Centragard eprinomectin and praziquantel transdermal solution is a monthly heartworm disease prevention product for cats that is applied topically. Elliot's mixture of deep-rooting grass for a four years ley; if you use that, you will have 'millions of men' working for you while you are asleep," says Lamin, and what he did with the dry, empty, sandy soil at his farm proved his point. There is no true heart wall or lining and the whole structure is curved or U-shaped, with one end directed dorsally and the other ventrally. Salt , pepper and other spices were prescribed for various ailments in various preparations for example mixed with vinegar. Galen thought that for a person to have gout , kidney stones , or arthritis was scandalous, which Gratzer likens to Samuel Butler's Erehwon where sickness is a crime. Some of the books in the library are in the public domain in many countries, but in other countries they are still under copyright protection.
By breaking down existing protein, the carbon skeleton of the various amino acids can be metabolized to intermediates in cellular respiration; the remaining ammonia is discarded primarily as urea in urine.
Carbohydrates may be classified as monosaccharides , disaccharides , or polysaccharides depending on the number of monomer sugar units they contain. They constitute a large part of foods such as rice , noodles , bread , and other grain -based products, also potatoes , yams, beans, fruits, fruit juices and vegetables.
Monosaccharides, disaccharides, and polysaccharides contain one, two, and three or more sugar units, respectively. Polysaccharides are often referred to as complex carbohydrates because they are typically long, multiple branched chains of sugar units. Traditionally, simple carbohydrates are believed to be absorbed quickly, and therefore to raise blood-glucose levels more rapidly than complex carbohydrates.
This, however, is not accurate. Dietary fiber is a carbohydrate that is incompletely absorbed in humans and in some animals. Like all carbohydrates, when it is metabolized it can produce four Calories kilocalories of energy per gram. However, in most circumstances it accounts for less than that because of its limited absorption and digestibility.
Dietary fiber consists mainly of cellulose, a large carbohydrate polymer which is indigestible as humans do not have the required enzymes to disassemble it. There are two subcategories: Whole grains, fruits especially plums , prunes , and figs , and vegetables are good sources of dietary fiber.
There are many health benefits of a high-fiber diet. Dietary fiber helps reduce the chance of gastrointestinal problems such as constipation and diarrhea by increasing the weight and size of stool and softening it. Insoluble fiber, found in whole wheat flour , nuts and vegetables, especially stimulates peristalsis ;— the rhythmic muscular contractions of the intestines, which move digest along the digestive tract. Soluble fiber, found in oats, peas, beans, and many fruits, dissolves in water in the intestinal tract to produce a gel that slows the movement of food through the intestines.
This may help lower blood glucose levels because it can slow the absorption of sugar. Additionally, fiber, perhaps especially that from whole grains, is thought to possibly help lessen insulin spikes, and therefore reduce the risk of type 2 diabetes.
The link between increased fiber consumption and a decreased risk of colorectal cancer is still uncertain. A molecule of dietary fat typically consists of several fatty acids containing long chains of carbon and hydrogen atoms , bonded to a glycerol. They are typically found as triglycerides three fatty acids attached to one glycerol backbone. Fats may be classified as saturated or unsaturated depending on the detailed structure of the fatty acids involved.
Saturated fats have all of the carbon atoms in their fatty acid chains bonded to hydrogen atoms, whereas unsaturated fats have some of these carbon atoms double-bonded , so their molecules have relatively fewer hydrogen atoms than a saturated fatty acid of the same length.
Unsaturated fats may be further classified as monounsaturated one double-bond or polyunsaturated many double-bonds. Furthermore, depending on the location of the double-bond in the fatty acid chain, unsaturated fatty acids are classified as omega-3 or omega-6 fatty acids. Trans fats are a type of unsaturated fat with trans -isomer bonds; these are rare in nature and in foods from natural sources; they are typically created in an industrial process called partial hydrogenation.
