Medical Biochemistry

and Metabolic Disease

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Vijay Yanamadala

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Medical Biochemistryand Metabolic Disease

Vijay’s Underground GuideTM

to

Vijay Yanamadala, M.A.Teaching Fellow

Human Biochemistry & Metabolic DiseasesHarvard-MIT Division of Health Sciences and Technology

Harvard Medical School

Underground Medical Press

Copyright © 2010 Vijay Yanamadala

Underground Medical Pressunderground.medical.press@gmail.com

All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage or retrieval system without written permission from the copyright owner.

The author and publisher are not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein. This publication contains information relating to the general principles of medical care that should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions.

Care has been taken to confirm the accuracy of the information presented in this book. However, the author and pub-lisher are not responsible for errors or omissions or for any consequences from the application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of this publication. Application of this information in a particular situation remains the professional responsi-bility of the practitioner.

The publishers have made every effort to trace copyright holders for borrowed material. If they have inadvertantly overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.

To send comments to the author, e-mail: yanamadala.vijay@gmail.com.

Printed in the United States of America

Library of Congress Cataloging-in-Publication has been applied for (ISBN: 978-1-4507-2237-7).

TABLE OF CONTENTSForeword 4

Introduction 5

1. Carbohydrate MetabolismBiologically Important Monosaccharides 9Overview of Carbohydrate Metabolism 9Glycolysis 11Pyruvate Metabolism 13Krebs Cycle and Oxidative Phosphorylation 15The Mitochondrial Shuttles 17Glycogen and Glycogen Storage Disorders 18Gluconeogenesis 21The Hexose Monophosphate Shunt 22Insulin Signaling 24Fructose and Galactose Metabolism 26Metabolism of Exercise 26Important Diseases of Carbohydrate Metabolism 27Review Questions 28

2. Lipid MetabolismBiologically Important Lipids 31The Carnitine Shuttle 33Fatty Acid b-Oxidation 34Ketone Bodies 37Fatty Acid Synthesis 38Insulin Signaling in Lipid Metabolism 41Metabolism of Glycerolipids and Sphingolipids 41The Sphingolipidoses 43Eicosanoids 45Metabolic Changes During Fasting 47Cholesterol 47Lipid Transport 48Disorders of Lipid Transport 52Important Lipid Modulating Drugs 53Important Cholesterol Derivatives 54Vitamin D in Calcium Homeostasis 56Important Diseases of Lipid Metabolism 57Review Questions 58

3. Amino Acid MetabolismBiologically Important Amino Acids 61Overview of Amino Acid Metabolism 61

Biosynthesis of the Nonessential Amino Acids 62Important Amino Acid Derivatives 65The Essence of Protein Synthesis 65Protein Degradation 67Overview of Amino Acid Degradation 68The Urea Cycle 69Regulation of the Urea Cycle 69Hepatic Encephalopathy and Urea Cycle Defects 70Ammonia Transport - The Glutamine Cycle 71The Alanine Cycle 71Catabolism of Amino Acid Carbon Skeletons 72Insulin and Glucagon in Amino Acid Metabolism 74Porphyrin and the Porphyrias 74Important Diseases of Amino Acid Metabolism 76Review Questions 76

4. Nucleotide MetabolismBiologically Important Nucleotides 79Purine Biosynthesis 80Purine Salvage 82Synthesis of Deoxyribonucleotides 82Purine Degradation - Production of Uric Acid 83Pathophysiology of Gout 84Pyrimidine Biosynthesis 85Pyrimidine Salvage 87Pyrimidine Degradation 87Rational Drug Design 87Important Diseases of Nucleotide Metabolism 88Review Questions 88

Appendix 1. VitaminsThe Fat Soluble Vitamins 89The Water Soluble Vitamins 90NAD+/NADH and FAD/FADH2 89Pyridoxal and Pyridoxamine 91Folic Acid and Vitamin B12 91Review Questions 92

Appendix 2. Questions and AnswersIntegration Questions 93Answers 95

Index 98

FOREWORDBack in the bad old days, biochemistry seemed like a tedious litany of metabolic pathways—relevant to clinical practice chiefly as a hurdle and rite of passage in medical school. You slogged through a massive tome (costing a significant frac-tion of your monthly living expenses), hopefully extracting the essentials that would get you through the exams. A year and a half later, you fell into the time-honored tradition of shelling out an additional smaller bundle to get the biochem-istry review book that would help you get through the Board exam. And then you promptly forgot 90% of it.

