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Pyruvate carboxylase deficiency
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
Pyruvate carboxylase (EC 6.4.1.1) is a biotin-containing mitochondrial enzyme, which catalyzes the conversion of pyruvate to oxalacetate by CO2 fixation (Figure 48.1) [1, 2]. As in the case of other carboxylases, the reaction mechanism is a two-step process in which biotin is first carboxylated and then the carboxyl group is transferred to the acceptor, pyruvate [3, 4]. There is a separate catalytic site for each of the two steps. The enzyme is a tetramer of 500 kDa whose individual equal-sized protomers have a different structure from other biotin-containing carboxylases [5], but the highly conserved amino acid sequence at the biotin site of biotin-containing carboxylases, Ala-Met-Lys-Met is present in pyruvate carboxylase [6]. The biotin is linked to the ε amino group of the lysine.
The vitamins
Published in Geoffrey P. Webb, Nutrition, 2019
Biotin functions as a coenzyme for several important carboxylase enzymes i.e. enzymes that add a carboxyl (COOH) group via fixation of carbon dioxide. The enzyme pyruvate carboxylase is important in gluconeogenesis (production of glucose from pyruvate and amino acids). Other carboxylase enzymes are important in fatty acid synthesis (acetyl CoA carboxylase) and the metabolism of branched chain amino acids.
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 are three distinct types of presentation of pyruvate carboxylase deficiency: type A patients typically become severely ill between 2 and 5 months of age with progressive hypotonia, recurrent episodes of vomiting and dehydration and metabolic acidosis typically precipitated by catabolic stress, before developing pyramidal tract signs. Hepatomegaly and renal dysfunction may also be present. Central imaging might show subepidymal cysts and delayed myelination; type B, the so-called French phenotype, presents shortly after birth with severe neurological dysfunction with rigidity and Parkinson-like features. Most of these patients die in the neonatal period. The third form is the most benign and uncommon, with patients presenting with episodes of lactic acidosis and ketoacidosis, though recovering well from these and being asymptomatic inbetween.
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.
Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
In the last period, CAs were not only considered as being involved in pH regulation/buffering in many cells and tissues, but also as metabolic enzymes16, due to their demonstrated role in several metabolic processes in tumours17,18 and normal cells, including fatty acid biosynthesis and de novo lipogenesis (DNL) – Figure 12,8–12. It has been known for decades that fatty acid biosynthesis and DNL involve both mitochondrial and cytosolic steps, in which several enzymes implicated both in the Krebs cycle as well as DNL, among which pyruvate carboxylase (PC) and acetyl-coenzyme A carboxylase (ACC) use bicarbonate and not CO2 as one of their substrate8–12. In order to achieve the very rapid interconversion between these two species, highly catalytically active CA isoforms (among which CA II in the cytosol13–15 and CA VA/VB in the mitochondria19,20) are necessary to participate21–25. It has been demonstrated already in the 90 s that this is indeed the case, and that inhibition of mitochondrial/cytosolic CAs interferes with fatty acid biosynthesis and DNL in various cells, tissues and animal models21–25.
Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors
Published in Drug Delivery, 2021
Xianhu Zeng, Zhipeng Li, Chunrong Zhu, Lisa Xu, Yong Sun, Shangcong Han
Gluconeogenesis can generate free glucose from non-carbohydrate carbon substrates (such as glycerol, lactic acid, pyruvate, and glycogenic amino acids). Although it is less studied than catabolic glycolysis or oxidative phosphorylation (OXPHOS), this anabolic pathway plays the same role in controlling the aerobic glycolysis of cancer cells (Seenappa et al. 2016). The complete pathway consists of 11 enzyme-catalyzed reactions, of which there are 7 reactions that are the opposite steps of glycolysis, and 3 reactions that are not involved in gluconeogenesis: (i) the conversion of pyruvate to phosphoenolpyruvate, which is determined by the reaction that catalyzes pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK); (ii) the catalyzation of the conversion of fructose-1,6-diphosphate to fructose-6-phosphate by fructose-1,6-bisphosphatase (FBPase); (iii) the catalyzation of the conversion of glucose-6-phosphate to glucose by glucose-6-phosphatase (G6Pase) (Icard et al. 2019). PEPCK, FBPase, and G6Pase are the key enzymes that control the gluconeogenesis flux, thereby affecting glycolysis, the TCA cycle, the PPP and other branched metabolic pathways (serine biosynthesis, glycogen health, gluconeogenesis, and glutamine decomposition) (Kang et al. 2016; Icard et al. 2019).