Neurotransmission at Parasympathetic Nerve Endings
Kenneth J. Broadley in Autonomic Pharmacology, 2017
It is located in the axonal cytoplasm in predominantly soluble form but also ionically bound to membrane lipids. It is transported down the axon after synthesis in the ribosomes of the cell body (perikaryon) and is concentrated at the nerve terminal. There are probably multiple forms of this enzyme and the primary structure has now been identified from molecular cloning (Berrard et al. 1989). The reaction sequence probably occurs with AcCoA binding initially to the enzyme, before choline, and then Ach dissociating first. The binding of AcCoA to the enzyme is probably by the 3′-phosphate to an arginine residue at the active site. The choline appears to bind with its cationic head to an anionic site. The hydroxyl group of choline attacks the thiol-ester groups of AcCoA to release the acetyl group; this is facilitated by the imidazole group of a histidine residue within the active centre (Figure 7.2). The AcCoA substrate is formed in the mitochondria, the membrane of which is relatively impermeable. It therefore has to pass to the cytoplasm in the form of pyruvate, citrate or acetate depending upon the location of the nerve. AcCoA is then reformed. Pyruvate is generated within the mitochondria by the action of pyruvate dehydrogenase. Citrate is derived from oxaloacetic acetate and AcCoA by citrate synthase and transported from the mitochondria. AcCoA is produced in the cytoplasm from citrate and ATP by the action of ATP citrate lysase. Acetate reacts with ATP under the influence of acetate thiokinase to form an enzyme-bound acetyl AMP, which in the presence of CoA undergoes transacetylation to form AcCoA. The second substrate, choline, is derived from phosphatidylcholine, a phospholipid formed mainly in the liver and supplied to the tissue via the circulation. There are four mechanisms of breakdown, the principal one being by deacylation to glycerylphosphorylcholine and subsequent cleavage to choline and glycerophosphoric acid. Phospholipase D may also directly cleave it to choline and diacylphosphatidate (phosphatidic acid) (see Figure 13.5). The second major source of choline (50–60%) for synthesis of Ach is that derived from the breakdown of released Ach by acetylcholinesterase. Finally, activation of muscarinic receptors causes release of choline into the extracellular spaces, probably by activation of phospholipase D (see Chapter 13). The rate of synthesis of Ach adapts to the rate of release so that relatively constant levels are maintained within the neurone. The enzyme activity of ChAT appears to operate well within its capabilities since the substrate concentrations are substantially below the K values.
Thiamin
Judy A. Driskell, Ira Wolinsky in Sports Nutrition, 2005
The CAC extracts energy nutrients throughout a chain of cyclic reactions. Thiamin pyrophosphate is the key coenzyme for α-ketoacid dehydrogenases, which catalyzes two reactions of CAC, the oxidative decarboxylation of pyruvate to acetyl CoA and the oxidative decarboxylation of α-ketoglutarate to succinyl CoA. These reactions lead to the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH and production of a molecule of CO for release. Thiamin pyrophosphate is also the cofactor for the pyruvate dehydrogenase component of the complex. Pyruvate dehydrogenase catalyzes the oxidative decarboxylation of pyruvate. Other components of the enzyme complex complete the conversion of pyruvate to acetyl CoA. Other reactions that require TPP involve α–ketoglutarate and branched-chain α-keto acids. This reaction has a similar metabolic pathway to that of pyruvate. Alpha-ketoglutarate is decarboxylated and the product is transferred to CoA to give succinyl CoA by action of TPP dependent α-ketoglutarate dehydrogenase. Also, in BCAA catabolism, TPP is required as a coenzyme for branched-chain keto-acid dehydrogenase for the oxidative decarboxylation of α-ketoglutarate and branched chains derived from certain amino acids (valine, luecine, isoluecine).
