Deficiency of the pyruvate dehydrogenase complex
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
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.
Immunopathogenesis of Vanishing Bile Duct Syndromes
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
AMAs (primarily comprised of IgM with substantial quantities of IgA, IgGl and IgG3 isotypes) are present in the sera of >95% of patients with PBC and react with antigens of the 2-oxoacid dehydrogenase complex located in the matrix associated with the inner mitochondrial membrane.59,63 Autoantigens include the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2), branched chain 2-oxoacid dehydrogenase complex (BCOADC-E2), 2-oxoglutarate dehydrogenase complex (OGDC-E2), dihydrolipoamide dehydrogenase binding protein (E3BP) and the E1α subunit of PDC. AMAs reactive with PDC-E2, OGDC-E2 and BCOADC-E2 recognize conformational epitopes with aa motifs of ETDKA, ETDK(T) and (GlnS)DKA with lipoic acid covalendy bound to the ε group of lysine (K). However, lipoic acid is not required for antigenicity, and PDC-E1α lacks a lipoyl domain. AMAs and PDC-E2, BCOADC-E2 and OGDC-E2 autoantigens are also present in bile and saliva, where secretory IgA is the dominant isotype.64–66
Environmental toxicants on Leydig cell function
C. Yan Cheng in Spermatogenesis, 2018
Cadmium is used as the stabilizer in the manufacture of polyvinyl chloride polymer, phosphate fertilizers, preservative pigments, and batteries. Cigarettes are also a major source of cadmium. Each cigarette contains 5 mg of cadmium. Cigarette smokers had significant levels of blood cadmium and the levels of cadmium in blood of smokers was 4–5 times higher than those in nonsmokers.229 Cadmium has a very long elimination half-life of 20–40 years and could lead to accumulation in the human body.230 When cadmium was exposed, it strongly accumulated in the interstitial cells in rat testis.231 Cadmium is a Leydig cell toxicant. Exposure to cadmium (0.015g/L in drinking water) for 1, 3, 6, and 12 months to rats reduced Leydig cell numbers and cell size.232 A low dose of cadmium reduced Leydig cell numbers in mice.233 Cadmium exposure to rats induced an increase in ROS level and decreased Star and Hsd3b1, and vitamin C and vitamin E were able to prevent the impairment.234 Exposure to cadmium (3 mg/kg BW/week, subcutaneous) to rats for 4 weeks inhibited serum testosterone levels, and alpha-tocopherol was able to prevent it. Cadmium could induce ROS in rat Leydig cells to inhibit testosterone production and 3β-HSD activity, and treatment with N-acetylcysteine was capable of preventing the damage.235 These results suggest a cadmium-mediated ROS-inducing mechanism236,237that could decrease intracellular levels of cAMP and dihydrolipoamide dehydrogenase activity to lower testosterone production in Leydig cells.230,238
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
Pyruvate dehydrogenase complex (PDC) is a 9.5 million Da multi-enzyme complex located in mitochondrial matrix and consisting of four major enzyme components: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), dihydrolipoamide dehydrogenase (E3), and E3-binding protein (E3BP), as well as the two kinds of dedicated regulatory enzymes: PDKs and pyruvate dehydrogenase phosphatase [47]. The detailed structure and function of PDC have been well reviewed [48]. As an important gatekeeper enzyme that links pyruvate to the TCA cycle, PDC catalyzes the conversion of pyruvate to acetyl-CoA coupled with the reduction of NAD+ to NADH. The modulation of PDC activities depends on the reversible phosphorylation and dephosphorylation [49]. Phosphorylation of E1α component, regardless of which one of the three serine residues, is enough to switch off PDC activity. Thus, phosphorylation of PDC by PDKs will downregulate its activity, and subsequently reduce the flux of pyruvate into the TCA cycle. In human, phosphorylation of PDC is catalyzed by any of four isoforms of pyruvate dehydrogenase kinase (PDK1-4) which are expressed differently in specific tissues. In particular, PDK1 is closely associated with cancer malignancy and serves as the only PDK isoform that could phosphorylate all serine sites of PDC [50]. To sum up, inhibiting PDKs has been one of the recognized strategies to fight against cancer by increasing OXPHOS and reversing Warburg effect.
High-throughput tool to discriminate effects of NMs (Cu-NPs, Cu-nanowires, CuNO3, and Cu salt aged): transcriptomics in Enchytraeus crypticus
Published in Nanotoxicology, 2018
Susana I. L. Gomes, Carlos P. Roca, Natália Pegoraro, Tito Trindade, Janeck J. Scott-Fordsmand, Mónica J. B. Amorim
The similar expression patterns of Cu-Nwires and Cu salt-aged was also reflected in the high number of commonly enriched biological processes. Among those processes is cell redox homeostasis, with the up-regulation of several transcripts (e.g. glutaredoxin 3, selenoprotein t, dihydrolipoamide dehydrogenase, thioredoxin peroxidase, etc.). Cu, including Cu-NPs, are known to induce oxidative stress to enchytraeids (Gomes, Novais, Gravato, et al. 2012) and the current results do indicate that potworms are responding to oxidative stress when exposed to Cu-Nwires and Cu salt-aged. Also affected by Cu-Nwires and Cu salt-aged is the endoplasmic reticulum dependent peroxisome organization, with involvement of the transcript coding for peroxisomal biogenesis factor 16 (qPCR confirmed). Among other functions, peroxisomes are involved in ROS regulation in the cells (Bonekamp et al. 2009), thus this process may be linked with cell redox homeostasis. The observed indication of oxidative stress for Cu-Nwires and Cu salt-aged, and not for Cu-NPs and CuNO3, is probably related with temporal variations in gene expression response and not a difference in the mechanism.
EEG Pattern in Neonatal Maple Syrup Urine Disease: Description and Clinical Significance
Published in The Neurodiagnostic Journal, 2021
Rajesh P. Poothrikovil, Khalid Al Thihli, Amna Al Futaisi
Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder characterized by deficiency of branched-chain keto acid dehydrogenase complex, which is required to metabolize the three branched chain amino acids (BCAAs) leucine, isoleucine and valine. This deficiency leads to an abnormal accumulation of BCAAs and their toxic byproducts, namely alpha-ketoacids, typically detectable in the blood and urine. MSUD is thus one of the main organic acidurias, a group of disorders characterized by the excretion of non-amino organic acids in urine (Clague and Thomas 2002). During the neonatal period, this metabolic dysfunction results in progressive encephalopathy with symptoms of lethargy, vomiting, posturing and abnormal movements in neonates; the classic form of the disease. If untreated, progressive brain damage causes coma, seizures and death usually within a few weeks (Seashore 2009). The major clinical features of MSUD are delayed psychomotor development, feeding difficulties and a characteristic odor of maple syrup which can be detected in the urine (Papetti et al. 2013). Currently, there are five types of MSUD: classic, intermediate, intermittent, thiamine responsive and dihydrolipoamide dehydrogenase deficient (Seashore 2009). These classifications are based on the severity of the disease, age of onset, response to thiamine therapy and the affected gene locus. All forms are inherited as autosomal recessive traits. Imaging in classic MSUD patients may show brain edema affecting the myelinated white matter, thalami and globi pallidi (Poretti et al. 2013)
Related Knowledge Centers
- Dihydrolipoamide
- Disulfide
- Enzyme
- Flavin Adenine Dinucleotide
- Flavoprotein
- Metabolic Pathway
- Protein Dimer
- Gene
- Lipoamide
- Oxidoreductase