Fast forward to the brave new world of genomics and proteomics, a deluge of sequences and gel bands that allow the modeling of whole systems…and bring us to the brink of a whole new “omics”—metabolomics. Suddenly, the salient features of glycolysis have ramifications for cancer biology (Warburg effect, anyone?), mitochondrial dysfunction lies at the heart of myriad diseases, and we increasingly have the capacity to design small molecule targets for a host of those previously esoteric biochemical pathways. Intermediary metabolism (AKA: biochemistry) has become relevant not only as a basic foundational building block in medical education but stands to provide some real therapeutic break-throughs.

So you need to understand this stuff…just preferably without spending a fortune or getting bogged down in the arcane details. With all the other material you’ve got to master in med school, the more focused, organized, and relevant you can get biochemistry the first time, the better. Moreover, if it’s accessible and understandable and pithy, you’ll come back to it again and again, like visiting an old friend.

Simply put, Vijay’s Underground Guide to Medical Biochemistry and Metabolic Disease is what you need and truly all you need to prime your Biochemistry pump…and provide the fundamental framework for med school, the Boards…and beyond. Does it hold every detail? No. If you buy it and don’t read it, will you pass the exam? No. Does it hold all the secrets of the universe? Not really. However, what it will do is provide the essentials in a crisp and elegant fashion, organize your thinking, and reduce your anxieties. I know this first hand because the students we’ve taught swear by it, and they did great in the course…and beyond.

Enjoy.

Rick Mitchell, MD, PhDAssociate Director of the Harvard-MIT Division of Health Sciences and Technology Lawrence J. Henderson Associate Professor of Pathology, Harvard Medical School

INTRODUCTIONThe purpose of this book is to efficiently provide students with the essentials of medical biochemistry that every medical student should know. Having served as a teaching as-sistant in biochemistry at Harvard Medical School in the Division of Health Sciences and Technology (HST) for three years, I came to realize that no current textbook delivers this material efficiently. With the limited time and ever increasing amount of information out there, I hope this book will provide everything you need to know and nothing more.

There are three strategies to approaching anything in medical school. The first is to see the amount of material you have, be overwhelmed, and cover only a portion of what you need to know. The second is to spend countless days and nights poring through everything you’ve been given and memorize it down to the last detail. The third is to really under-stand why you are learning what you are learning so that you can really remember those details well into the future when you will use them. This third strategy is clearly the ideal

one but is difficult to accomplish because we don’t intrinsically know what the key concepts are before we begin. That’s where this book is designed to help you. I have tried to emphasize key points so that you can develop that understanding of what is important and what isn’t – and focus only on what is!

In using this book, your goal should really be twofold: 1) to understand the points of a metabolic pathway that con-tribute to disease pathogenesis and 2) to understand the points of those pathways that are therapeutically targeted and potentially targetable in the future. When you look at every pathway with these two goals in mind, it really comes alive and bears meaning that you might not have appreciated before. The importance of biochemistry within medicine is unquestionably growing, with new discoveries in all aspects of metabolism, from new work on the Warburg Effect in carbohydrate metabolism, expanding discoveries on the pharmacology of eicosanoids and cholesterol in the realm of lipid metabolism, and the continuing investigation of proteasome inhibitors and nucleotide metabolism inhibitors as chemotherapeutics within the realms of amino acid and nucleotide metabolism, respectively. Understanding biochem-istry will be central to taking care of patients and making new discoveries in medicine.

Most of the material in this book was written in 2008, when I first taught HST biochemistry, and was primarily designed to be review notes for the students. My students were so happy with my notes that they bound a copy of my notes into a book that they gifted me. They called it “Vijay’s Underground Guide to Biochemistry,” which is where the title of this book originated. Since that time, numerous people have encouraged me to turn this material into a book so that more people could benefit from it. It is my sincere hope that in finally putting this book together, I have provided a useful ser-vice to fellow medical students throughout the country.

In making this book possible, a number of people helped me tremendously. My first class of students in 2008 inspired me to write these notes and encouraged me to compile them into this book. Dr. Richard N. Mitchell, the Associate Master of Health Sciences and Technology, and Dr. Charles N. Serhan, Professor of Anesthesiology and Biochemistry at Harvard Medical School, gave me invaluable advice throughout this process. Most importantly, I have to thank my parents and sister who stand by me no matter what endeavor I take on and without whose support this would not have been possible. I also thank the Paul and Daisy Soros Fellowship for their assistance over my medical school years.

With all my best,

Vijay YanamadalaHarvard Medical School, Class of 2011

19

takes UDP-glucose as its substrate and adds it to a preformed glycogen chain, releasing UDP in the process. This UDP is then freed to reform UTP for continued production of UDP-glucose. This is shown in figure 1.14. Glycogen syn-thase is the rate limiting enzyme of glycogen synthesis and is highly regulated. Its activity is upregulated by G6P. Its activity is also highly regulated by phosphorylation and dephosphorylation. It is active in the dephosphorylated state and inactive in the phosphorylated state. In turn, Glycogen Synthase Kinase 3 (GSK3) phosphorylates glycogen synthase and various phosphatases dephosphorylate it.