There are nine kilocalories in each gram of fat. Fatty acids such as conjugated linoleic acid , catalpic acid, eleostearic acid and punicic acid , in addition to providing energy, represent potent immune modulatory molecules.
Saturated fats typically from animal sources have been a staple in many world cultures for millennia. Saturated and some trans fats are typically solid at room temperature such as butter or lard , while unsaturated fats are typically liquids such as olive oil or flaxseed oil.
Trans fats are very rare in nature, and have been shown to be highly detrimental to human health, but have properties useful in the food processing industry, such as rancidity resistance. Most fatty acids are non-essential, meaning the body can produce them as needed, generally from other fatty acids and always by expending energy to do so.
However, in humans, at least two fatty acids are essential and must be included in the diet. An appropriate balance of essential fatty acids— omega-3 and omega-6 fatty acids —seems also important for health, although definitive experimental demonstration has been elusive. Both of these "omega" long-chain polyunsaturated fatty acids are substrates for a class of eicosanoids known as prostaglandins , which have roles throughout the human body.
They are hormones , in some respects. The omega-3 eicosapentaenoic acid EPA , which can be made in the human body from the omega-3 essential fatty acid alpha-linolenic acid ALA , or taken in through marine food sources, serves as a building block for series 3 prostaglandins e.
The omega-6 dihomo-gamma-linolenic acid DGLA serves as a building block for series 1 prostaglandins e. An appropriately balanced intake of omega-3 and omega-6 partly determines the relative production of different prostaglandins, which is one reason why a balance between omega-3 and omega-6 is believed important for cardiovascular health. In industrialized societies, people typically consume large amounts of processed vegetable oils, which have reduced amounts of the essential fatty acids along with too much of omega-6 fatty acids relative to omega-3 fatty acids.
Moreover, the conversion desaturation of DGLA to AA is controlled by the enzyme deltadesaturase , which in turn is controlled by hormones such as insulin up-regulation and glucagon down-regulation. The amount and type of carbohydrates consumed, along with some types of amino acid, can influence processes involving insulin, glucagon, and other hormones; therefore, the ratio of omega-3 versus omega-6 has wide effects on general health, and specific effects on immune function and inflammation , and mitosis i.
Proteins are structural materials in much of the animal body e. They also form the enzymes that control chemical reactions throughout the body. Each protein molecule is composed of amino acids , which are characterized by inclusion of nitrogen and sometimes sulphur these components are responsible for the distinctive smell of burning protein, such as the keratin in hair.
The body requires amino acids to produce new proteins protein retention and to replace damaged proteins maintenance. As there is no protein or amino acid storage provision, amino acids must be present in the diet.
Excess amino acids are discarded, typically in the urine. For all animals, some amino acids are essential an animal cannot produce them internally and some are non-essential the animal can produce them from other nitrogen-containing compounds.
About twenty amino acids are found in the human body, and about ten of these are essential and, therefore, must be included in the diet. A diet that contains adequate amounts of amino acids especially those that are essential is particularly important in some situations: A complete protein source contains all the essential amino acids; an incomplete protein source lacks one or more of the essential amino acids.
It is possible with protein combinations of two incomplete protein sources e. However, complementary sources of protein do not need to be eaten at the same meal to be used together by the body. Water is excreted from the body in multiple forms; including urine and feces , sweating , and by water vapour in the exhaled breath. Therefore, it is necessary to adequately rehydrate to replace lost fluids. Early recommendations for the quantity of water required for maintenance of good health suggested that 6—8 glasses of water daily is the minimum to maintain proper hydration.
Most of this quantity is contained in prepared foods. For healthful hydration, the current EFSA guidelines recommend total water intakes of 2. These reference values include water from drinking water, other beverages, and from food. The EFSA panel also determined intakes for different populations. Recommended intake volumes in the elderly are the same as for adults as despite lower energy consumption, the water requirement of this group is increased due to a reduction in renal concentrating capacity.
