DOCSLIB.ORG

Medium-Chain Acyl-Coa Dehydrogenase Deficiency in Children with Non-Ketotic Hypoglycemia and Low Carnitine Levels

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Medium-Chain Acyl-Coa Dehydrogenase Deficiency in Children with Non-Ketotic Hypoglycemia and Low Carnitine Levels ACYL-COA DEHYDROGENASE DEFICIENCY 003 1-3998/83/17 1 1-0877$02.00/0 PEDIATRIC RESEARCH Vol. 17. No. 11. 1983 Copyright 0 1983 International Pediatric Research Foundation, Inc. Primed in U.S. A. Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Children with Non-Ketotic Hypoglycemia and Low Carnitine Levels CHARLES A. STANLEY,'34' DANIEL E. HALE, PAUL M. COATES, CAROLE L. HALL, BARBARA E. CORKEY, WILLIAM YANG, RICHARD I. KELLEY, ELISA L. GONZALES, JOHN R. WILLIAMSON, AND LESTER BAKER Division (?fEndocrinolog.v/Diabetes,[C.A.S., D.E.H., E.L.G., L.B.], Genetics[P.M.C.], and Metabolis~n [W. Y.,R.I.K.]ofthe Department ofPediatrics and the Department of Biochemistry and Biophysics [B.E.C.,J. W.R.], University of Penns.vlvania School of Medicine; The Children's Hospital of Philadelphia, Philadelphia, Pennsvlvunia and the School of Chemistry, Georgia Institute of Technology [C.L.H.], Atlanta, Georgia, USA Summary The oxidation of fatty acids for energy production not only plays an important rolein working skeletal and cardiac muscle, Three children in two families presented in early childhood but also is crucial for maintenance of fuel homeostasis during with episodes of illness associated with fasting which resembled periods of fasting. During fasting, the utilization of fatty acids Reye's syndrome: coma, hypoglycemia, hyperammonemia, and helps to conserve glucose for brain metabolism and the oxidation fatty liver. One child died with cerebral edema during an episode. of fatty acids to ketones in the liver yields both energy for Clinical studies revealed an absence of ketosis on fasting (plasma gluconeogenesis as well as fat-derived substrates that can be used beta-hydroxybutyrate ~0.4mmole/liter) despite elevated levels by the brain to further spare glucose consumption. In the past of free fatty acids (2.6-4.2 mmole/liter) which suggested that several years, an increasing number of inherited defects in the hepatic fatty acid oxidation was impaired. Urinary dicarboxylic pathway of fatty acid oxidation have been described. Depending acids were elevated during illness or fasting. Total carnitine levels on the degree of involvement of liver, heart, and skeletal muscle, were low in plasma (18-25 pmole/liter), liver (200-500 nmole/ the clinical features of these disorders range from recurrent g), and muscle (500-800 nmolelg); however, treatment with L- episodes of fasting coma and hypoglycemia, which may mimic carnitine failed to correct the defect in ketogenesis. Studies on Reye's syndrome, to progressive muscle weakness resembling ketone production from fatty acid substrates by liver tissue in muscular dystrophy. In some of these disorders, such as carnitine vitro showed normal rates from short-chain fatty acids, but very palmityl-transferase (2,8)and hydroxymethyl-glutaryl-CoA lyase low rates from all medium and long-chain fatty acid substrates. deficiencies (27), the site of the metabolic defect has been iden- These results suggested that the defect was in the mid-portion of tified. In others, such as type I1 glutaric aciduria (24) and the the intramitochondrial beta-oxidation pathway at the medium- dicarboxylic acidurias (I, 4, 13, 23, 3l), the site of defect has not chain acyl-CoA dehydrogenase step. A new assay for the electron yet been established. One of the disorders where the site of defect transfer flavoprotein-linked acyl-CoA dehydrogenases was used remains uncertain is a heterogeneous group associated with to test this hypothesis. This assay follows the decrease in electron deficiency of carnitine, a co-factor required for transport of long- transfer flavoprotein fluorescence as it is reduced by acyl-CoA-- chain fatty acids into mitochondria. At least two clinical syn- acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as dromes appear to be associated with carnitine deficiency: a substrate indicated that patients had less than 2.5% normal systemic form (16) and a myopathic form (9). Carnitine replace- activity of medium-chain acyl-CoA dehydrogenase. The activities ment therapy has sometime? been effective (5),but frequently is of short-chain and isovaleryl acyl-CoA dehydrogenases were not (3), suggesting that the primary abnormality in many of these normal; the activity of long-chain acyl-CoA dehydrogenase was cases is not in carnitine biosynthesis (10, 11). one-third normal. The present report describes two families with a defect in fatty These results define a previously unrecognized inherited met- acid oxidation associated with low plasma and tissue carnitine abolic disorder of fatty acid oxidation due to deficiency of me- levels in which carnitine deficiency is not the cause, but instead dium-chain acyl-CoA dehydrogenase. The carnitine deficiency in may be the consequence of impaired fatty acid