Insulin and glucagon are important regulators of glycogen synthase activity. Insulin activates Akt, a kinase that phos-phorylates and inactivates GSK3, thus leading to the overall dephosphorylation of glycogen synthase and its main-tenance in an active state. On the other hand, glucagon and epinephrine both activate the heterotrimeric G protein, Gαs, leading to cAMP production and PKA activation, ultimately leading to activation of GSK3 and inhibition of the phosphatase, thus leading to glycogen synthase phosphorylation and inactivation.

The third step in glycogen synthesis is branching. Once a chain is at least 11 residues long, branching occurs: specifical-ly, amylo-(1,4-1,6)-transglyco-sylase (the branching enzyme) removes a chain of 6-7 glucoses and attaches it to another chain by an α1→6 glucosidic bond, as shown in figure 1.15.

Glycogenolysis: The first step of glycogenolysis is the the hy-drolysis of terminal glucose resi-dues to glucose-1-phosphate by glycogen phosphorylase. This requires the addition of inorgan-

Figure 1.11. The Malate Shuttle

Figure 1.12. Representations of glycogen linkages

Glycogen and Glycogen Storage Disorders

28 Carbohydrate Metabolism

REVIEW QUESTIONS

Choose the correct answer(s) for the following questions (each question may have multiple cor-rect answers).

1. Which of the following vitamins and minerals is not required for the conversion of glucose to acetyl-CoA? A. Calcium B. Cobalamin (Vitamin B12) C. Lipoic Acid D. Magnesium E. Niacin (Vitamin B3) F. Pantothenate (Vitamin B5) G. Phosphate H. Riboflavin (Vitamin B2) I. Thiamine (Vitamin B1)

2. Which of the following statements about glucose transport is false? A. Glucose is actively transported across the apical membranes of enterocytes. B. Glucose diffuses in a concentration-de pendent manner through GLUT1 into neurons and erythrocytes. C. Hexokinase is able to generate a constant flux of glucose across the plasma membrane because it converts glucose to glucose-6- phosphate, which does not readily cross the plasma membrane. D. Glucose passively diffuses through Glut4 into β-cells of the pancreas, where it induces insulin release. E. Glucose diffuses through the basolateral mem brane of enterocytes via GLUT1. 3. Which of the following enzyme deficiencies is incor-rectly matched with a common presenting symptom? A. Glycogen Synthase Deficiency – early severe hypoglycemia B. Lysosomal α-glucosidase Deficiency – infant heart failure C. Glucose-6-Phophate Dehydrogenase Defi ciency – lactic acidosis and hypoglycemia D. Galactokinase Deficiency – liver failure

E. Essential Fructosuria – mental retardation F. Glucose-6-Phosphatase Deficiency – hemo lytic anemia

4. A neonate is admitted to the hospital with severe fasting hypoglycemia. He has no hepatomegaly on physical exam. A liver biopsy is performed and studies reveal no glycogen stores. Which of the following proteins could he be miss-ing? Please circle the appropriate answer(s). A. Glycogen phosphorylase B. Glycogenin C. UDP-glucose pyrophosphorylase D. G6P dehydrogenase E. Glycogen synthase F. Phosphorylase kinase

5-8. Each of the following cell types are capable of carry-ing out the oxidative phase of the hexose monophosphate shunt. Match the cellular process that the product of the oxidative phase is required for in each of these cell types. A. oxidative burst B. reduction of glutathione C. fatty acid synthesis D. steroid synthesis

5. Hepatocytes (liver) 6. Leydig cells (testis) 7. Erythrocytes 8. Neutrophils

34 Lipid Metabolism

Acylcarnitine Translocase then allows the acylcarnitine to enter the mitochondrial matrix in exchange for a free carni-tine molecule. Within the matrix, carnitine palmitoyl-transferase II then serves to convert acyl-carnitine back to acyl-CoA. The acyl-CoA is then metabolized within the mitochondrial matrix by a process known as β-oxidation. Carnitine Palmitoyl-transferase I is generally regarded as the rate limiting enzyme of fatty acid oxidation. As such, it is highly regu-lated. Malonyl-CoA, a key intermediate in fatty acid synthesis, inhibits CPTI, thus inhibiting oxidation of fatty acids while synthesis is actively taking place. Insulin also influences the activity of CPTI, as described subsequently.