Dehydration and over-hydration - too little and too much water, respectively - can have harmful consequences. Drinking too much water is one of the possible causes of hyponatremia , i.
Pure ethanol provides 7 calories per gram. For distilled spirits , a standard serving in the United States is 1. A 5 ounce serving of wine contains to calories. A 12 ounce serving of beer contains 95 to calories.
Alcoholic beverages are considered empty calorie foods because other than calories, these contribute no essential nutrients. The micronutrients are minerals , vitamins , and others. Dietary minerals are inorganic chemical elements required by living organisms,  other than the four elements carbon , hydrogen , nitrogen , and oxygen that are present in nearly all organic molecules. The term "mineral" is archaic, since the intent is to describe simply the less common elements in the diet.
Some are heavier than the four just mentioned, including several metals , which often occur as ions in the body. Some dietitians recommend that these be supplied from foods in which they occur naturally, or at least as complex compounds, or sometimes even from natural inorganic sources such as calcium carbonate from ground oyster shells.
Some minerals are absorbed much more readily in the ionic forms found in such sources. On the other hand, minerals are often artificially added to the diet as supplements; the most famous is likely iodine in iodized salt which prevents goiter. Many elements are essential in relative quantity; they are usually called "bulk minerals". Some are structural, but many play a role as electrolytes. Many elements are required in trace amounts, usually because they play a catalytic role in enzymes.
Vitamins are essential nutrients,  necessary in the diet for good health. Vitamin D is an exception, as it can be synthesized in the skin in the presence of UVB radiation , and many animal species can synthesize vitamin C. Vitamin deficiencies may result in disease conditions, including goitre , scurvy , osteoporosis , impaired immune system, disorders of cell metabolism, certain forms of cancer, symptoms of premature aging, and poor psychological health , among many others. Phytochemicals such as polyphenols are compounds produced naturally in plants phyto means "plant" in Greek.
In general, the term is used to refer to compounds which do not appear to be nutritionally essential and yet may have positive impacts on health. To date, there is no conclusive evidence in humans that polyphenols or other non-nutrient compounds from plants have health benefit effects.
While initial studies sought to reveal if nutrient antioxidant supplements might promote health, one meta-analysis concluded that supplementation with vitamins A and E and beta-carotene did not convey any benefits and may in fact increase risk of death.
Vitamin C and selenium supplements did not impact mortality rate. Health effects of non-nutrient phytochemicals such as polyphenols were not assessed in this review. Animal intestines contain a large population of gut flora.
In humans, the four dominant phyla are Firmicutes , Bacteroidetes , Actinobacteria , and Proteobacteria. Bacteria in the large intestine perform many important functions for humans, including breaking down and aiding in the absorption of fermentable fiber, stimulating cell growth, repressing the growth of harmful bacteria, training the immune system to respond only to pathogens, producing vitamin B 12 , and defending against some infectious diseases.
There is not yet a scientific consensus as to health benefits accruing from probiotics or prebiotics. Carnivore and herbivore diets are contrasting, with basic nitrogen and carbon proportions vary for their particular foods.
Many herbivores rely on bacterial fermentation to create digestible nutrients from indigestible plant cellulose, while obligate carnivores must eat animal meats to obtain certain vitamins or nutrients their bodies cannot otherwise synthesize. Plant nutrition is the study of the chemical elements that are necessary for plant growth. Some elements are directly involved in plant metabolism. However, this principle does not account for the so-called beneficial elements, whose presence, while not required, has clear positive effects on plant growth.
A nutrient that is able to limit plant growth according to Liebig's law of the minimum is considered an essential plant nutrient if the plant cannot complete its full life cycle without it. There are 16 essential plant soil nutrients, besides the three major elemental nutrients carbon and oxygen that are obtained by photosynthetic plants from carbon dioxide in air, and hydrogen , which is obtained from water.
