Overview Structure two types acetoacetate β-hydroxybutyrate β-hydroxybutyrate + NAD+ → acetoacetate + NADH ↑ NADH:NAD+ ratio results in ↑ β-hydroxybutyrate:acetoacetate ratio 1 ketone body = 2 acetyl-CoA Function produced by the liver brain can use ketones if glucose supplies fall >1 week of fasting can provide energy to body in prolonged energy needs prolonged starvation glycogen and gluconeogenic substrates are exhausted can provide energy if citric acid cycle unable to function diabetic ketoacidosis cycle component (oxaloacetate) consumed for gluconeogenesis alcoholism ethanol dehydrogenase consumes NAD+ (converts to NADH) ↑ NADH:NAD+ ratio in liver favors use of oxaloacetate for ketogenesis rather than gluconeogenesis. RBCs cannot use ketones as they lack mitochondria Synthesis occurs in hepatocyte mitochondria liver cannot use ketones as energy lacks β-ketoacyl-CoA transferase (thiophorase) which converts acetoacetate to acetoacetyl under normal conditions acetoacetate = β-hydroxybutyrate HMG CoA synthase is rate limiting enzyme Clinical relevance ketoacidosis pathogenesis ↑ ketone levels caused by poorly controlled type I diabetes mellitus liver ketone production exceeds ketone consumption in periphery possible in type II diabetes mellitus but rare alcoholism chronic hypoglycemia results in ↑ ketone production presentation β-hydroxybutyrate > acetoacetate due to ↑ NADH:NAD+ ratio acetone gives breath a fruity odor polyuria ↑ thirst tests ↓ plasma HCO3 hypokalemia individuals are initially hyperkalemic (lack of insulin + acidosis) because K leaves the cells overall though the total body K is depleted replete K in these patients once the hyperkalemia begins to correct nitroprusside urine test for ketones may not be strongly + does not detect Continue reading >>
Excess ketones are dangerous for someone with diabetes... Low insulin, combined with relatively normal glucagon and epinephrine levels, causes fat to be released from fat cells, which then turns into ketones. Excess formation of ketones is dangerous and is a medical emergency In a person without diabetes, ketone production is the body’s normal adaptation to starvation. Blood sugar levels never get too high, because the production is regulated by just the right balance of insulin, glucagon and other hormones. However, in an individual with diabetes, dangerous and life-threatening levels of ketones can develop. What are ketones and why do I need to know about them? Ketones and ketoacids are alternative fuels for the body that are made when glucose is in short supply. They are made in the liver from the breakdown of fats. Ketones are formed when there is not enough sugar or glucose to supply the body’s fuel needs. This occurs overnight, and during dieting or fasting. During these periods, insulin levels are low, but glucagon and epinephrine levels are relatively normal. This combination of low insulin, and relatively normal glucagon and epinephrine levels causes fat to be released from the fat cells. The fats travel through the blood circulation to reach the liver where they are processed into ketone units. The ketone units then circulate back into the blood stream and are picked up by the muscle and other tissues to fuel your body’s metabolism. In a person without diabetes, ketone production is the body’s normal adaptation to starvation. Blood sugar levels never get too high, because the production is regulated by just the right balance of insulin, glucagon and other hormones. However, in an individual with diabetes, dangerous and life-threatening levels of ketone Continue reading >>
What Is Ketone? - Definition, Structure, Formation & Formula
Background of Ketone Did you know that our friend aldehyde has a very close relative named ketone? By definition, a ketone is an organic compound that contains a carbonyl functional group. So you may be wondering if aldehydes and ketones are relatives, what makes them different? Well, I am glad you asked because all you have to remember is this little guy: hydrogen. While aldehyde contains a hydrogen atom connected to its carbonyl group, ketone does not have a hydrogen atom attached. There are a few ways to know you are encountering a ketone. The first is by looking at the ending of the chemical word. If the suffix ending of the chemical name is '-one,' then you can be sure there is a ketone present in that compound. Want to know another way to tell if a ketone is lurking around the corner? By its physical property. Ketones have high boiling points and love water (high water solubility). Let's dig a little deeper with the physical property of a ketone. The oxygen in a ketone absolutely loves to take all the electrons it can get its hands on. But, by being an electron-hogger, oxygen's refusal to share creates a sticky situation where some atoms on the ketone have more or less charge than others. In chemistry, an electron-hogging atom is referred to as being electronegative. An electronegative atom is more attractive to other compounds. This attractiveness, called polarity, is what contributes to ketones' physical properties. Structure & Formula Ketones have a very distinct look to them; you can't miss it if you see them. As shown in Diagram 1, there are two R groups attached to the carbonyl group (C=O). Those R groups can be any type of compound that contains a carbon molecule. An example of how the R group determines ketone type is illustrated in this diagram here. The Continue reading >>
Diabetic Ketoacidosis- Enzyme For Ketones Formation?