Carnitine deficiencies can result in a syndrome called fasting hypoketotic hypoglycemia. The syndrome is associated with muscle weakness and myoglobinuria after prolonged exercise (as muscle breaks down, releasing myoglobin). The same symptoms are seen with genetic defects in the carnitine palmitoyl transferase I.

Short and medium chain fatty acids (less than 12 carbons) freely penetrate the inner mitochondrial membrane in their nonionized forms and are simply activated by an acyltransferase to acyl-CoA within the mitochondrial matrix.

FATTY ACID b-OXIDATION

Within the mitochondrial matrix, fatty acids are oxidized two carbons at a time from the carboxyl end to form units of acetyl-CoA. This acetyl-CoA then enters the TCA cycle. The bond between the α and the β carbons is cleaved, hence the name β-oxidation. The general scheme of β-oxidation is shown in figure 2.10.

Congenital defects in the medium chain acyl-CoA Dehydrogenase (MCAD) lead to the accumulation of medium chain fatty acids in the mitochondria. Because medium chain fatty acids are an important source of acetyl-CoA that supplies the energy required for gluconeogenesis and ketone body synthesis (as we will later learn), this disorder is also associated with fasting hypoketotic hypoglycemia. Symptoms can include vomiting, coma, and death due to insuf-ficient energy delivery to the brain.

Figure 2.9. The Carnitine Shuttle allows for the transport of activated fatty acids in the form of acyl-CoA into the mitochondrial matrix, where oxidation occurs. CPTI is Carnitine Palmitoyl Transferase I, and is the rate limiting step of the shuttle. CPTII is Carnitine Palmitoyl Transferase II.

44 Lipid Metabolism

phages of the brain, called microglia, to form multinucleated giant cells, called globoid cells. This is the histological pathognemonic of this disease. Early symptoms of the disease result from neurodegeneration with developmental delay, hypotonia, microcephaly and absent reflexes. Eventually seizures develop, with death ensuing.

Fabry Disease: a-galactosidase A deficiency results in the accumulation of ceramide trihexoside primarily within endothelial cells, leading to compromised blood flow and the formation of abnormal capillaries called angiokeratomas. Compromised blood flow within the capillary beds of the kidney lead to renal failure, while angiokeratomas form in the skin and corneas, leading to corneal clouding.

Some of these diseases can be treated with enzyme replacement therapy, as listed in table 2.2. Because cells are con-stantly endocytosing material from the extracellular space, it is possible to simply intravenously infuse a patient with functional enzyme. Because these lysosomal enzymes are normally functional only at the acidic pH of the lysosome, they are harmless in the blood and extracellular fluid. Once they are endocytosed, they end up in lysosomes of the cell, where they can be activated by the acidic pH and perform their degradative function.

There are two other major lysosomal storage disorders that are not defects in sphingolipid metabolism but rather de-fects in glycosaminoglycan metabolism, called mucopolysaccharidoses. These are Hurler Syndrome and Hunter Syn-drome. Hurler Syndrome results from a deficiency in α-L-iduronidase. The disease is associated with corneal clouding and mental retardation. Hunter Syndrome results from a deficiency in iduronate sulfatase and results in a milder form of disease associated with some mental retardation but no corneal clouding. Hunter Syndrome is X-linked recessive.

Table 2.2. The Sphingolipidoses

50 Lipid Metabolism

acids are slowly removed. These chylomicrons then interact with HDL once again, now exchanging Apo CII and getting Apo E, becoming chylomicron remnants. Chylomicron remnants are important in the process of reverse cholesterol transport, which will be described subsequently. Apo E binds to the LDL receptor or the LDL-receptor Related Protein (LRP), and these chylomicron remnants are then endocytosed by the liver, thus completing the chylomicron life cycle.

Summary of Chylomicrons• Least dense of lipoproteins• Formed in smooth ER of intestinal mucosa and secreted into lymphatics to transport dietary lipids• Triacylglycerol in the chylomicrons is hydrolyzed by LPL in vasculature of cardiac, skeletal muscle and adipose tissue• Apo B48 is unique to chylomicrons• Apo C-II activates LPL and results in fatty acid release to the heart, skeletal muscle, and mammary glands• Apo E allows clearance of chylomicron remnants by the liver by binding to the LDL receptor on hepatocytes

VLDL, IDL, and LDL: As you remember, there are two sources of cholesterol and triglycerides – the diet and the liver! Hence there are two modes of delivery. As the chylomicron is the delivery system for lipids absorbed through the diet, the VLDL system is the mode of systemic delivery for lipids synthesized by the liver. The pathways for the two systems are remarkably similar, but different in some very critical ways! The majority of the cholesterol in the body is synthe-sized in the liver – this far outweighs the amount of cholesterol received through the diet!