oxidation. The these patients appears to be a secondary consequence of their affected children in these two families presented in early child- defect in fatty acid oxidation. It is possible that other patients hood with life-threatening episodes of fasting coma and hypogly- with "systemic carnitine deficiency," who fail to respond to cemia that resembled Reye's syndrome. Clinical studies revealed carnitine therapy, may also have defects in fatty acid oxidation an absence of ketosis during fasting, which suggested that hepatic similar to medium-chain acyl-CoA dehydrogenase deficiency. fatty acid oxidation was impaired. Because there were no signs Abbreviations of muscle weakness, liver biopsies were obtained to analyze the pathway of fatty acid oxidation. These studies demonstrated a ACD, acyl-CoA dehydrogenase, defect in intramitochondrial beta-oxidation at the medium-chain BOB, beta-hydroxybutyrate acyl-CoA dehydrogenase step. A specific deficiency of this en- CPT, carnitine palmityl transferase zyme was confirmed using a new assay that was developed for CPT,, CPT activity on outer surface of mitochondria use in small samples of unfractionated tissue. Subsequent studies ETF, electron transfer flavoprotein have shown that this defect can now also be demonstrated in FFA, free fatty acid cultured skin fibroblasts (6). 878 STANLEY ET AL. PATIENTS The past medical history was femarkable only for a prior Patienr M-1. This female patient was first admitted to the unexplained episode of hypoglycemia at 6 months of age. Growth, development, and muscle strength had been normal. Children's Hospital of Philadelphia at 13 months of age because of coma. She had been the 2660 g product of a normal pregnancy Specimens of liver and skeletal muscle were obtained soon after and, except for frequent ear infections, had been well. Her growth death. Total carnitine levels in these tissues were found to be low (see "Results") and suggested the possibility of an inherited and development had also been normal. Four days before ad- mission she developed symptoms of a viral illness with low grade metabolic defect in fatty acid oxidation. fever, irritability, mild diarrhea, and intermittent vomiting. On Patient B-2. Patient B-2 is the oldest brother of patient B-1. the morning of admission she was found unarousable in bed At age 2 3/~2, he had an episode of coma and hypoglycemia after with labored breathing. She stopped breathing on the way to sleeping late one morning. He cried out and was found unre- another hospital and was given mouth-to-mouth ventilation. In sponsive by his parents. He was taken to an emergency room where he was noted to be staring and unresponsive with arms the emergency room she had a generalized seizure and received a large dose of diazepam. She was stabilized and transported to and legs stiffly flexed. Laboratory studies showed plasma glucose, 8 mg/dl (0.44 mmole/liter); normal serum sodium, potassium the Children's Hospital of Philadelphia. On arrival she was and chloride; serum bicarbonate, 19 mmole/liter; and moderate obtunded, responded only to painful stimuli, and required me- ketonuria. He was transferred to Children's Hospital of Phila- chanical ventilation. Physical examination was normal; the liver was not enlarged. Laboratory studies showed a spinal fluid glu- delphia where additional laboratory tests showed an elevated blood ammonia (185 pg/dl; 109 pmole/liter) compared to a cose of 23 mg/dl (1.3 mmole/liter); normal serum sodium, control (1 50 &dl; 88 pmole/liter), slightly elevated transaminase potassium, and chloride; bicarbonate, 11 mmole/liter; urea ni- (64 U/ml; 0.5 pmol .s-'/liter-'), and normal prothrombin time. trogen, 14 mg/dl (5.0 mmole/liter); blood ammonia, 52 pgldl The liver was not enlarged. He had several seizures after treat- (30 pmole/liter); hemoglobin, 12.3 g/dl (7.7 mmole/liter); and ment was started with intravenous fluids. He improved slowly white blood count, 21,700/mm3 (2 1.7 x 109/liter); and a small over 3 days. One week later, he tolerated a fast of 36 h without amount of ketones in the urine. She was treated with intravenous developing hypoglycemia (lowest plasma glucose, 58 mg/dl; 3.2 dextrose and fluids and began to improve slowly. On the third day, when the intravenous fluids were stopped and nasogastric mmole/liter) or symptoms. Because the episode of coma had feedings were begun she became obtunded again and had a occurred after a longer period of overnight fasting than was usual for him, the parents were advised to avoid letting him fast more cardiorespiratory arrest. At this time the liver was noted to be firm and enlarged to 4 cm below the costal margin. The plasma than 12 h. He has had no further episodes of coma. At age 10 glucose was 34 mg/dl (I .9 mmole/liter); serum bicarbonate, 16 years, he appears physically and developmentally normal and has no signs of muscle weakness. His total plasma carnitine level mmole/liter; and blood ammonia, 138 &dl (8 1 pmole/liter). A urine specimen at the time of this episode showed very elevated is low (25 pmole/liter).