Case details A 54- year-old man with Type 1 diabetes is referred to an ophthalmologist for evaluation of developing cataract. Blood chemistry results are shown below- Fasting blood glucose 198 mg/dl Hemoglobin A 15 gm/dl Hemoglobin A 1c 10% of total Hb Urine ketones Positive Urine glucose Positive Which of the following enzymes is most strongly associated with ketones formation in this patient? A) Pyruvate dehydrogenase complex B) Thioesterase C) Thiophorase D) Thiokinase E) Thiolase. The correct answer is- E- Thiolase. Out of the given options thiolase is the only enzyme involved in the ketogenesis. The process of ketogenesis starts from the action of thiolase. In fact, the actual specific enzyme for ketogenesis is HMG Co A Synthase (mitochondrial isoform) which is not mentioned in the given options. Ketone bodies Acetoacetate, D (-3) -hydroxybutyrate (Beta hydroxy butyrate), and acetone are often referred to as ketone bodies (figure-1). Figure-1- Acetoacetate is the primary ketone body, the other ketone bodies are derived from it. The term “ketones” is actually a misnomer because beta-hydroxybutyrate is not a ketone and there are ketones in blood that are not ketone bodies, e.g., pyruvate, fructose. Ketogenesis takes place in liver using Acetyl co A as a substrate or a precursor molecule. Enzymes responsible for ketone body formation are associated mainly with the mitochondria. Steps of synthesis Acetoacetate (First ketone body) is formed from acetyl CoA in three steps (Figure-2). 1) Two molecules of acetyl CoA condense to form Acetoacetyl CoA. This reaction, which is catalyzed by thiolase, is the reverse of the thiolysis step in the oxidation of fatty acids. 2) Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) Continue reading >>
To gain a better understanding of ketosis and the ketogenic diet, it is important to take a look at the physiology behind the diet. If you recall from the article What is a Ketogenic Diet? the goal of a ketogenic diet is to induce ketosis by increasing ketone body production. A key step in understanding the diet is to learn what ketosis is, what are ketones and what do they do. “Normal” Metabolism Learning the basics of the various metabolic processes of the body will better your ability to understand ketosis. Under the normal physiological conditions that are common today, glucose is our body’s primary source of energy. Following ingestion, carbohydrates are broken down into glucose and released into the blood stream. This results in the release of insulin from the pancreas. Insulin not only inhibits fat oxidation but also acts as a key holder for cells by allowing glucose from the blood to be shuttled into cells via glucose transporters (GLUT). The amount of insulin required for this action varies between individuals depending on their insulin sensitivity. Once inside the cell, glucose undergoes glycolysis, a metabolic process that produces pyruvate and energy in the form of adenosine triphosphate (ATP). Once pyruvate is formed as an end product of glycolysis, it is shuttled into the mitochondria, where it is converted to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA then enters the TCA cycle to produce additional energy with the aid of the electron transport chain. Since glucose is so rapidly metabolized for energy production and has a limited storage capacity, other energy substrates, such as fat, get stored as triglycerides due to our body’s virtually infinite fat storage capacity. When a sufficient source of carbohydrates is not available, the body adap Continue reading >>
Ketosis, Ketone Bodies, And Ketoacidosis – An Excerpt From Modern Nutritional Diseases, 2nd Edition
The following text is excerpted from Lipids (Chapter 8) of Modern Nutritional Diseases, 2nd Edition. Ketone Bodies and Ketosis: Ketones are organic chemicals in which an interior carbon in a molecule forms a double bond with an oxygen molecule. Acetone, a familiar chemical, is the smallest ketone possible. It is composed of three carbons, with the double bond to oxygen on the middle carbon. Biological ketone bodies include acetone, larger ketones, and biochemicals that can become ketones. The most important of the ketone bodies are hydroxybutyrate and acetoacetate, both of which are formed from condensation of two acetyl CoA molecules. Acetone is formed from a nonenzymatic decarboxylation of acetoacetate. Ketone bodies are fuel molecules that can be used for energy by all organs of the body except the liver. The production of ketone bodies is a normal, natural, and important biochemical pathway in animal biochemistry (17, p. 577). Small quantities of ketone bodies are always present in the blood, with the quantity increasing as hours without food increase. During fasting or carbohydrate deprivation, larger amounts of ketone bodies are produced to provide the energy that is normally provided by glucose. Excessive levels of circulating ketone bodies can result in ketosis, a condition in which the quantity of circulating ketone bodies is greater than the quantity the organs and tissues of the body need for energy. People who go on extremely low-carbohydrate diets to lose a large excess of body fat usually go into a mild ketosis that moderates as weight is lost. There is no scientific evidence that a low-carbohydrate diet is capable of producing sufficient ketone bodies to be harmful. Excess ketone bodies are excreted by the kidneys and lungs. Exhaled acetone gives the brea Continue reading >>
