the natural (R)-lipoic acid, but so far there has been no substantial evidence to support that this enzyme functions in LA metabolism in vivo (36). This is consistent with the inability for exogenous LA to rescue defects in cells derived from LIAS deficient patients, embryonic lethality in LIAS deficient mice, or to ameliorate symptoms in patients with this disease (22,30,32). Taken together, this suggests that mammalian LA metabolism is similar to S. cerevisiae where LIPT2 transfers octanoate from ACP to the H-protein of GCS, LIAS inserts sulfur atoms into the octanoyl group on H-protein, and LIPT1 transfers the lipoyl group from the H-protein to E2 subunits.…”

“…Although less well understood in mammalian systems, the LA biosynthetic pathway in mice and humans is carried out by an octanoyltransferase otholog of LipB/Lip2 and a lipoic acid synthase ortholog of LipA/Lip5 known as LIPT2 and LIAS, respectively ( Figure 1C) (30)(31)(32). Deficiencies in either of these enzymes, as well as disruptions in mitochondrial FASII or iron sulfur biogenesis, result in diminished lipoylation of PDH and OGDH and ultimately impaired mitochondrial function (30,33,34).…”

“…Deficiencies in either of these enzymes, as well as disruptions in mitochondrial FASII or iron sulfur biogenesis, result in diminished lipoylation of PDH and OGDH and ultimately impaired mitochondrial function (30,33,34). The lipoyltransferase ortholog in mammals is LIPT1 and similar to Lip3 in S.cerevisiae, it lacks the ability to generate an activated lipoyl-AMP and therefore is thought to be downstream of LIPT2 (9,30,35).…”

“…Deficiencies in either of these enzymes, as well as disruptions in mitochondrial FASII or iron sulfur biogenesis, result in diminished lipoylation of PDH and OGDH and ultimately impaired mitochondrial function (30,33,34). The lipoyltransferase ortholog in mammals is LIPT1 and similar to Lip3 in S.cerevisiae, it lacks the ability to generate an activated lipoyl-AMP and therefore is thought to be downstream of LIPT2 (9,30,35). There has been a report identifying a mammalian lipoic acid-activating enzyme that could activate exogenous lipoic acid (36); however, this function was ultimately attributed to the mitochondrial medium-chain acyl CoA synthetase (ACSM1) (37,38).…”