Load more

Recommended publications
  • Hepatic Glycogen Storage Diseases: Pathogenesis, Clinical Symptoms and Therapeutic Management
    State of the art paper Hepatology Hepatic glycogen storage diseases: pathogenesis, clinical symptoms and therapeutic management Edyta Szymańska1, Dominika A. Jóźwiak-Dzięcielewska2, Joanna Gronek2, Marta Niewczas3, Wojciech Czarny4, Dariusz Rokicki1, Piotr Gronek2 1Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Corresponding author: The Children’s Memorial Health Institute, Warsaw, Poland Edyta Szymańska MD, PhD 2Laboratory of Genetics, Department of Gymnastics and Dance, University School Department of Physical Education, Poznan, Poland of Gastroenterology, 3Department of Sport, Faculty of Physical Education, University of Rzeszow, Rzeszow, Hepatology, Feeding Poland Disorders and 4Department of Human Sciences, Faculty of Physical Education, University of Rzeszow, Pediatrics Rzeszow, Poland The Children’s Memorial Health Institute Submitted: 13 October 2017; Accepted: 8 December 2017; Al. Dzieci Polskich 20 Online publication: 18 February 2019 Warsaw, Poland Phone: +48 22 815 74 94 Arch Med Sci 2021; 17 (2): 304–313 E-mail: edyta.szymanska@ DOI: https://doi.org/10.5114/aoms.2019.83063 ipczd.pl Copyright © 2019 Termedia & Banach Abstract Glycogen storage diseases (GSDs) are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. Due to the enzymatic defect at some stage of glycogenolysis/glycogenesis, excess glycogen or its pathologic forms are stored in the body tissues. The first symptoms of the disease usually appear during the first months of life and are thus the domain of pediatricians. Due to the fairly wide access of the authors to unpublished materials and research, as well as direct contact with the GSD patients, the article addresses the problem of actual diag- nostic procedures for patients with the suspected diseases.
    [Show full text]
  • What Is Ketotic Hypoglycemia?
    KETOTICHYPOGLYCEMIA.ORGv Ketotic Hypoglycemia International Who we are, what we do and why Ketotic Hypoglycemia INTERNATIONAL What is ketotic hypoglycemia? “Ketotic hypoglycemia may be unexplained, or idiopathic (IKH). This is a challenge and should urge for more research” For the patients In a normal person, fuel for the brain and the general cell metabolism primarily comes from the burning of sugar deposits (glycogen). When the glycogen stores are depleted, the body will switch to burn fat deposits. The fat burn lead to two fuels for the brain, both glucose (sugar) and ketone bodies. However, ketones in the blood will lead to nausea and eventually vomiting. This will lead to a vicious circle, where you cannot eat or drink sugar-rich items, which again leads to further fat burn and production of ketone bodies. In a KH-patient, the glycogen stores are somehow insufficient. This leads to For the doctors decreased fasting tolerance with earlier Ketotic hypoglycemia can be seen in children Emergency treatment constitutes of oral onset of fat burn and hence ketone bodies. In because of growth hormone deficiency, cortisol or i.v. glucose, eventually i.m. glucagon, to most patients, the hypoglycemia is relatively deficiency, metabolic diseases with intact fatty raise the plasma glucose, which will prevent mild, and the ketone bodies helps to provide acid consumption, including glycogen storage further lipolysis. However, the ketones can fuel to the brain, which prevents loss of diseases (glycogenosis; GSD) type 0, III, VI, and take hours to be eliminated. In more severely consciousness and convulsions. However, in IX, or disturbances in transport or metabolism affected patients, the ketone production relatively few patients, the condition is more of ketone bodies.
