Metabolism refers to the whole sum of reactions that occur throughout the body within each cell and that provide the body with energy. This energy gets used for vital processes and the synthesis of new organic material. Every living organism uses its environment to survive by taking nutrients and substances that act as building blocks for movement, growth, development, and reproduction. All of these are mediated by enzymes, which are proteins with specialized functions in anabolism and catabolism. The rate of energy production is called the basal metabolic rate and is affected by factors such as sex, race, exercise, diet, age, and diseases such as sepsis or cancer.
The chemical reactions by which metabolism occurs is almost the same in all living organisms that include animals, plants, bacteria, and fungi. All these chemical reactions are mediated by proteins that act as catalysts under specific environmental conditions such as pH and temperature. The synthesis of many of the catalysts that mediate chemical reactions throughout our body has its origins in DNA. The deoxyribonucleic acid is the molecule residing within the nucleus, is made of four bases called adenine, guanine, cytosine, and thymine. RNA is the molecule used by some living organisms instead of DNA, and this molecule is comprised of ribose and uracil instead of thymine. The environment, mostly plants, use sunlight to transform water and carbon dioxide to synthesize carbohydrates. Living organisms do the opposite, consuming carbohydrates and other organic materials to produce energy.
It is impossible to discuss metabolism without taking a look at the laws of thermodynamics. The first two laws, particularly, merit particular attention. The first two laws of thermodynamics state that energy can neither be created nor destroyed and that the outcome of physical and chemical changes is to increase entropy in the universe. The energy that is actually useful, or free energy, is that kind of energy capable of doing work under no difference of temperature. Less useful forms of energy become liberated in the form of heat.
The chemical carrier of energy is called ATP. Synthesis of ATP takes place within an intracellular organelle bounded by an external membrane and an inner membrane. The dissociation of water to a molecule of hydrogen and a hydroxyl group that takes place in the inner milieu of the body is essential for the synthesis of ATP. The catabolic reactions, which will be discussed later, release significant amounts of protons, most of which are transported to the mitochondria to produce ATP. These protons are transported through a series of complexes in the inner membrane of the mitochondria to activate an ATPase, using the energy released by the electron chain transport mechanism.
The food organisms eat gets processed in three different stages. The first stage involves the reduction of complex molecules to simple molecules; this includes the breakdown of complex proteins to oligopeptides and free amino acids to facilitate absorption, the breakdown of complex sugars to disaccharides or monosaccharides and lipids are broken down to glycerol and free fatty acids. All these processes are called digestion and only make about 0.1% of energy production, which cannot be used by the cell. In the second phase, all these small molecules undergo incomplete oxidation. Oxidation means the removal of electrons or hydrogen atoms. The end-product of these processes is water and carbon dioxide, and three principal substances, namely: acetyl coenzyme A, oxaloacetate and alpha–oxoglutarate. Of these, the most common compound is acetyl coenzyme A, which forms 2/3 of the carbon in carbohydrates and glycerol, all the carbon in fatty acids and half the carbon in amino acids. The third and final phase of this process occurs on a cycle called the Krebs cycle, discovered by Sir Hans Krebs. In this cycle, acetyl coenzyme A and oxaloacetate come together and form citrate. In this stepwise reactions, occurs a liberation of protons, which are transferred to the respiration chain to synthesize ATP.
The imbalance between anabolism and catabolism can lead to obesity and cachexia, respectively. Metabolic energy is to be transported by high energy phosphate groups like ATP, GTP and creatine phosphate; or by electron carriers like NADH, FADH, and NADPH.
The pancreas is the key metabolic organ that regulates the number of carbohydrates in blood, either releasing significant amounts of insulin to downregulate the levels of blood glucose or glucagon to upregulate them. The utilization of carbohydrates and lipids by the organism is called the Randle cycle, regulated by insulin.
The liver is the organ in charge of processing the absorbed amino acids and lipids from the small intestine. It also regulates the urea cycle and essential metabolic processes like gluconeogenesis and glycogen deposition.
Characteristics of carbohydrates include being soluble, relatively easy to transport, non-toxic molecules that serve as the substrate of energy when oxygen levels are compromised.
The most energy-dense molecule are lipids and is the principal energy molecule for mammals and tissues. Because they are not soluble, they are not readily transportable in the blood, are not usable anaerobically, and they require more oxygen to extract energy from them (2.8 ATP/oxygen molecule). They cannot cross the blood-brain barrier, and erythrocytes or renal cells are unable to use them. Amino acids act as substrates to produce glucose only in states of prolonged starvation when there is depletion of glycogen stores.
The metabolism of these three principal substrates converges into one molecule, acetyl–CoA, in the mitochondria. Metabolism of this intermediate molecule generates 3 NADH, 1 FADH, 1 GTP, and 2 CO2, all of which participate in the respiratory chain in the mitochondria to synthesize ATP.
