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Deficiency of the pyruvate dehydrogenase complex
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The pyruvate dehydrogenase complex (PDHC) is a mitochondrial multienzyme system that catalyzes the oxidation of pyruvate to CO2 and acetylCoA and concomitantly generates reduced nicotinamideadenine-dinucleotide (NADH) (Figure 50.1) [1]. Cofactors include thiaminepyrophosphate (TPP), lipoic acid, coenzyme A (CoA), flavineadeninedinucleotide (FAD), and nicotinamideadeninedinucleotide (NAD1); Mg is required. There are eight different protein components, in seven of which human deficiency disease has been documented. The three basic components E1 (pyruvate dehydrogenase, PDH) E2 (dihydrolipoamide acetyltransferase) and E3 (dihydrolipoamide dehydrogenase) are functional catalytic proteins, of types that are shared by all oxoacid dehydrogenases. There are two regulatory components, E1kinase and phospho-E1-phosphatase with thiamine pyrophosphate (TPP) as a cofactor.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
PDHC is a multi-subunit enzyme complex, governing the conversion of pyruvate into acetyl CoA. Its four main subunits are E1 – the decarboxylase that is a heterodimer of an α (PDHA1) and β (PDHB) subunit; E2 – the dihydrolipoamide acetyltransferase (DLAT); E3 – dihydroliopamide dehydrogenase(DLD), which is also a component of branched chain α-ketoacid dehydrogenase complex; and E3BP – the E3 binding protein. PDHC uses thiamine as a cofactor. Only the E1 α subunit is encoded on the X chromosome, but defects are typically the result of new mutations.
Tubulointerstitial nephritis and Fanconi syndrome in a patient with primary Sjögren’s syndrome accompanied by antimitochondrial antibodies: A case report and review of the literature
Published in Modern Rheumatology, 2018
Takako Saeki, Akihiro Nakajima, Tomoyuki Ito, Takuma Takata, Naofumi Imai, Kazuhiro Yoshita, Hideyuki Kabasawa, Hajime Yamazaki, Ichiei Narita
The pathogenesis of TIN and Fanconi syndrome in patients with AMA is uncertain. In PBC, most AMA have been shown to react against the dihydrolipoamide acetyltransferase component (E2 subunit) of pyruvate dehydrogenase (PDC-E2), which is normally found in the inner mitochondrial membrane of all cells, and PDC-E2-autoreactive T cells are present in the liver at high frequency [6]. Recent experimental data have suggested that the breaking of tolerance to PDCE2 by some environmental xenobiotics is a pivotal event in the initial etiology of PBC. Chemical modification of the PDCE2 epitope may render it susceptible to becoming a neoantigen and triggering an immune response in genetically susceptible hosts [6]. Lino et al. have reported that such abnormal antigen expression may occur in renal tubular cells and lead to infiltration of the renal interstitium by autoreactive T cells [11]. Indeed, inflammatory cells around areas of tubulitis were mainly T cells in the present case. It would be interesting to determine whether these T cells include PDC-E2-autoreactive T cells. On the other hand, proximal tubular cells have a high metabolic rate and are rich in mitochondria. Therefore the most frequent renal tubular feature in patients with mitochondrial cytopathies is a defect of the proximal tubules [23]. Because serum from one patient with TIN and Fanconi syndrome positive for AMA exerted an inhibitory effect on the main targets of AMA, Lino et al. also suggested that AMA may in some instances interfere with the intrarenal mitochondrial machinery [11]. Accumulation of similar cases and further investigations will be necessary to clarify the pathogenesis of TIN and Fanconi syndrome in patients with AMA.
The role of sialic acid-binding immunoglobulin-like-lectin-1 (siglec-1) in immunology and infectious disease
Published in International Reviews of Immunology, 2023
Shane Prenzler, Santosh Rudrawar, Mario Waespy, Sørge Kelm, Shailendra Anoopkumar-Dukie, Thomas Haselhorst
Released IFN-α is able to bind IFN-α receptors on macrophages in an autocrine manner inducing upregulation of Siglec-1 (Figure 4) [20]. Due to small numbers of CHB cases that have been appropriately documented, especially with regard to maternal data, further research is needed in this area [20]. However, there is no doubt that upregulation of Siglec-1 is a considerable hallmark of autoimmune diseases given its tendency to correlate with other biomarkers. Primary biliary cirrhosis (PBC) patients show the formation of anti-mitochondrial antibodies that react to dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex-E2 [21]. Lymphocyte infiltration occurs in the periportal area which causes significant inflammation characterized by the destruction of interlobular bile ducts, necrosis of the hepatocytes at the portal area, bile obstruction, liver fibrosis and eventual liver cirrhosis [21, 42]. Patients with PBC show a larger portion of monocytes in blood that highly expressed Siglec-1 that indicates differentiation into macrophages, which have a prominent role in PBC [21]. Unequivocally, the upregulation of Siglec-1 in PBC patients displayed the highest expression compared to healthy individuals and post hepatitis cirrhosis patients [21]. Besides macrophages, other immune cells have been shown to congregate at the periportal area including CD8+ T-cells, CD4+ T-cells, regulatory T-cells, NK cells and some B-cells [21]. The precise role Siglec-1 plays in PBC is yet to be fully determined however, interaction with sialic acids present on bile duct epithelial cells as well as surrounding mononuclear cells is likely resulting in cell-to-cell signaling [21] and subsequently, into activation of surrounding mononuclear cells and release of pro-inflammatory cytokines including IL-8, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein -1α/β (MIP-1α/β) [21]. The release of these cytokines would enable further infiltration of lymphocytes into the periportal area allowing them to participate in and progress the early stages of PBC [21]. Weak correlation of Siglec-1 expression on blood monocytes was shown with gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP), which are common biomarkers that reflect degree of obstruction and inflammation in the liver [21]. This could imply that Siglec-1 might also be able to be used as a biomarker in PBC for when it is necessary to show the inflammatory response in a patient [21].