There is a lot of confusion about the term ketosis among medical professionals as well as laypeople. It is important to understand when and why nutritional ketosis occurs, and why it should not be confused with the metabolic disorder we call ketoacidosis. Ketosis is a metabolic state where the liver produces small organic molecules called ketone bodies. Most cells in the body can use ketone bodies as a source of energy. When there is a limited supply of external energy sources, such as during prolonged fasting or carbohydrate restriction, ketone bodies can provide energy for most organs. In this situation, ketosis can be regarded as a reasonable, adaptive physiologic response that is essential for life, enabling us to survive periods of famine. Nutritional ketosis should not be confused with ketoacidosis, a metabolic condition where the blood becomes acidic as a result of the accumulation of ketone bodies. Ketoacidosis can have serious consequences and may need urgent medical treatment. The most common forms are diabetic ketoacidosis and alcoholic ketoacidosis. What Is Ketosis? The human body can be regarded as a biologic machine. Machines need energy to operate. Some use gasoline, others use electricity, and some use other power resources. Glucose is the primary fuel for most cells and organs in the body. To obtain energy, cells must take up glucose from the blood. Once glucose enters the cells, a series of metabolic reactions break it down into carbon dioxide and water, releasing energy in the process. The body has an ability to store excess glucose in the form of glycogen. In this way, energy can be stored for later use. Glycogen consists of long chains of glucose molecules and is primarily found in the liver and skeletal muscle. Liver glycogen stores are used to mai Continue reading >>
How Are Ketones Formed?
Ketones are a very important functionnal group in organic chemistry, and thus there are several ways to prepare them, the 2 most common being oxidations, and reductions. The first is straightforward. You can oxidize a secondary alcohol to a ketone. There are a lot of reagents that can do that, the most practical are probably the hypervalent iodine reagents (IBX, Dess-Martin periodinane, although the latter is more used for oxidation of primary alcohol to the aldehyde). Chromium and Manganese oxides can also be used, in some cases. Then there are the methodologies which will cleave a double bond and give you two ketones, like ozonolysis, or Osmium oxide reaction on double bonds. The second is a bit more devious: because it doesn't look like a typical reduction. But when a organocopper, organizinc or organomagnesium reagent (or other organometallic reagents, these are just the most commonly used in the lab), when they react with an acid derivative, it is a reduction ( the oxidation of the carbon goes from +3 to +2). Possibilities include reaction of the organometallic reagent with anhydrides or acyl chlorides, possibly catalyzed by a transition metal (Ni, Pd, Co, Fe…), reactions with Weinreb amides , or with morpholine amides, in the case of Grignard reagents. Remember that you cannot use directly an ester and a Grignard, apart from the 2 aforementioned cases, the ketone will be more reactive and thus the Grignard will react with the ketone as soon as it is formed, to form the tertiary alcohol. You can use carbonylation reactions. In these reactions, you use a nucleophile (typically an organostannane, but other can be used), an electrophile (usually an aryl or vinyl halide), under carbon monoxide atmosphere, with a Palladium catalyst. There's also the Pauson-Khand react Continue reading >>
Clinical Review: Ketones And Brain Injury
Abstract Although much feared by clinicians, the ability to produce ketones has allowed humans to withstand prolonged periods of starvation. At such times, ketones can supply up to 50% of basal energy requirements. More interesting, however, is the fact that ketones can provide as much as 70% of the brain's energy needs, more efficiently than glucose. Studies suggest that during times of acute brain injury, cerebral uptake of ketones increases significantly. Researchers have thus attempted to attenuate the effects of cerebral injury by administering ketones exogenously. Hypertonic saline is commonly utilized for management of intracranial hypertension following cerebral injury. A solution containing both hypertonic saline and ketones may prove ideal for managing the dual