    [Show full text]
  • Recurrent Severe Hypoglycemia Due to Isolated Growth Hormone
    C O R R E S P O N D E N C E Recurrent Severe Hypoglycemia hyperinsulinism, ketotic hypoglycemia and hormonal deficiencies such as cortisol, GH and thyroxine [1]. GH due to Isolated Growth Hormone deficiency may occasionally manifest as recurrent Deficiency hypoglycemia as seen in our patient. The mechanisms of hypoglycemia in GH deficiency are increased insulin sensitivity and hypoglycemia unawareness [2]. Additionally, GH deficiency impairs carbohydrate meta- A 6-year-old boy presented to us with repeated episodes bolism resulting in deceased basal insulin level, impaired of seizures since early infancy. He was born small for insulin secretion and carbohydrate intolerance with gestational age to non-consanguineous parents at term. reactive hypoglycemia [1,2]. Although hypoglycemia is During neonatal period, he suffered multiple episodes of described in GH deficiency, severe symptomatic hypoglycemia requiring intravenous dextrose but no hypoglycemia is extremely rare and usually occurs in etiological investigations were done. Three of the four association with another causative factor such as hypoglycemic events beyond neonatal age were glycogen storage disorder [3,4]. Children with even associated with seizures. There were no precipitating complete GH deficiency do not usually manifest factors for hypoglycemia such as prolonged fasting, an hypoglycemia [5]. Our patient unusually developed intercurrent illness or intake of medications. There was recurrent episodes of severe symptomatic hypoglycemia no family history of similar illness, metabolic disorders or due to an isolated GH deficiency. an unexplained death. DEVI DAYAL AND JAIVINDER Y ADAV* On examination, he was short (106 cm, -2.02 z-score) Department of Pediatrics, and underweight (13.8 kg, -3.15 z-score) and had normal PGIMER, Chandigarh, India.
    [Show full text]
  • Beta (Β)-Oxidation of Fatty Acid and Its Associated Disorders
    Vol. 5 (1), pp. 158-172, December, 2018 ©Global Science Research Journals International Journal of Clinical Biochemistry Author(s) retain the copyright of this article. http://www.globalscienceresearchjournals.org/ Review Article Beta (β)-Oxidation of Fatty Acid and its associated Disorders Satyam Prakash Assistant Professor, Dept. of Biochemistry, Janaki Medical College Teaching Hospital, Janakpur, Nepal Mobile: +977-9841603704, E-mail: [email protected] Accepted 18 December, 2018 The lipids of metabolic significance in the mammalian organisms include triacylglycerols, phospholipids and steroids, together with products of their metabolism such as long-chain fatty acids, glycerol and ketone bodies. The fatty acids which are present in the triacylglycerols in the reduced form are the most abundant source of energy and provide energy twice as much as carbohydrates and proteins. Fatty acids represent an important source of energy in periods of catabolic stress related to increased muscular activity, fasting or febrile illness, where as much as 80% of the energy for the heart, skeletal muscles and liver could be derived from them. The prime pathway for the degradation of fatty acids is mitochondrial fatty acid β-oxidation (FAO). The relationship of fat oxidation with the utilization of carbohydrate as a source of energy is complex and depends upon tissue, nutritional state, exercise, development and a variety of other influences such as infection and other pathological states. Inherited defects for most of the FAO enzymes have been identified and characterized in early infancy as acute life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting or febrile illness. Therefore, this review briefly highlights mitochondrial β-oxidation of fatty acids and associated disorders with clinical manifestations.
