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The Metabolic Cart
Published in Michael M. Rothkopf, Jennifer C. Johnson, Optimizing Metabolic Status for the Hospitalized Patient, 2023
Michael M. Rothkopf, Jennifer C. Johnson
For example, when we eat carbohydrates, the gastrointestinal (GI) tract digests them into glucose, which is absorbed and delivered to the bloodstream. The cells then transport the glucose into the cytoplasm, where the Embden–Meyerhoff (cytosolic) pathway converts glucose into pyruvate. The pyruvate dehydrogenase complex then makes pyruvate into acetyl CoA. This pathway produces energy, but the net gain from the cytosolic process is only two molecules of ATP.
Introduction to lactic acidemias
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
We regularly employ a modified oral glucose tolerance test in which the standard 1.75 g/kg is monitored by assessment of concentrations of lactate, pyruvate, and alanine which may rise as much as four-fold over control levels in a patient with PDHC deficiency. This evidence of glucose intolerance may be useful in designing therapy that avoids carbohydrate and substitutes fat, as well in monitoring the efficacy of therapeutic interventions. Fructose loading has been used in assessing in vivo pyruvate dehydrogenase activity and its activation. After a 12–24-hour fast, blood samples are drawn for lactate, pyruvate, glucose, and insulin before and 45 minutes after an oral load of 1 g/kg of fructose. The test is then repeated after an oral glucose load. The rise in blood pyruvate and lactate was reported to be almost twice as great in the fasted as in the postglucose state, suggesting the conversion of pyruvate dehydrogenase to its active form by glucose feeding. Studies have not been reported on actual patients with problems with pyruvate dehydrogenase, and we have not found this to be especially useful. Empirically, an occasional patient has responded to fructose with a marked increase in lactic acid but, as a group, the patients with mitochondrial disease have not been reliably distinguishable from control in their response to fructose.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
There is no curative therapy so treatment is generally supportive. A variety of vitamins and other medications have been tried with anecdotal reports of their benefit. These include thiamine, riboflavin, coenzyme Q, carnitine, biotin and folinic acid. Ketogenic diet has been used in pyruvate dehydrogenase defects.
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Abraham J. Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch
Elevation of pyruvate levels is a useful biomarker to detect pyruvate dehydrogenase (PDH) and pyruvate carboxylase deficiencies. As pyruvate is unstable, blood samples must be collected in ice-cold tubes containing perchlorate, and blood pyruvate levels may vary depending on the sample collection and handling techniques [28]. PDH deficiencies are one of the most common causes of congenital lactic acidosis [29]. Lactate and pyruvate levels are used to determine the lactate/pyruvate ratio, which indicates the NADH/NAD+ redox state and is helpful for differentiating MDs from PDH deficiencies in patients with lactic acidosis (Figure 1). When lactate levels are above 2.5 mmol/L, lactate/pyruvate ratios greater than 25 are suggestive of an MD [30], but may also be due to secondary impairment of OXPHOS function that is independent of the genetic cause.
Hyperglycaemia and the risk of post-surgical adhesion
Published in Archives of Physiology and Biochemistry, 2022
Gordon A. Ferns, Seyed Mahdi Hassanian, Mohammad-Hassan Arjmand
Hyperglycaemia increases superoxide production (Nishikawa et al.2000). Under hyperglycaemic conditions, there is increased glucose entering the glycolytic pathway (important biochemical pathway in the cells for glucose metabolism) that produced two molecules of pyruvate. In aerobic conditions, pyruvates are converted to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA produced by pyruvate entered to the Krebs cycle in mitochondria. Three molecules of NADH are produced by each Krebs cycle (Sabri 1984). NADH is an electron carrier to transport electron in complex 1 of the electron transport chain in mitochondria for ATP synthesis. An excessive amount of NADH causes reductive stress by intracellular production of superoxide O2– (Liu et al.2002) (Figure 3). Superoxide is one of the most important ROS factors and can damage biomolecules and increase of inflammation (McCord 1980). Increase of ROS such as superoxide causes excessive production of proinflammatory cytokines and growth factors by immune cells which are associated with adhesion formation post-surgical (Fortin et al.2015).
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.