Plants uptake essential elements from the soil through their roots and from the air consisting of mainly nitrogen and oxygen through their leaves. Green plants obtain their carbohydrate supply from the carbon dioxide in the air by the process of photosynthesis.
Carbon and oxygen are absorbed from the air, while other nutrients are absorbed from the soil. These hydrogen ions displace cations attached to negatively charged soil particles so that the cations are available for uptake by the root. In the leaves, stomata open to take in carbon dioxide and expel oxygen. The carbon dioxide molecules are used as the carbon source in photosynthesis. Although nitrogen is plentiful in the Earth's atmosphere, very few plants can use this directly. Most plants, therefore, require nitrogen compounds to be present in the soil in which they grow.
This is made possible by the fact that largely inert atmospheric nitrogen is changed in a nitrogen fixation process to biologically usable forms in the soil by bacteria.
Plant nutrition is a difficult subject to understand completely, partially because of the variation between different plants and even between different species or individuals of a given clone.
Elements present at low levels may cause deficiency symptoms, and toxicity is possible at levels that are too high. Furthermore, deficiency of one element may present as symptoms of toxicity from another element, and vice versa. Canada's Food Guide is an example of a government-run nutrition program.
Produced by Health Canada , the guide advises food quantities, provides education on balanced nutrition, and promotes physical activity in accordance with government-mandated nutrient needs. Like other nutrition programs around the world, Canada's Food Guide divides nutrition into four main food groups: Dietary and physical activity guidelines from the USDA are presented in the concept of MyPlate , which superseded the food pyramid , which replaced the Four Food Groups.
Department of Health and Human Services provides a sample week-long menu that fulfills the nutritional recommendations of the government. Governmental organisations have been working on nutrition literacy interventions in non-primary health care settings to address the nutrition information problem in the U.
The FNP has developed a series of tools to help families participating in the Food Stamp Program stretch their food dollar and form healthful eating habits including nutrition education. It is designed to assist limited-resource audiences in acquiring the knowledge, skills, attitudes, and changed behavior necessary for nutritionally sound diets, and to contribute to their personal development and the improvement of the total family diet and nutritional well-being.
Launched in , this program promotes lifelong healthful eating patterns and physically active lifestyles for children and their families. It is an interactive educational program designed to help prevent childhood obesity through classroom activities that teach children healthful eating habits and physical exercise. Nutrition is taught in schools in many countries. In England and Wales , the Personal and Social Education and Food Technology curricula include nutrition, stressing the importance of a balanced diet and teaching how to read nutrition labels on packaging.
In many schools, a Nutrition class will fall within the Family and Consumer Science or Health departments. In some American schools, students are required to take a certain number of FCS or Health related classes.
Nutrition is offered at many schools, and, if it is not a class of its own, nutrition is included in other FCS or Health classes such as: In many Nutrition classes, students learn about the food groups, the food pyramid, Daily Recommended Allowances, calories, vitamins, minerals, malnutrition, physical activity, healthful food choices, portion sizes, and how to live a healthy life.
In the US, Registered dietitian nutritionists RDs or RDNs  are health professionals qualified to provide safe, evidence-based dietary advice which includes a review of what is eaten, a thorough review of nutritional health, and a personalized nutritional treatment plan. They also provide preventive and therapeutic programs at work places, schools and similar institutions.
Certified Clinical Nutritionists or CCNs, are trained health professionals who also offer dietary advice on the role of nutrition in chronic disease, including possible prevention or remediation by addressing nutritional deficiencies before resorting to drugs. These Board Certified Nutritionists typically specialize in obesity and chronic disease.
Be smart- either set your money on fire or buy a Medela! I was looking for something affordable which, really, I should've just looked at double electrics since this one is half the price of good doubles and I read the single review that said it was a great pump for a stay-at-home mom. I only work part time, so I don't pump every single day, so I thought maybe it would be fine.
No, it's completely useless. It takes about 3 seconds for one cycle. Secondly, the suction on the highest setting is barely noticeable. I pumped with it for minutes and only ended up with about a teaspoon of milk and never had a let down.