    [Show full text]
  • (Idiopathic) Ketotic Hypoglycemia in Children
    (Idiopathic) Ketotic hypoglycemia in children *Leena Priyambada, **Srinivas Raghavan *E-mail: [email protected] **Department of Pediatrics, Jawaharlal Institute of Medical Education and Research, Puducherry, India Abstract Idiopathic Ketotic Hypoglycemia is the most common non-iatrogenic cause of hypoglycemia in children beyond infancy. It improves with age and is rare after puberty. Early morning hypoglycemia, responding promptly to glucose, is a typical presentation. Etiology of hypoglycemia is unclear; deficiency of gluconeogenic substrate (hypoalaninemia) has been widely proposed. Idiopathic Ketotic Hypoglycemia is a diagnosis of exclusion. Rule out specific etiologies first. Ketonuria precedes hypoglycemia by several hours, testing for ketonuria helps in early detection. For prevention, avoiding fasting states and bedtime snacks are helpful. Keywords: Ketotic hypoglycemia, children, hypoalaninemia Introduction classic presentation is the appearance of ‘G, a 4 yr old developmentally normal girl, recurrent episodes of hypoglycemia and ketosis presented with recurrent seizures (3 episodes) provoked by fasting for 12 to 24 hours. Early for the past three months. The seizures were morning hypoglycemia before breakfast generalised tonic clonic in nature, preceded by especially when associated with strenuous vomiting early in the morning and responding physical activity the previous evening or during immediately to glucose. There was no suggestive intercurrent illnesses is a classic presentation. past, neonatal or family history. Clinical These episodes respond promptly to glucose examination, baseline biochemical, neurological administration and neurological sequelae are investigations in the interictal period when the rare. child was referred to us was normal. Fasting IKH usually presents between 18 months and test resulted in blood sugar of 26 mg/dl with five years of age.
    [Show full text]
  • Effect of Ketone Bodies on Glucose Production and Utilization in the Miniature Pig
    Effect of ketone bodies on glucose production and utilization in the miniature pig. M J Müller, … , U Paschen, H J Seitz J Clin Invest. 1984;74(1):249-261. https://doi.org/10.1172/JCI111408. Research Article The effect of ketone bodies on glucose production (Ra) and utilization (Rd) was investigated in the 24-h starved, conscious unrestrained miniature pig. Infusing Na-DL-beta-OH-butyrate (Na-DL-beta-OHB) and thus shifting the blood pH from 7.40 to 7.56 resulted in a decrease of Ra by 52% and of Rd by 45%, as determined by the isotope dilution technique. Simultaneously, the concentrations of arterial insulin and glucagon were slightly enhanced, whereas the plasma levels of glucose, lactate, pyruvate, alanine, alpha-amino-N, and free fatty acids (FFA) were all reduced. Infusion of Na- bicarbonate, which yielded a similar shift in blood pH, did not mimick these effects. Infusion of equimolar amounts of the ketoacid, yielding a blood pH of 7.35, induced similar metabolic alterations with respect to plasma glucose, Ra, Rd, and insulin; however, plasma alanine and alpha-amino-N increased. Infusing different amounts of Na-DL-beta-OHB resulting in plasma steady state levels of ketones from 0.25 to 1.5 mM had similar effects on arterial insulin and glucose kinetics. No dose dependency was observed. Prevention of the Na-DL-beta-OHB-induced hypoalaninemia by simultaneous infusion of alanine (1 mumol/kg X min) did not prevent hypoglycemia. Infusion of Na-DL-beta-OHB plus insulin (0.4 mU/kg X min) showed no additive effect on the inhibition of Ra.
    [Show full text]
  • Insights Into the Hexose Liver Metabolism—Glucose Versus Fructose
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 Insights into the Hexose Liver Metabolism-Glucose versus Fructose Geidl-Flueck, Bettina ; Gerber, Philipp A Abstract: High-fructose intake in healthy men is associated with characteristics of metabolic syndrome. Extensive knowledge exists about the differences between hepatic fructose and glucose metabolism and fructose-specific mechanisms favoring the development of metabolic disturbances. Nevertheless, the causal relationship between fructose consumption and metabolic alterations is still debated. Multiple effects of fructose on hepatic metabolism are attributed to the fact that the liver represents the major sink of fructose. Fructose, as a lipogenic substrate and potent inducer of lipogenic enzyme expression, enhances fatty acid synthesis. Consequently, increased hepatic diacylglycerols (DAG) are thought to directly interfere with insulin signaling. However, independently of this effect, fructose may also counteract insulin-mediated effects on liver metabolism by a range of mechanisms. It may drive gluconeogenesis not only as a gluconeogenic substrate, but also as a potent inducer of carbohydrate responsive element binding protein (ChREBP), which induces the expression of lipogenic enzymes as well as gluconeogenic enzymes. It remains a challenge to determine the relative contributions of the impact of fructose on hepatic transcriptome, proteome and allosterome changes and consequently on the regulation of plasma glucose metabolism/homeostasis. Mathematical models exist modeling hepatic glucose metabolism. Fu- ture models should not only consider the hepatic adjustments of enzyme abundances and activities in response to changing plasma glucose and insulin/glucagon concentrations, but also to varying fructose concentrations for defining the role of fructose in the hepatic control of plasma glucose homeostasis.