Metabolic disorders, including glucose homeostasis and inborn errors of metabolism
Janet M Rennie, Giles S Kendall in A Manual of Neonatal Intensive Care, 2013
This can be due to a variety of enzyme defects, and some cases remain unexplained. The two most commonly recognized defects are fructose 1,6-diphosphatase deficiency reported (approx. 1:200,000) and deficiencies of pyruvate dehydrogenase complex (approx. 1:200,000). They are autosomal recessive disorders but only the pyruvate dehydrogenase disorders are diagnosable antenatally. Most cases present with lactic acidaemia and pallor, with hyperventilation in some. In others there is primarily a neurological picture with hypotonia, seizures and delayed (or absent) neurological maturation. The plasma lactate level is >2 mmol/L, often being 10 times this value. Ideally, the sample should be arterial in order to avoid problems with stasis when collecting venous blood. Urinary lactate levels are also raised. Precise diagnosis requires enzyme studies of fibroblasts or a liver biopsy. A small proportion of those with pyruvate dehydrogenase complex defects do not have a lactic acidaemia and the underlying cause of the neurological syndrome may be difficult to establish. While establishing the diagnosis in any group, treat as described above. Nutrition should be given as a high-fat, high-protein, low-carbohydrate diet, in particular avoiding fructose. Most cases that present neonatally are unresponsive to long-term therapy.
Perioperative care of an infant with pyruvate dehydrogenase deficiency
Published in Southern African Journal of Anaesthesia and Analgesia, 2012
E Dewhirst, S Rehman, JD Tobias
The authors present the anaesthetic management of two infants with pyruvate dehydrogenase complex deficiency (PDCD), a rare genetic disorder of carbohydrate metabolism leading to lactic acidosis and neurological impairment. In the first case, a seven-month-old infant, undergoing closed reduction of a dislocated hip, received general anaesthesia with a volatile agent. In the second case, spinal anaesthesia was administered to a six-month-old infant undergoing Achilles tendon lengthening. There were no adverse outcomes in both cases. Key components of perioperative care included minimising perioperative stress, and avoiding exacerbation of the lactic acidosis. Previous reports regarding the perioperative care of such patients are reviewed, and recommendations for anaesthetic care discussed.
Two dichloric compounds inhibit in vivo U87 xenograft tumor growth
Published in Cancer Biology & Therapy, 2019
Dmitriy Ovcharenko, Catrina Chitjian, Alex Kashkin, Alex Fanelli, Victor Ovcharenko
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK) that has been shown to reverse the Warburg effect and cause tumor cell death. Clinical research into the anti-cancer activity of DCA revealed high dosage requirements and reports of toxicity. While there have been subsequent mechanistic investigations, a search for DCA alternatives could result in a safer and more effective anticancer therapy. This study evaluates eight small compounds with a conserved dichloric terminal and their in vitro and in vivo potential for anticancer activity. Initial viability screening across six cancer cell lines reveals even at 10 mg/mL, compound treatments do not result in complete cell death which suggests minimal compound cytotoxicity. Furthermore, in vivo data demonstrates that cationic dichloric compounds DCAH and DCMAH, which were selected for further testing based on highest in vitro viability impact, inhibit tumor growth in the U87 model of glioblastoma, suggesting their clinical potential as accessible anti-cancer drugs. Immunoblotting signaling data from tumor lysates demonstrates that the mechanism of actions of cationic DCAH and DCMAH are unlikely to be consistent with that of the terminally carboxylic DCA and warrants further independent investigation.
Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy
Published in Expert Opinion on Therapeutic Targets, 2016
Andrew JM Lewis, Stefan Neubauer, Damian J Tyler, Oliver J Rider
Introduction: Obesity cardiomyopathy is a major public health problem with few specific therapeutic options. Abnormal cardiac substrate metabolism with reduced pyruvate dehydrogenase (PDH) activity is associated with energetic and functional cardiac impairment and may be a therapeutic target. Areas covered: This review summarizes the changes to cardiac substrate and high energy phosphorus metabolism that occur in obesity and describes the links between abnormal metabolism and impairment of cardiac function. The available evidence for the currently available pharmacological options for selective metabolic therapy in obesity cardiomyopathy is reviewed. Expert opinion: Pharmacological restoration of PDH activity is in general associated with favourable effects upon cardiac substrate metabolism and function in both animal models and small scale human studies, supporting a potential role as a therapeutic target.
Related Knowledge Centers
- Cellular Respiration
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- Insulin
- Autoimmune
- Gluten Intolerance
- Pyruvate Dehydrogenase Complex Deficiency Disease