I am not new to pumping, this is my second breastfed baby. My first pump was a lansinoh double electric which has seen better days and I need something efficient. This is not it!! Of course it can't be returned to WM. I have emailed Nuk twice with no reply, so I guess I will have to call to try and get a refund. Do not buy this pump unless you don't need an efficient and useful pump.
I love this pump. The motor isn't very loud. I like the overall design. Functionally, it does it's job. It's a nice little portable pump without any fuss. It has no individual speed control or suction strength setting.
It just increases both gradually the higher you turn it up. The woman that says she can't feel it on it's highest setting must have some pretty tough nipples because this is also my second breastfed child and I have to keep it on about half or my nipples start bleeding.
So far I've used this pump to help in the stimulation of milk production because it took my son 4 days to effectively latch. It worked very well for that purpose. And now I'm using it after feedings to finish emptying my supply to bother further production and store extra milk for that first growth spurt!
The pump is designed to fit NUK bottles and there are no adapters for it. So if you want to use bottles other than NUK you will have to pump and pour. It also uses 3 AAA batteries aside from the wall adapter.
I would suggest rechargeable batteries. It is a closed system pump. Your milk never comes in contract with the motor. Which makes it extremely easy to clean. Extra parts, adapters, etc. DivineInsanity, July 13, Sent my husband to store for pump and he brought this one home. Pyruvate is a versatile metabolite that can enter several metabolic pathways, both anabolic and catabolic, depending on the type of cell, the energy state of the cell and the availability of oxygen.
With the exception of some variations encountered in bacteria, exploited, for example, in food industry for the production of various foods such as many cheeses, there are essentially three pathways in which pyruvate may enter:. This allows glycolysis to proceed in both anaerobic and aerobic conditions.
It is therefore possible to state that the catabolic fate of the carbon skeleton of glucose is influenced by the cell type, the energetic state of the cell, and the availability of oxygen.
In animals, with few exceptions, and in many microorganisms when oxygen availability is insufficient to meet the energy requirements of the cell, or if the cell is without mitochondria, the pyruvate produced by glycolysis is reduced to lactate in the cytosol, in a reaction catalyzed by lactate dehydrogenase EC 1.
The conversion of glucose to lactate is called lactic acid fermentation. The overall equation of the process is:. In other words, in the conversion of glucose, C 6 H 12 O 6 , to lactate, C 3 H 6 O 3 , the ratio of hydrogen to carbon atoms of the reactants and products does not change.
From an energy point of view, it should however be emphasized that fermentation extracts only a small amount of the chemical energy of glucose. In humans, much of the lactate produced enters the Cori cycle for glucose production via gluconeogenesis.
We can also state that lactate production shifts part of the metabolic load from the extrahepatic tissues, such as skeletal muscle during intense bouts of exercise, like a meter, when the rate of glycolysis can almost instantly increase 2,fold, to the liver. Therefore, portion of the lactate released by skeletal muscle engaged in intense exercise is used by the heart muscle for fuel. Lactate produced by microorganisms during lactic acid fermentation is responsible for both the scent and taste of sauerkraut, namely, fermented cabbage, as well as for the taste of soured milk.
The first step involves the non-oxidative decarboxylation of pyruvate to form acetaldehyde, an essentially irreversible reaction.
The reaction is catalyzed by pyruvate decarboxylase EC 4. The enzyme is absent in vertebrates and in other organisms that perform lactic acid fermentation. In the second step, acetaldehyde is reduced to ethanol in a reaction catalyzed by alcohol dehydrogenase EC 1.
At neutral pH, the equilibrium of the reaction lies strongly toward ethyl alcohol formation. The conversion of glucose to ethanol and CO 2 is called alcoholic fermentation. The overall reaction is:. And, as for lactic fermentation, even in alcoholic fermentation no net oxidation-reduction occurs. Alcoholic fermentation is the basis of the production of beer and wine. In cells with mitochondria and under aerobic conditions, the most common situation in multicellular and many unicellular organisms, the oxidation of NADH and pyruvate catabolism follow distinct pathways.