It focuses on one specific kind of sugar, glucose. After a cell uptakes a molecule of glucose, it gets immediately metabolized to glucose-6-phosphate, which cannot exit the cell. The catalyzing enzyme in this reaction is called hexokinase (in the liver and pancreas) or glucokinase in every other tissue. This metabolite is usable by almost every metabolic process, including glycolysis and glycogenesis. Carbohydrates are stored as glycogen granules for rapid mobilization of glucose when required.
Glycogen is a polymer of glucose, assembled by the glycogen synthase, with branch points every ten glucose molecules, which gives the glycogen a tree-like structure, which is beneficial for glucose mobilization. Some tissues utilize glycogen for their own maintenance, like a skeletal muscle; some other tissues use glycogen to maintain serum glucose levels stable, such as the liver. The liver can store almost 100 g of glycogen that supplies glucose for 24 hours, the skeletal muscle stores 350 g that are sufficient for 60 minutes of muscle contraction. Glucose is metabolized by glycolysis in all cells to form pyruvate. This process doesn’t use oxygen, and it generates two molecules of pyruvate, 2 NADH, and 2 ATP.
Pyruvate may have three fates within the cell: it can be transported into the mitochondria and generate acetyl–CoA, it can remain in the cytosol and generate lactate, or it can be used in glyconeogenesis by the enzyme alanine aminotransferase (ALT). The fate of pyruvate in tissues will depend on hormonal regulation, oxygen availability, and the particular tissue. For example, in the liver, excess pyruvate is metabolized to acetyl–CoA, and then this is used for lipid synthesis, whereas in muscle, it undergoes complete oxidation to CO2.
Glucose–6–phosphate is also usable by the pentose phosphate pathway. This pathway is used for the synthesis of nucleotides, synthesis of specific lipids and to maintain glutathione in its active form. This process is under the regulation of glucose–6–phosphate dehydrogenase.
Carbohydrate metabolism is regulated mainly by insulin, as it stimulates glycolysis and glycogenesis. Catecholamines, glucagon, cortisol and growth hormone, stimulate gluconeogenesis and glycogenolysis.
Fatty acids are used for energy production in oxidative tissues. Some of them are amphipathic and potentially toxic, and they are transported bounded to albumin. The intestines absorb fatty acids in the form of micelles; these get engulfed by the enterocytes in the intestinal wall. Once inside, these molecules of fat get broken down to smaller molecules, free fatty acids and glycerol that are posteriorly conjugated to form triglycerides. These are bound to proteins, to form chylomicrons outside the enterocyte.
These chylomicrons are very rich in cholesterol and triglycerides, which are transported by the portal vein system to the liver. The liver will process these complex molecules to extract a fraction of cholesterol and triglycerides. The liver secretes a new form of a complex molecule called VLDL that transports endogenous lipids and fat to peripheral tissues that express hormone-sensitive lipase and lipoprotein lipase.
This enzyme reduces VLDL into LDL, which contains more cholesterol than the other molecules, and it gets finally engulfed by target tissues. All this process is called “forward cholesterol metabolism.” When too much fat or cholesterol exists in peripheral tissues, it travels within a lipoprotein called HDL, which will enter the biliary system for excretion. This process is called “reverse cholesterol metabolism.” Both are regulated by insulin, which stimulates lipases in the organism but suppresses lipolysis.
Amino Acid Metabolism
We consume almost 100 g of protein per day. The body contains nearly 10 kg of protein that is metabolized by 300 g per day. Proteins are made of amino acids, some of them are essential (meaning that the body cannot synthesize them, they must be obtained from the diet) and non–essential amino acids (which can be synthesized). Proteins are absorbed in the form of amino acids by the enterocytes. Amino acids contain a nitrogen group, and a two-carbon skeleton called 2–oxoacid.
Metabolism of amino acids generates ammonium, which is a toxic molecule, especially for the CNS. Ammonium can be metabolized in the liver for excretion, into the ornithine (urea) cycle. Amino acid metabolism occurs into two kinds of chemical reactions. The first is called transamination, in which alanine aminotransferase (ALT) and aspartate aminotransferase (AST) participate. These two reactions require a three-carbon skeleton to interchange the amino group; the skeleton for these two enzymes is alpha-ketoglutarate. In the reaction regulated by ALT, alanine transfers the amino group to alpha-ketoglutarate to form pyruvate and glutamate. In the reaction regulated by AST, occurs the inverse situation. It takes the donated amino group from glutamate to form aspartate to donate a second amino atom to the Urea cycle. The second reaction is deamination, in which the glutamate dehydrogenase metabolizes glutamate to form alpha-ketoglutarate and ammonia, which has to be detoxified by the urea cycle.
After deamination, the skeleton undergoes intermediate metabolism. The metabolism of amino acids can yield seven types of skeleton, namely: alpha-ketoglutarate, oxaloacetate, succinyl–CoA, fumarate, pyruvate, acetyl–CoA, and acetoacetyl–CoA. The first five have three or more carbons, and they are useful for glyconeogenesis, the last two have only two carbons, and they are unusable for glyconeogenesis. Instead, they are used for lipid synthesis.