In the liver, hepatocytes do not possess the APOBEC1 editing machinery and thus synthesize Apo B-100, the full length Apo B protein. This is then translipidated by MTP in the liver to form VLDL. The liver then secretes VLDL particles

Figure 2.20. The Chylomicron Cycle.

98

IndexNumbers

1,3-bisphosphoglycerate (1,3BPG) 131-α-hydroxylase 562,3-bisphosphoglycerate (2,3BPG) 132,3-bisphosphoglycerate phosphatase 133β-hydroxysteroid dehydrogenase 555-fluorouracil 876-mercaptopurine 817α-hydroxylase 5411β-hydroxylase 5517α-hydroxylase 5521-hydroxylase 5525-hydroxylase 56

A

ACAT 49acetaminophen 45acetoacetate 37, 41, 72acetyl-CoA 14-16, 21, 28, 34-41, 47-48, 70, 72Acetyl-CoA Carboxylase 38, 41, 97acetyl-coenzyme A see acetyl-CoAAcute Intermittent Porphyria 74, 96Acyl-CoA Synthetase 33adenine 79, 82Adenine Phosphoribosyltransferase 82, 88adenosine 18, 63, 79, 80, 83, 88, 94, 96, 97Adenosine Deaminase 83, 93, 97

deficiency 83adiponectin 27adipose 10, 22, 39, 41, 42, 49, 50ADP 13, 14, 15, 17, 18, 69, 79adrenal gland 22, 37, 54, 55, 58Acute Respiratory Distress Syndrome 32a-galactosidase A 44a-ketoglutarate 18, 93, 97a-Ketoglutarate Dehydrogenase 15a-L-iduronidase 44, 94a-linolenic acid 31Akt 19, 24alanine 13, 14, 61, 62, 69, 70, 71, 72, 73, 87, 88Alanine Aminotransferase see ALTalanine cycle 71Aldolase 12, 26, 27

Aldolase A deficiency 12Aldolase B 26, 94

aldosterone 54Alkaptonuria 73, 76, 94allopurinol 85, 88, 96ALT 14, 62, 63, 69, 72, 73amino acid 5, 14, 36, 47, 61-76, 91

glucogenic 36, 72, 73ketogenic 72, 73, 96nutritionally essential and non-essential 61

ammonia 62, 68, 69, 70, 71, 72, 74, 76

AMP 11, 33, 69, 79, 80, 81, 82, 83, 97AMPK 11, 26, 27, 41anandamide 47Andersen Disease 21androgen 55anemia 12, 13, 24-28, 43, 61, 64, 76, 85, 95-98

hemolytic anemia 12, 13, 24, 27, 95megaloblastic anemia 64, 85, 92, 97

antimycin A 17APOBEC1 (ApoB Editing Complex 1) 49arachidonic acid 31, 45, 46, 47arginine 61, 65, 68, 69, 70, 73Arginosuccinase 69arginosuccinate 68, 69Arginosuccinate Lyase 69Arginosuccinate Synthase 69Aromatase 55arsenic 14Asparagine Synthase 62aspartate 13-18, 61-62, 67-72, 85-88, 96, 97aspartate-arginosuccinate shunt 68, 69, 72Aspartate Transcarbamoylase 85aspirin 17Asthma 46Atherosclerosis 31, 51, 52, 63, 64, 94ATP 11, 13-18, 20-24, 33, 36- 38, 47, 62, 65,

67, 69, 71-86, 93, 95-97autophagy 67

B

β-cells 24, 27, 28, 95β-hydroxybutyrate 37, 41, 93β-hydroxybutyrate dehydrogenase 37β-oxidation 34, 37, 39bile acids 54biotin 21, 36Branched Chain α-ketoDehydrogenase 74brown fat 17

C

calcitriol 56calcium 14, 20, 24, 56, 57, 73cAMP 19, 79carbamoyl phosphate 69, 85Carbamoyl Phosphate Synthase I 69Carbamoyl Phosphate Synthase II 85carbon monoxide 17carnitine 3, 29, 33, 34, 58, 93Carnitine Palmitoyl Transferase I 33Carnitine Palmitoyl Transferase II 34catecholamine 54Catechol-O-Methyltransferase 65CETP 51, 52, 54, 58, 95

CETP inhibitors 54chemiosmotic theory 17chemotherapy 11, 67, 82, 85cholesterol 3, 29, 47, 48, 49, 51, 54chylomicron 49, 50, 58

nascent chylomicron 49, 96

citrate 11, 38, 48, 93, 97Citrate Lyase 38citrate shuttle 38, 39Citrate Synthase 38citric acid cycle see TCAcitrulline 68, 69cobalamin 28, 58, 92coenzyme A 14-16, 21, 28, 33- 42, 47-48, 53,