problems of refractory intracranial hypertension and low cerebral energy levels. The purpose of the present review is to explore the physiology of ketone body utilization by the brain in health and in a variety of neurological conditions, and to discuss the potential for ketone supplementation as a therapeutic option in traumatic brain injury. Introduction Ketogenesis is the process by which ketone bodies (KB), during times of starvation, are produced via fatty acid metabolism. Although much feared by physicians, mild ketosis can have therapeutic potential in a variety of disparate disease states. The principle ketones include acetoacetate (AcAc), β-hydroxybutyrate (BHB) and ace-tone. In times of starvation and low insulin levels, ketones supply up to 50% of basal energy requirements for most tissues, and up to 70% for the brain. Although glucose is the main metabolic substrate for neurons, ketones are capable of fulfilling the energy requirements of the brain. The purpose of the present review is to e Continue reading >>
The term “ketone bodies” refers primarily to two compounds: acetoacetate and β‐hydroxy‐butyrate, which are formed from acetyl‐CoA when the supply of TCA‐cycle intermediates is low, such as in periods of prolonged fasting. They can substitute for glucose in skeletal muscle, and, to some extent, in the brain. The first step in ketone body formation is the condensation of two molecules of acetyl‐CoA in a reverse of the thiolase reaction. The product, acetoacetyl‐CoA, accepts another acetyl group from acetyl‐CoA to form β‐hydroxy‐β‐hydroxymethylglutaryl‐CoA (HMG‐CoA). HMG‐CoA has several purposes: It serves as the initial compound for cholesterol synthesis or it can be cleaved to acetoacetate and acetyl‐CoA. Acetoacetate can be reduced to β‐hydroxybutyrate or can be exported directly to the bloodstream. Acetoacetate and β‐hydroxybutyrate circulate in the blood to provide energy to the tissues. Acetoacetate can also spontaneously decarboxylate to form acetone: Although acetone is a very minor product of normal metabolism, diabetics whose disease is not well‐managed often have high levels of ketone bodies in their circulation. The acetone that is formed from decarboxylation of acetoacetate is excreted through the lungs, causing characteristic “acetone breath.” Continue reading >>
Ketone Bodies Metabolic Pathway (pw:0000069)
Description The ketone bodies metabolic pathway is used to convert acetyl-CoA formed in the liver into "ketone bodies": acetone, and more importantly acetoacetate and 3-hydroxybutyrate, which are transported in the blood to extrahepatic tissues where they are converted to acetyl-CoA and oxidized via the citrate cycle pathway for energy. The brain, which usually uses glucose for energy, can utilize ketone bodies under starvation conditions, when glucose is not available. When acetyl-CoA is not being metaboli...(more) Description: ENCODES a protein that exhibits 3-hydroxybutyrate dehydrogenase activity (ortholog); NAD binding (ortholog); oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor (ortholog); INVOLVED IN epithelial cell differentiation (ortholog); fatty acid beta-oxidation (ortholog); heme metabolic process (ortholog); PARTICIPATES IN butanoate metabolic pathway; ketone bodies metabolic pathway; FOUND IN cytoplasm (ortholog); cytosol (ortholog); extracellular exosome (ortholog); INTERACTS WITH 2,3,7,8-tetrachlorodibenzodioxine; 2,4-dinitrotoluene; 2,6-dinitrotoluene Continue reading >>
What Are Ketones?
With the gradual resurgence of low-carb diets in recent years, the word “ketones” is thrown around a lot. But many people aren’t really aware of the details. What are ketones, really? And what do they do in the body? There can be a lot of misinformation regarding the answers to these questions, so read on for a full overview of ketones and their role in a ketogenic diet. Ketones, also known as “ketone bodies,” are byproducts of the body breaking down fat for energy that occurs when carbohydrate intake is low. Here’s how it works: When there isn’t a sufficient level of available glucose — which is what the body uses for its main source of fuel — and glycogen levels are depleted, blood sugar and insulin are lowered and the body looks for an alternative source of fuel: in this case, fat. This process can happen when a person fasting, after prolonged exercise, during starvation, or when eating a low-carb, ketogenic diet. And when the body begins breaking down fats for energy like this, a process known as beta-oxidation, ketones are formed for use as fuel for the body and brain. This is known as ketosis. People following a ketogenic diet specifically reduce their carbohydrate intake for this reason: to create ketones for energy. Many people use the benefits of ketosis — less reliance on carbs and more burning of fat — to possibly help lower blood pressure, reduce cravings, improve cholesterol, increase weight loss, improve energy, and more. TYPES OF KETONE BODIES So, what else about ketones do we need to know? To start, there are technically three types of ketone bodies: Acetoacetate (AcAc) Beta-hydroxybutyric acid (BHB) Acetone Both acetoacetate and beta-hydroxybutyrate are responsible for transporting energy from the liver to other tissues in the body Continue reading >>