In the mitochondrial matrix, pyruvate is first converted to acetyl-CoA in a reaction catalyzed by the pyruvate dehydrogenase complex. In the reaction, a oxidative decarboxylation , pyruvate loses a carbon atom as CO 2 , and the remaining two carbon unit is bound to Coenzyme A to form acetyl-coenzyme A or acetyl-CoA.
Pyruvate dehydrogenase therefore represents a bridge between glycolysis, which occurs in the cytosol, and the citric acid cycle, which occurs in the mitochondrial matrix.
In turn, electrons derived from oxidations that occur during glycolysis are transported into mitochondria via the reduction of cytosolic intermediates. Here the electrons flow to oxygen to form H 2 O, a transfer that supplies the energy needed for the synthesis of ATP through the process of oxidative phosphorylation. Of course, also the electrons carried by NADH formed by pyruvate dehydrogenase and citric acid cycle and by FADH 2 formed by citric acid cycle meet a similar fate.
Under anabolic conditions, the carbon skeleton of pyruvate may have fates other than complete oxidation to CO 2 or conversion to lactate. In fact, after its conversion to acetyl-CoA, it may be used, for example, for the synthesis of fatty acids , or of the amino acid alanine see Fig. In the glycolytic pathway the glucose molecule is degraded to two molecules of pyruvate.
In the first phase, the preparatory phase, two ATP are consumed per molecule of glucose in the reactions catalyzed by hexokinase and PFK In the second phase, the payoff phase, 4 ATP are produced through substrate-level phosphorylation in the reactions catalyzed by phosphoglycerate kinase and pyruvate kinase. So there is a net gain of two ATP per molecule of glucose used.
In addition, in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase, two molecules of NADH are produced for each glucose molecule. Here are the two reactions. Cancelling the common terms on both sides of the equation, we obtain the overall equation shown above.
Under anaerobic conditions , regardless of what is the metabolic fate of pyruvate, conversion to lactate, ethanol or other molecules, there is no additional production of ATP downstream of glycolysis. Under aerobic conditions , in cells with mitochondria, the amount of chemical energy that can be extracted from glucose and stored within ATP is much greater than under anaerobic conditions.
If we consider the two NADH produced during glycolysis, the flow of their 4 reducing equivalents along the mitochondrial electron transport chain allows the production of ATP per electron pair through oxidative phosphorylation. Therefore, 6 to 8 ATP are produced when one molecule of glucose is converted into two molecules of pyruvate, 2 from glycolysis and from oxidative phosphorylation. Considering both estimates, the production of ATP is about 15 times greater than under anaerobic condition.
Other carbohydrates besides glucose, both simple and complex, can be catabolized via glycolysis, after enzymatic conversion to one of the glycolytic intermediates. Among the most important are:. Dietary starch and disaccharides must be hydrolyzed in the intestine to the respective monosaccharides before being absorbed. Once in the venous circulation, monosaccharides reach the liver through the portal vein; this organ is the main site where they are metabolized.
Regarding the phosphorolytic breakdown of starch and endogenous glycogen refer to the corresponding articles. Under physiological conditions, the liver removes much of the ingested fructose from the bloodstream before it can reach extrahepatic tissues. The hepatic pathway for the conversion of the monosaccharide to intermediates of glycolysis consists of several steps.
In the first step fructose is phosphorylated to fructose 1-phosphate at the expense of one ATP. This reaction is catalyzed by fructokinase EC 2. As for glucose, fructose phosphorylation traps the molecule inside the cell. In the second step fructose 1-phosphate aldolase catalyzes the hydrolysis , an aldol cleavage, of fructose 1-phosphate to dihydroxyacetone phosphate and glyceraldehyde.