58, 64, 70-75, 87, 93-97coenzyme Q 16colchicine 85, 88Congenital Adrenal Hyperplasia 55Congenital Lactic Acidosis 14, 27Cori cycle 22, 24cortisol 54, 56C-peptide 24creatine 18creatine phosphate 18

creatine phosphate shuttle 18creatinine 18cyanide 17Cyclooxygenase 45, 47, 85

COX1 45, 47COX2 45, 47

cystathionine 63, 76, 94Cystathionine β-synthase 63cysteine 61Cystinuria 73cytochrome C 16cytosine/cytidine 79, 87cytosol 17-21, 22, 33, 38, 39, 48, 54, 65-69, 85

D

Desmolase 55DHAP 12, 13, 17, 26, 42Diabetes Mellitus 27Diabetic Ketoacidosis 27, 41, 57Diabetic Neuropathy 10Diacylglycerol Acyltransferase 42, 49dihydrobiopterin 64, 65Dihydrobiopterin Reductase 64Dihydrobiopterin Synthase 65Dihydrofolate Reductase 82, 87Dihydrolipoyl Dehydrogenase 14Dihydrolipoyl Transacetylase 14, 27Dihydroorotase 85dihydroxyacetone-1-phosphate see DHAPdinitrophenol 17docosahexaenoic acid 31dopamine 65dyslipidemia 27

E

eicosapentaenoic acid 31electron transport chain 11, 16, 17, 37, 90encephalopathy 3, 17, 36, 58-59, 70, 76Enolase 13enzyme replacement therapy 44epinephrine 19, 20, 54, 65

99erythrocyte 10, 26Essential Fructosuria 26estradiol 55ezetimibe 54

F

F0/F1 ATPase 16, 17Fabry Disease 44FAD 3, 14, 17, 37, 79, 82, 89, 90, 91, 95Fasting Hypoketotic Hypoglycemia 34, 57fatty acid 22, 26, 28, 31-42, 47-50, 93, 95, 97

very long chain fatty acid 37trans fatty acid 31

Fatty Acid Synthase 38, 39fatty acid synthesis 15, 22, 26-41, 93, 95, 97fish oil 47folic acid (folate) 63, 89, 91, 92, 95Forbe Disease 21Fructokinase 26fructose 9, 11, 12, 22, 23, 26Fructose-1,6-bisphosphatase 22fructose-1,6-bisphosphate (F2,6BP) 11-12, 23fructose-1-phosphate 26fructose-2,6-bisphosphate 11fructose-6-phosphate 11Fructose Intolerance 26fumarate 68, 69, 72, 73, 93

G

Galactocerebrosidase 43, 94Galactokinase 26

deficiency 26galactose 3, 7, 9, 26, 27galactose-1-phosphate 26Galactose-1-phosphate Uridyltransferase 26Galactosemia 26, 27Gaucher Disease 43glucagon 12, 19, 20, 26, 41, 48, 74, 93, 97Glucan Transferase 20Glucocerebrosidase 43glucocerebroside 43glucocorticoid 54Glucokinase 11, 12, 13, 21gluconeogenesis 15, 20-26, 34-41, 47, 57,

67-76, 96glucose-1-phosphate 18, 20Glucose-6-phosphatase 20, 22, 94glucose-6-phosphate 11, 18, 20, 22, 23, 94Glucose-6-phosphate Dehydrogenase 24 deficiency 24glucose transporters 10

GLUT1 10, 28GLUT2 10, 24, 95GLUT4 10, 11, 24, 26GLUT5 11, 26

glutamate 14, 18, 49, 61-65, 68-74, 80, 88glutamate-aspartate transporter 18Glutamate Dehydrogenase 62, 69, 97Glutaminase 62, 69, 71

glutamine 61glutamine cycle 71Glutamine Synthase 62, 69, 71glutathione 22, 24, 28, 95glyceraldehyde-1-phosphate (GAP) 12, 13, 26Glyceraldehyde-1-phosphate Dehydrogenase

(GAPDH) 13, 14glycerol phosphate shuttle 13, 17, 42glycine 61glycogen 9, 10, 18, 19, 20, 21, 24, 26, 28, 42,

47, 94, 95branching 18, 21debranching 20, 94

Glycogen Phosphorylase 20, 24, 26, 28, 87, 94Glycogen Storage Disorders 95Glycogen Synthase 19, 20, 24, 26, 94, 95Glycogen Synthase Kinase 3 19glycogen synthesis 10, 18, 19, 21, 26, 42glycolysis 4, 9, 11, 12, 13, 14, 16, 17, 18, 21,

