PMC:3905285 / 2374-5365 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3905285","sourcedb":"PMC","sourceid":"3905285","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3905285","text":"Background\nPyruvate dehydrogenase complex (PDHc) deficiency most often occurs as an isolated enzyme defect caused by mutations in X-linked PDHA1 [MIM 300502] and associates with a spectrum of clinical presentations ranging from fatal infantile lactic acidosis to mild psychomotor retardation and/or Leigh disease [1]. A smaller number of PDHc deficient individuals have mutations in PDHB, PDHX, dihydrolipoyl transacetylase (DLAT), dihydrolipoyl dehydrogenase (DLD), or PDP1, which is responsible for the reactivation of phosphorylated PDHc [1]. Lipoic acid is a sulphur-containing cofactor covalently attached to the PDHc E2 subunit (DLAT) and is functionally required. A defect of lipoic acid metabolism is expected to affect PDHc as well as the other key enzymatic complexes that have similar structure and are lipoic acid dependent, notably α-ketoglutarate dehydrogenase (α-KGDH), branched chain keto acid dehydrogenase (BCKDH) and the glycine cleavage system [2,3].\nTwo pathways lead to attachment of lipoic acid to apoenzymes in bacteria. In the endogenous or de novo pathway, biosynthesis of lipoic acid follows mitochondrial fatty acid synthesis (FASII) and iron sulphur cluster biosynthesis. The first lipoic acid specific enzyme of this pathway is a lipoyl(octanoyl)transferase which catalyzes the attachment of octanoate to specific lysyl residues in lipoate-dependent enzymes (bacterial LipB and likely LIPT2 in humans). The second enzyme involved is lipoic acid synthase (LipA in bacteria and LIAS in humans), which catalyzes the conversion of the octanoyl side chain to an active lipoyl. The enzyme is an iron sulphur protein with two [4Fe-4S] clusters [4]. The [4Fe-4S] cluster is a cofactor of LIAS as well as of many proteins involved in intermediary metabolism and oxidative phosphorylation, where it participates in electron transfer reactions and in the functions of complexes I, II and III [5]. Assembly of the [4Fe-4S] cluster involves a complex metabolic pathway that includes NFU1 (NFU Iron-Sulfur cluster scaffold homolog), ISCU (Iron-Sulfur cluster scaffold homolog) and BOLA3 [3] (bolA homolog 3).\nThe exogenous or salvage pathway involves attachment of free lipoic acid to the specific lysine residues of the target proteins. It is still unclear to which degree the lipoic acid salvage pathway (LplA in bacteria) is conserved in humans, as the LplA orthologous gene, LIPT1, encodes a lipoyl transferase that uses free AMP-activated lipoic acid as a substrate, yet in yeasts, the LIPT1 orthologue lip3 may act downstream, rather than independently of the de novo pathway [6,7] (see Discussion). LIPT1 is organized into four exons in humans, only one of which is coding, and maps to chromosome 2q11.2.\nAs yet, mutations have been described in genes involved in the de novo pathway, i.e., NFU1, BOLA3, LIAS and IBA57[2,3,8-11]. Here we describe a new lipoate-related disease that involves impaired lipoate attachment on PDHc and α-KGDH and is due to LIPT1 