Dihydroxyacetone phosphate is an intermediate of the glycolytic pathway and, after conversion to glyceraldehyde 3-phosphate, may flow through the pathway. Conversely, glyceraldehyde is not an intermediate of the glycolysis, and is phosphorylated to glyceraldehyde 3-phosphate at the expense of one ATP.
The reaction is catalyzed by triose kinase EC 2. In hepatocytes, therefore, a molecule of fructose is converted to two molecules of glyceraldehyde 3-phosphate , at the expense of two ATP, as for glucose.
In extrahepatic sites , such as skeletal muscle, kidney or adipose tissue, fructokinase is not present, and fructose enters the glycolytic pathway as fructose 6-phosphate.
In fact, as previously seen , hexokinase can catalyzes the phosphorylation of fructose at C However, the affinity of the enzyme for fructose is about 20 times lower than for glucose, so in the hepatocyte, where glucose is much more abundant than fructose , or in the skeletal muscle under anaerobic conditions, that is, when glucose is the preferred fuel, little amounts of fructose 6-phosphate are formed. Conversely, in adipose tissue , fructose is more abundant than glucose, so that its phosphorylation by hexokinase is not competitively inhibited to a significant extent by glucose.
In this tissue, therefore, fructose 6-phosphate synthesis is the entry point into glycolysis for the monosaccharide. Conversely, when fructose is phosphorylated at C-6, it enters the glycolytic pathway upstream of PFK Fructose is the entry point into glycolysis for sorbitol , a sugar present in many fruits and vegetables, and used as a sweetener and stabilizer, too. In the liver, sorbitol dehydrogenase EC 1. Galactose , for the most part derived from intestinal digestion of the lactose , once in the liver is converted, via the Leloir pathway , to glucose 1-phosphate.
For a more in-depth discussion of the Leloir pathway , see the article on galactose. The metabolic fate of glucose 1-phosphate depends on the energy status of the cell. Under conditions promoting glucose storage, glucose 1-phosphate can be channeled to glycogen synthesis. Conversely, under conditions that favor the use of glucose as fuel, glucose 1-phosphate is isomerized to glucose 6-phosphate in the reversible reaction catalyzed by phosphoglucomutase EC 5.
Mannose is present in various dietary polysaccharides, glycolipids and glycoproteins. In the intestine, it is released from these molecules, absorbed, and, once reached the liver, is phosphorylated at C-6 to form mannose 6-phosphate, in the reaction catalyzed by hexokinase. Mannose 6-phosphate is then isomerized to fructose 6-phosphate in the reaction catalyzed by mannose 6-phosphate isomerase EC 5.
The flow of carbon through the glycolytic pathway is regulated in response to metabolic conditions, both inside and outside the cell, essentially to meet two needs: And in the liver, to avoid wasting energy, glycolysis and gluconeogenesis are reciprocally regulated so that when one pathway is active, the other slows down.
As explained in the article on gluconeogenesis , during evolution this was achieved by selecting different enzymes to catalyze the essentially irreversible reactions of the two pathways, whose activity are regulated separately. Indeed, if these reactions proceeded simultaneously at high speed, they would create a futile cycle or substrate cycle. A such fine regulation could not be achieved if a single enzyme operates in both directions.
The control of the glycolytic pathway involves essentially the reactions catalyzed by hexokinase , PFK-1 , and pyruvate kinase , whose activity is regulated through:.
Glucokinase differs from the other hexokinase isozymes in kinetic and regulatory properties. Isoenzymes or isozymes are different proteins that catalyze the same reaction, and that generally differ in kinetic and regulatory properties, subcellular distribution, or in the cofactors used.
They may be present in the same species, in the same tissue or even in the same cell. Hexokinase I and II have a K m for glucose of 0. Therefore these isoenzymes work very efficiently at normal blood glucose levels, mM. Conversely, glucokinase has a high K m for glucose, approximately 10 mM ; this means that the enzyme works efficiently only when blood glucose concentration is high, for example after a meal rich in carbohydrates with a high glycemic index. Hexokinases I-III are allosterically inhibited by glucose 6-phosphate , the product of their reaction.