Ketone Body Formation
Ketone body formation occurs as an alternative energy source during times of prolonged stress e.g. starvation. It occurs in the liver from an initial substrate of: long chain fatty acids; the fatty acids undergo beta-oxidation by their normal pathway within mitochondria until acetyl-CoA is produced, or ketogenic amino acids; amino acids such as leucine and lysine, released at times of energy depletion, are interconverted only to acetyl-CoA Then, three molecules of acetyl-CoA are effectively joined together in three enzyme steps sequentially catalyzed by: acetyl CoA acetyltransferase HMG-CoA transferase HMG-CoA lyase Coenzyme A is regenerated and the ketone body acetoacetate is formed. Finally, acetoacetate is reduced to another ketone body, D-3-hydroxybutyrate, in a reaction catalyzed by 3-hydroxybutyrate dehydrogenase. This requires NADH. The oxidate state of the liver is such that the forward reaction is generally favoured; this results in more hydroxybutyrate being formed than acetoacetate. Continue reading >>
Ketone Bodies Metabolism
1. Metabolism of ketone bodies Gandham.Rajeev Email:[email protected] 2. • Carbohydrates are essential for the metabolism of fat or FAT is burned under the fire of carbohydrates. • Acetyl CoA formed from fatty acids can enter & get oxidized in TCA cycle only when carbohydrates are available. • During starvation & diabetes mellitus, acetyl CoA takes the alternate route of formation of ketone bodies. 3. • Acetone, acetoacetate & β-hydroxybutyrate (or 3-hydroxybutyrate) are known as ketone bodies • β-hydroxybutyrate does not possess a keto (C=O) group. • Acetone & acetoacetate are true ketone bodies. • Ketone bodies are water-soluble & energy yielding. • Acetone, it cannot be metabolized 4. CH3 – C – CH3 O Acetone CH3 – C – CH2 – COO- O Acetoacetate CH3 – CH – CH2 – COO- OH I β-Hydroxybutyrate 5. • Acetoacetate is the primary ketone body. • β-hydroxybutyrate & acetone are secondary ketone bodies. • Site: • Synthesized exclusively by the liver mitochondria. • The enzymes are located in mitochondrial matrix. • Precursor: • Acetyl CoA, formed by oxidation of fatty acids, pyruvate or some amino acids 6. • Ketone body biosynthesis occurs in 5 steps as follows. 1. Condensation: • Two molecules of acetyl CoA are condensed to form acetoacetyl CoA. • This reaction is catalyzed by thiolase, an enzyme involved in the final step of β- oxidation. 7. • Acetoacetate synthesis is appropriately regarded as the reversal of thiolase reaction of fatty acid oxidation. 2. Production of HMG CoA: • Acetoacetyl CoA combines with another molecule of acetyl CoA to produce β-hydroxy β-methyl glutaryl CoA (HMC CoA). • This reaction is catalyzed by the enzyme HMG CoA synthase. 8. • Mitochondrial HMG CoA is used for ketogenesis. Continue reading >>
What Are Ketone Bodies And Why Are They In The Body?
If you eat a calorie-restricted diet for several days, you will increase the breakdown of your fat stores. However, many of your tissues cannot convert these fatty acid products directly into ATP, or cellular energy. In addition, glucose is in limited supply and must be reserved for red blood cells -- which can only use glucose for energy -- and brain tissues, which prefer to use glucose. Therefore, your liver converts many of these fatty acids into ketone bodies, which circulate in the blood and provide a fuel source for your muscles, kidneys and brain. Video of the Day Low fuel levels in your body, such as during an overnight fast or while you are dieting, cause hormones to increase the breakdown of fatty acids from your stored fat tissue. These fatty acids travel to the liver, where enzymes break the fatty acids into ketone bodies. The ketone bodies are released into the bloodstream, where they travel to tissues that have the enzymes to metabolize ketone bodies, such as your muscle, brain, kidney and intestinal cells. The breakdown product of ketone bodies goes through a series of steps to form ATP. Conditions of Ketone Body Utilization Your liver will synthesize more ketone bodies for fuel whenever your blood fatty acid levels are elevated. This will happen in response to situations that promote low blood glucose, such as an overnight fast, prolonged calorie deficit, a high-fat and low-carbohydrate diet, or during prolonged low-intensity exercise. If you eat regular meals and do not typically engage in extremely long exercise sessions, the level of ketone bodies in your blood will be highest after an overnight fast. This level will drop when you eat breakfast and will remain low as long as you eat regular meals with moderate to high carbohydrate content. Ketone Bodi Continue reading >>