22, 23, 24, 26, 42, 63, 68, 71, 97Gout 3, 77, 84, 88

ChronicGout 84, 85, 96GTP 15, 16, 22, 37, 69, 79, 80, 81, 93, 97guanine 79, 80, 82, 83, 94, 96guanosine 79, 80, 83

H

HDL 27, 31, 49-54, 58, 92, 95Hepatic Lipase 51Her Disease 21Hexokinase 11, 12, 13Hexosaminadase A 43hexose monophosphate shunt 22, 25, 28, 95HGPRT 82, 83, 88, 94histamine 65histidine 61HMG-CoA 37, 48, 53HMG-CoA Reductase 48HMG-CoA Synthase 37Homocysteinuria 63, 73Homogentisate Oxidase 72, 73, 76, 94Hunter Syndrome 44Hurler Syndrome 44hydroxyurea 82hyperammonemia 36, 58, 70, 76, 92, 96hyperphenylalaninemia 64hypertension 27, 47, 53, 55, 73hyperuricemia 26, 83, 84, 85, 88

I

Iduronate Sulfatase 44IMP Dehydrogenase 81inosine 80, 82, 83insulin 10, 12, 14-15, 20, 24, 26-28, 38, 41, 48,

56-57, 74, 93, 95, 97insulin resistance 27insulin synthesis and secretion 24insulin action 24

Intermittent Branched-Chain Ketonuria 74

isoleucine 61Isovaleric Acidemia 74

K

ketone body 34, 37, 41, 73kidney 15, 21, 43, 44, 45, 46, 54, 56, 57, 65,

71, 73, 82, 84, 85, 88kidney stone 88Krabbe Disease 43Krebs Cycle see TCAKwashiorkor 61, 76

L

lactate 11, 13, 14, 17, 22, 37Lactate Dehydrogenase 14lactic acidosis 14, 15, 17, 21, 22, 27, 28

Congenital Lactic Acidosis 14, 27lactulose 71LCAT 49, 51, 58, 95LDL 27, 31, 50-58, 92, 95, 96leflunimide 87Lesch-Nyhan Syndrome 82, 83, 88, 94leucine 61linoleic acid 31lipoic acid 14lipoprotein 49, 51-59

AI 49, 51, 54, 58, 95B-48 49, 58B-100 49, 50, 51, 58C-II 49, 50E 28, 49, 50, 51, 58

Lipoprotein Lipase 49, 51, 54, 58Lipoxygenase 47liver 10, 11, 15, 20-28, 37, 38, 39, 41, 43, 47-

58, 61-63, 69, 70-74, 76, 83, 92, 94, 95liver failure 21, 26-28, 37, 58, 63, 70-76, 92lysine 61lysosome 44, 67

M

magnesium 14, 28malate 13, 17, 18, 21, 22, 93malate shuttle 13, 17malonyl-CoA 38, 39, 41Marasmus 61, 76Maturity Onset Diabetes of the Young 27MCAD 34, 58McArdle Disease 21melanin 64MELAS 17melatonin 65Metabolic Syndrome 27metformin 26Methemoglobinemia 75, 94methionine 61Methionine Synthase 63methotrexate 82, 87Methylmalonic Acidemia 36Methylmalonyl-CoA Isomerase 36

100Methylmalonyl-CoA Racemase 36mevalonate 48Microsomal Transfer Protein 49, 50, 58, 95mineralocorticoid 54, 55mitochondria 11, 12, 14, 15, 17, 34, 37, 85mitochondrial matrix 13-21, 33-39, 68-69Monoamine Oxidase 65Multiple Sclerosis 32mycophenolate mofetil 81

N

N5-formyltetrahydrofolate 82N5,N10-methylenetetrahydrofolate 85N-acetylglutamate 70, 85, 93, 96, 97NADH 3, 11-18, 22, 24, 36-41, 75-82, 89-95NADH-cytochrome b5 reductase 75NADPH 22, 24, 39, 48, 54, 62-65, 79, 82, 95Na+/K+-ATPase 10, 61niacin 14, 95Niemann-Pick Disease 43, 94norepinephrine 65Nucleoside Phosphorylase 87nucleotide 5, 22, 79, 81, 83, 87, 96

O

obesity 27oligomycin 17ornithine 68, 69, 70Ornithine Transcarbamoylase 68, 69Osteomalacia 56oxaloacetate 18-22, 36, 38, 62, 69, 72, 93, 97oxidative phosphorylation 3, 7, 13, 17oxidative stress 46, 47