    [Show full text]
  • Regulation of Ketone Body and Coenzyme a Metabolism in Liver
    REGULATION OF KETONE BODY AND COENZYME A METABOLISM IN LIVER by SHUANG DENG Submitted in partial fulfillment of the requirements For the Degree of Doctor of Philosophy Dissertation Adviser: Henri Brunengraber, M.D., Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August, 2011 SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of __________________ Shuang Deng ____________ _ _ candidate for the ________________________________degree Doctor of Philosophy *. (signed) ________________________________________________ Edith Lerner, PhD (chair of the committee) ________________________________________________ Henri Brunengraber, MD, PhD ________________________________________________ Colleen Croniger, PhD ________________________________________________ Paul Ernsberger, PhD ________________________________________________ Janos Kerner, PhD ________________________________________________ Michelle Puchowicz, PhD (date) _______________________June 23, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. I dedicate this work to my parents, my son and my husband TABLE OF CONTENTS Table of Contents…………………………………………………………………. iv List of Tables………………………………………………………………………. viii List of Figures……………………………………………………………………… ix Acknowledgements………………………………………………………………. xii List of Abbreviations………………………………………………………………. xiv Abstract…………………………………………………………………………….. xvii CHAPTER 1: KETONE BODY METABOLISM 1.1 Overview……………………………………………………………………….. 1 1.1.1 General introduction
    [Show full text]
  • CHAPTER-IV LIPID METABOLISM BETA-OXIDATION Beta-Oxidation Is
    CHAPTER-IV LIPID METABOLISM BETA-OXIDATION Beta-oxidation is the process by which fatty acids, in the form of acyl-CoA molecules, are broken down in mitochondria and/or peroxisomes to generate acetyl-CoA, the entry molecule for the citric acid cycle. The beta oxidation of fatty acids involve three stages: 1. Activation of fatty acids in the cytosol 2. Transport of activated fatty acids into mitochondria (carnitine shuttle) 3. Beta oxidation proper in the mitochondrial matrix Fatty acids are oxidized by most of the tissues in the body. However, some tissues such as the adrenal medulla do not use fatty acids for their energy requirements and instead use carbohydrates. Energy yield The ATP yield for every oxidation cycle is 14 ATP (according to the P/O ratio), broken down as follows: Source ATP Total [citation needed] 1 FADH2 x 1.5 ATP = 1.5 ATP (some sources say 2 ATP) 1 NADH x 2.5 ATP = 2.5 ATP (some sources say 3 ATP) 1 acetyl CoA x 10 ATP = 10 ATP (some sources say 12 ATP) TOTAL = 14 ATP For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary, and the final process yields an additional acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2 = total ATP For instance, the ATP yield of palmitate (C16, n = 8) is: (8 - 1) * 14 + 10 - 2 = 106 ATP Represented in table form: Source ATP Total 7 FADH2 x 1.5 ATP = 10.5 ATP 7 NADH x 2.5 ATP = 17.5 ATP 8 acetyl CoA x 10 ATP = 80 ATP Activation = -2 ATP NET = 106 ATP For sources that use the larger ATP production numbers described above, the total would be 129 ATP ={(8-1)*17+12-2} equivalents per palmitate.