Like all the other metabolic pathways, insulin is the main regulator. In contrast, the regulator in the amino acid metabolism is cortisol and thyroid hormone that mediates muscle breakdown.
The pancreas senses glucose concentrations in blood and some amino acids such as arginine and leucine. High levels in these substances indicate nutritional repletion, and this message is sent to the body by the pancreas in the form of insulin. Insulin is the unique metabolic hormone in charge of the disposition of nutrients in the body, which means that insulin deficiency implicates pleiotropic changes in human metabolism. With insulin deficiency, there is less inhibition of catabolic responses; this drives a net mobilization of substrates from tissues. Pancreas senses metabolite status, peripheral tissues sense insulin concentration status. When peripheral tissues sense a fall in insulin, they become catabolic, and substrates start to mobilize. The liver responds to low insulin by increasing glucose synthesis with gluconeogenesis and glycogenolysis. As seen in amino acid metabolism, the principal gluconeogenic substrate is alanine, which arises from muscle waste and proteolysis. Adipose tissue responds as well, augmenting lipolysis leading to fatty acid accumulation and glycerol. Increased delivery of non-esterified fatty acids (NEFA) to the liver increases ketogenesis.
Sepsis, Trauma, and Burns
Catabolism can also initiate from an excessive inflammatory reaction, characterized by the upregulation and expression of proinflammatory cytokines such as TNF-alfa, IL-6, and IL-1. This process is called a systemic inflammatory response syndrome (SIRS). It has three phases with regards to metabolism. The ebb phase or shock phase, the catabolic phase, and the anabolic phase. In these scenarios, there is a considerable mobilization of substrate throughout the body.
It is a deficiency well distributed in equatorial regions. It is X-linked, and it reduces levels of NADPH, hence decreasing levels of the active form of glutathione and increased oxidative stress for red blood cells; this leads to hemolysis presented as a crisis, depending on the insult. It appears as Heinz bodies and blister cells on a peripheral blood smear.
|||Liu X,Chen T,Jain PK,Xu W, Revealing the Thermodynamic Properties of Elementary Chemical Reactions at the Single-Molecule Level. The journal of physical chemistry. B. 2019 Jul 25; [PubMed PMID: 31246466]|
|||Ramnanan CJ,Edgerton DS,Kraft G,Cherrington AD, Physiologic action of glucagon on liver glucose metabolism. Diabetes, obesity [PubMed PMID: 21824265]|
|||Szabo I,Zoratti M, Mitochondrial channels: ion fluxes and more. Physiological reviews. 2014 Apr; [PubMed PMID: 24692355]|
|||Hue L,Taegtmeyer H, The Randle cycle revisited: a new head for an old hat. American journal of physiology. Endocrinology and metabolism. 2009 Sep; [PubMed PMID: 19531645]|
|||KREBS HA, The tricarboxylic acid cycle. Harvey lectures. 1948-1949; [PubMed PMID: 14849928]|
|||Dashty M, A quick look at biochemistry: carbohydrate metabolism. Clinical biochemistry. 2013 Oct; [PubMed PMID: 23680095]|
|||Abumrad NA,Davidson NO, Role of the gut in lipid homeostasis. Physiological reviews. 2012 Jul; [PubMed PMID: 22811425]|
|||Goldstein JL,Brown MS, The LDL receptor. Arteriosclerosis, thrombosis, and vascular biology. 2009 Apr; [PubMed PMID: 19299327]|
|||Jaworski K,Sarkadi-Nagy E,Duncan RE,Ahmadian M,Sul HS, Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. American journal of physiology. Gastrointestinal and liver physiology. 2007 Jul; [PubMed PMID: 17218471]|
|||Peirce V,Carobbio S,Vidal-Puig A, The different shades of fat. Nature. 2014 Jun 5; [PubMed PMID: 24899307]|
|||Deutz NE,Wolfe RR, Is there a maximal anabolic response to protein intake with a meal? Clinical nutrition (Edinburgh, Scotland). 2013 Apr; [PubMed PMID: 23260197]|
|||Finn PF,Dice JF, Proteolytic and lipolytic responses to starvation. Nutrition (Burbank, Los Angeles County, Calif.). 2006 Jul-Aug; [PubMed PMID: 16815497]|
|||Vandenberg RJ,Ryan RM, Mechanisms of glutamate transport. Physiological reviews. 2013 Oct; [PubMed PMID: 24137018]|
|||Zaccardi F,Webb DR,Yates T,Davies MJ, Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. Postgraduate medical journal. 2016 Feb; [PubMed PMID: 26621825]|
|||Cecconi M,Evans L,Levy M,Rhodes A, Sepsis and septic shock. Lancet (London, England). 2018 Jul 7; [PubMed PMID: 29937192]|
|||Steiner M,Lüdemann J,Krammer-Steiner B, Favism and Glucose-6-Phosphate Dehydrogenase Deficiency. The New England journal of medicine. 2018 Mar 15; [PubMed PMID: 29542311]|