P

palmitic acid (palmitate) 31, 32, 38, 39pancreas 10, 11, 27, 28, 61, 95pantothenate (pantothenic acid) 14, 28, 58partial hydrogenation 31peroxisomes 37phenylalanine 61Phenylalanine Hydroxylase 64, 65, 74, 76, 96Phenylketonuria 64, 65, 74, 96Phosphoglucomutase 18phosphoenol pyruvate 13Phosphoenolpyruvate Carboxykinase 15, 22Phosphofructokinase-1 11, 12, 21, 22, 26Phosphofructokinase-2/fructose-2,6-bisphos-

phatase 11Phosphoglycerate Mutase 13Phosphohexose Isomerase 11Phospholipase A2 45phospholipid 32, 46phosphoribosylamine 80phosphoribosyl pyrophosphate see PRPPphosphorylation 3, 7, 11, 12, 17, 41p-Hydroxyphenylpyruvate Hydroxylase 73PI3K (PI3 Kinase) 10, 24Protein Kinase A (PKA) 12, 19, 20, 38, 41

PLTP 51, 58, 95Pompe Disease 21Porphyria 74, 76, 96Porphyria Cutanea Tarda 74porphyrin 3, 59, 65, 74, 76Primary Hyperoxaluria 73probenecid 85, 88progesterone 55proline 61propionic acid and derivatives 36, 58, 63, 96Propionic Acidemia 36Propionyl-CoA Carboxylase 36prostacyclin 47prostaglandin 45, 47, 85proteasome 5, 67PRPP 80, 81, 82, 86, 87, 93, 97PRPP Glutamyl Amidotransferase 80, 81PRPP Synthase 80, 93, 97pulmonary surfactant 32purine 80, 81, 82, 83, 84, 85, 87, 88, 91, 92, 96pyridoxal phosphate (PLP) 62, 65, 69, 89, 91pyridoxine 62, 69pyrimidine 80, 81, 85, 87, 91Pyrophosphatase 18, 33pyruvate 3, 7, 11, 13, 14, 15, 21, 27, 93, 94Pyruvate Carboxylase 21Pyruvate Dehydrogenase 13-18, 24, 38, 41Pyruvate Kinase 13, 93

deficiency 13

R

rate limiting step (rate determining step) 11, 12, 19, 22, 26, 34, 37, 38, 45, 48, 53, 54, 55, 65, 69, 70, 80

resistin 27reverse cholesterol transport 51riboflavin 14, 95, 96ribonucleotide 82, 88Ribonucleotide Reductase 82, 83, 96ribose 22, 79, 80, 83, 85, 87Richner-Hanhart Syndrome 73Rickets 56rotenone 17

S

S-adenosylhomocysteine Hydrolase 63, 64S-adenosylmethionine (SAM) 63, 64, 91S-adenosylmethionine Synthase 63serine 61, 63, 64, 76Serine Hydroxymethyltransferase 63, 92Serine Transaminase 63serotonin 65SGPT 14, 62SGOT 18Severe Combined Immunodeficiency 83, 88sorbitol 26sphingolipid 33Sphingomyelinase 43squalene 48

steroid 22, 28, 47, 48, 54, 55, 56Succinate Thiokinase 15succinyl-CoA 36SUR1 24

T

TCA 7, 11, 15-22, 34-37, 47, 62, 68-73, 87, 93testis 22, 28, 95testosterone 55tetrahydrobiopterin 64, 65tetrahydrofolate (THF) 63, 80, 82, 91, 92thiamine 14, 96Thiolase 37, 48Thiophorase 37thioredoxin 82threonine 61thromboxane 47thymidine 79, 86Thymidylate Synthase 85, 87, 91thymine 79transamination 62, 68, 69, 71, 91Triose Phosphate Isomerase 13, 61tryptophan 61tumor 11, 80, 81, 82, 85tumor lysis syndrome 85tyrosine 61, 64, 65, 66, 72, 73, 76, 96Tyrosinemia 73Tyrosine Transaminase 73

U

ubiquitin 67UDP-galactose 26, 42UDP-glucose 18, 19, 26, 28, 42UMP Synthase 85uracil 79urea cycle 65, 69, 70, 71, 72, 85, 96uric acid (urate) 82, 83, 84, 85, 88, 96Uricase 85uridine 26, 79Uridine Diphosphogalactose-4 Epimerase 26UTP 18, 19, 79, 86

V

valine 61Vioxx 47VLDL 26, 39, 49, 50, 51, 52, 53, 54, 58, 95, 96Von Gierke Disease 21, 94, 95

W

Warburg Effect 5, 11

X

Xanthine Oxidase 83X-linked Adrenoleukodystrophy 37

Z

Zellweger Syndrome 37, 58

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