mutations.","divisions":[{"label":"Title","span":{"begin":0,"end":10}}],"tracks":[{"project":"2_test","denotations":[{"id":"24341803-21914562-81583034","span":{"begin":314,"end":315},"obj":"21914562"},{"id":"24341803-21914562-81583035","span":{"begin":542,"end":543},"obj":"21914562"},{"id":"24341803-22077971-81583036","span":{"begin":965,"end":966},"obj":"22077971"},{"id":"24341803-21944046-81583037","span":{"begin":967,"end":968},"obj":"21944046"},{"id":"24341803-20226757-81583038","span":{"begin":1668,"end":1669},"obj":"20226757"},{"id":"24341803-18606475-81583039","span":{"begin":1912,"end":1913},"obj":"18606475"},{"id":"24341803-21944046-81583040","span":{"begin":2104,"end":2105},"obj":"21944046"},{"id":"24341803-10103005-81583041","span":{"begin":2599,"end":2600},"obj":"10103005"},{"id":"24341803-8206978-81583042","span":{"begin":2601,"end":2602},"obj":"8206978"},{"id":"24341803-22077971-81583043","span":{"begin":2842,"end":2843},"obj":"22077971"},{"id":"24341803-21944046-81583044","span":{"begin":2844,"end":2845},"obj":"21944046"},{"id":"24341803-11156534-81583045","span":{"begin":2846,"end":2847},"obj":"11156534"},{"id":"24341803-23462291-81583045","span":{"begin":2846,"end":2847},"obj":"23462291"},{"id":"24341803-22562699-81583045","span":{"begin":2846,"end":2847},"obj":"22562699"},{"id":"24341803-22152680-81583045","span":{"begin":2846,"end":2847},"obj":"22152680"},{"id":"T35277","span":{"begin":314,"end":315},"obj":"21914562"},{"id":"T34238","span":{"begin":542,"end":543},"obj":"21914562"},{"id":"T51880","span":{"begin":965,"end":966},"obj":"22077971"},{"id":"T34486","span":{"begin":967,"end":968},"obj":"21944046"},{"id":"T61937","span":{"begin":1668,"end":1669},"obj":"20226757"},{"id":"T59526","span":{"begin":1912,"end":1913},"obj":"18606475"},{"id":"T18006","span":{"begin":2104,"end":2105},"obj":"21944046"},{"id":"T80047","span":{"begin":2599,"end":2600},"obj":"10103005"},{"id":"T75634","span":{"begin":2601,"end":2602},"obj":"8206978"},{"id":"T85809","span":{"begin":2842,"end":2843},"obj":"22077971"},{"id":"T25490","span":{"begin":2844,"end":2845},"obj":"21944046"},{"id":"T97381","span":{"begin":2846,"end":2847},"obj":"11156534"},{"id":"T70146","span":{"begin":2846,"end":2847},"obj":"23462291"},{"id":"T84776","span":{"begin":2846,"end":2847},"obj":"22562699"},{"id":"T48767","span":{"begin":2846,"end":2847},"obj":"22152680"}],"attributes":[{"subj":"24341803-21914562-81583034","pred":"source","obj":"2_test"},{"subj":"24341803-21914562-81583035","pred":"source","obj":"2_test"},{"subj":"24341803-22077971-81583036","pred":"source","obj":"2_test"},{"subj":"24341803-21944046-81583037","pred":"source","obj":"2_test"},{"subj":"24341803-20226757-81583038","pred":"source","obj":"2_test"},{"subj":"24341803-18606475-81583039","pred":"source","obj":"2_test"},{"subj":"24341803-21944046-81583040","pred":"source","obj":"2_test"},{"subj":"24341803-10103005-81583041","pred":"source","obj":"2_test"},{"subj":"24341803-8206978-81583042","pred":"source","obj":"2_test"},{"subj":"24341803-22077971-81583043","pred":"source","obj":"2_test"},{"subj":"24341803-21944046-81583044","pred":"source","obj":"2_test"},{"subj":"24341803-11156534-81583045","pred":"source","obj":"2_test"},{"subj":"24341803-23462291-81583045","pred":"source","obj":"2_test"},{"subj":"24341803-22562699-81583045","pred":"source","obj":"2_test"},{"subj":"24341803-22152680-81583045","pred":"source","obj":"2_test"},{"subj":"T35277","pred":"source","obj":"2_test"},{"subj":"T34238","pred":"source","obj":"2_test"},{"subj":"T51880","pred":"source","obj":"2_test"},{"subj":"T34486","pred":"source","obj":"2_test"},{"subj":"T61937","pred":"source","obj":"2_test"},{"subj":"T59526","pred":"source","obj":"2_test"},{"subj":"T18006","pred":"source","obj":"2_test"},{"subj":"T80047","pred":"source","obj":"2_test"},{"subj":"T75634","pred":"source","obj":"2_test"},{"subj":"T85809","pred":"source","obj":"2_test"},{"subj":"T25490","pred":"source","obj":"2_test"},{"subj":"T97381","pred":"source","obj":"2_test"},{"subj":"T70146","pred":"source","obj":"2_test"},{"subj":"T84776","pred":"source","obj":"2_test"},{"subj":"T48767","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#daec93","default":true}]}]}}