    [Show full text]
  • Mitochondrial B-Oxidation
    Eur. J. Biochem. 271, 462–469 (2004) Ó FEBS 2004 doi:10.1046/j.1432-1033.2003.03947.x MINIREVIEW Mitochondrial b-oxidation Kim Bartlett1 and Simon Eaton2 1Department of Child Health, Sir James Spence Institute of Child Health, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne; 2Surgery Unit and Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, UK Mitochondrial b-oxidation is a complex pathway involving, chondrial control at multiple sites. However, at least in the in the case of saturated straight chain fatty acids of even liver, carnitine palmitoyl transferase I exerts approximately carbon number, at least 16 proteins which are organized into 80% of control over pathway flux under normal conditions. two functional subdomains; one associated with the inner Clearly, when one or more enzyme activities are attenuated face of the inner mitochondrial membrane and the other in because of a mutation, the major site of flux control will the matrix. Overall, the pathway is subject to intramito- change. Introduction acids are also b-oxidized by a peroxisomal pathway, this pathway is quantitatively minor, and, although inherited The b-oxidation of long-chain fatty acids is central to the disorders of the peroxisomal system result in devastating provision of energy for the organism and is of particular disease, is not considered further. Similarly, the auxiliary importance for cardiac and skeletal muscle. However, a systems required for the metabolism of polyunsaturated and number of other tissues, primarily the liver, but also the branched-chain long-chain fatty acids are not discussed kidney, small intestine and white adipose tissue, can utilize and the interested reader is referred to recent reviews.
    [Show full text]
  • Fatty Acid Catabolism Part II
    Topic: Fatty acid Catabolism Part II B.Sc (H) Zoology Sem IV Paper: Biochemistry of Metabolic Processes Teacher: Dr. Renu Solanki Oxidation of Fatty acids • Fatty acid oxidation takes place in three steps: Stages of fatty acid oxidation. Stage 1: A long-chain fatty acid is oxidized to yield acetyl residues in the form of acetyl-CoA. This process is called beta oxidation. Stage 2: The acetyl groups are oxidized to CO2 via the citric acid cycle. Stage 3: Electrons derived from the oxidations of stages 1 and 2 pass to O2 via the mitochondrial respiratory chain, providing the energy for ATP synthesis by oxidative phosphorylation. • In the first stage—beta oxidation—fatty acids undergo oxidative re- moval of successive two-carbon units in the form of acetyl-CoA, starting from the carboxyl end of the fatty acyl chain. For example, the 16-carbon palmitic acid (palmitate at pH 7) undergoes seven passes through the oxidative sequence, in each pass losing two carbons as acetyl-CoA. At the end of seven cycles the last two car- bons of palmitate (originally C-15 and C-16) remain as acetyl-CoA. The overall result is the conversion of the 16-carbon chain of palmitate to eight two-carbon acetyl groups of acetyl-CoA molecules. Formation of each acetyl-CoA reQuires removal of four hydrogen atoms (two pairs of electrons and four H+) from the fatty acyl moiety by dehydrogenases. • In the second stage of fatty acid oxidation, the acetyl groups of acetyl- CoA are oxidized to CO2 in the citric acid cycle, which also takes place in the mitochondrial matrix.
    [Show full text]
  • Fatty Acid Oxidation- Notes
    Fatty acid oxidation- Notes See how fatty acids are broken down and used to generate ATP . Fatty acids provide highly efficient energy storage, delivering more energy per gram than carbohydrates like glucose. In tissues with high energy requirement, such as heart, up to 50– 70% of energy, in the form of ATP production, comes from fatty acid (FA) beta-oxidation. During fatty acid β-oxidation long chain acyl-CoA molecules – the main components of FAs – are broken to acetyl-CoA molecules. Fatty acid transport into mitochondria Fatty acids are activated for degradation by conjugation with coenzyme A (CoA) in the cytosol. The long-chain fatty-acyl-CoA is then modified by carnitine palmitoyltransferase 1 (CPT1) to acylcarnitine and transported across the inner mitochondrial membrane by carnitine translocase (CAT). CPT2 then coverts the long chain acylcarnitine back to long- chain acyl-CoA before beta-oxidation. Breakdown of fats yields fatty acids and glycerol. Glycerol can be readily converted to DHAP for oxidation in glycolysis or synthesis into glucose in gluconeogenesis. Fatty acids are broken down in two carbon units of acetyl-CoA. To be oxidized, they must be transported through the cytoplasm attached to coenzyme A and moved into mitochondria. The latter step requires removal of the CoA and attachment of the fatty acid to a molecule of carnitine. The carnitine complex is transported across the inner membrane of the mitochondrion after which the fatty acid is reattached to coenzyme A in the mitochondrial matrix. Dr Anjali Saxena Page 1 Figure- Movement of Acyl-CoAs into the Mitochondrial Matrix The process of fatty acid oxidation, called beta oxidation, is fairly simple.
    [Show full text]