This ensures that glucose 6-phosphate does not accumulate in the cytosol when glucose is not needed for energy, for glycogen synthesis , for the pentose phosphate pathway , or as a source of precursors for biosynthetic pathways, leaving, at the same time, the monosaccharide in the blood, available for other organs and tissues. For example, when PFK-1 is inhibited, fructose 6-phosphate accumulates and then, due to phosphoglucose isomerase reaction, glucose 6-phosphate accumulates.
In skeletal muscle , the activity of hexokinase I and II is coordinated with that of GLUT4 , a low K m glucose transporter 5mM , whose translocation to the plasma membrane is induced by both insulin and physical activity. The combined action of GLUT4 on plasma membrane and hexokinase in the cytosol maintains a balance between glucose uptake and its phosphorylation. Glucokinase differs in three respects from hexokinases I-III, and is particularly suitable for the role that the liver plays in glycemic control.
The binding between glucokinase and GKRP is much tighter in the presence of fructose 6-phosphate , whereas it is weakened by glucose and fructose 1-phosphate. In the absence of glucose, glucokinase is in its super-opened conformation that has low activity. The rise in cytosolic glucose concentration causes a concentration dependent transition of glucokinase to its close conformation, namely, its active conformation that is not accessible for glucokinase regulatory protein.
Hence, glucokinase is active and no longer inhibited. Hence, fructose relieves the inhibition of glucokinase by glucokinase regulatory protein. Example After a meal rich in carbohydrates , blood glucose levels rise, glucose enters the hepatocyte through GLUT2, and then moves inside the nucleus through the nuclear pores. In the nucleus glucose determines the transition of glucokinase to its close conformation, active and not accessible to GKRP, allowing glucokinase to diffuse in the cytosol where it phosphorylates glucose.
Conversely, when glucose concentration declines, such as during fasting when blood glucose levels may drop below 4 mM, glucose concentration in hepatocytes is low, and fructose 6-phosphate binds to GKRP allowing it to bind tighter to glucokinase. This results in a strong inhibition of the enzyme. This mechanism ensures that the liver, at low blood glucose levels, does not compete with other organs, primarily the brain, for glucose.
In the cell, fructose 6-phosphate is in equilibrium with glucose 6-phosphate, due to phosphoglucose isomerase reaction. Through its association with GKRP, fructose 6-phosphate allows the cell to decrease glucokinase activity, so preventing the accumulation of intermediates. To sum up, when blood glucose levels are normal, glucose is phosphorylated mainly by hexokinases I-III, whereas when blood glucose levels are high glucose can be phosphorylated by glucokinase as well.
Phosphofructokinase 1 is the key control point of carbon flow through the glycolytic pathway. The enzyme, in addition to substrate binding sites, has several binding sites for allosteric effectors.
It should be noted that ATP, an end product of glycolysis, is also a substrate of phosphofructokinase 1. Indeed, the enzyme has two binding sites for the nucleotide: What do allosteric effectors signal? The equilibrium constant, K eq , of the reaction is:. Therefore, considering that the total adenylate pool is constant over the short term, even a small reduction in ATP concentration leads, due to adenylate kinase activity, to a much larger relative increase in AMP concentration.
Therefore, the activity of phosphofructokinase 1 depends on the cellular energy status:. There are two reasons. A further control point of carbon flow through glycolysis and gluconeogenesis is the substrate cycle between phosphoenolpyruvate and pyruvate, catalyzed by pyruvate kinase for glycolysis, and by the combined action of pyruvate carboxylase and phosphoenolpyruvate carboxykinase EC 4.
All isozymes of pyruvate kinase are allosterically inhibited by high concentrations of ATP , long-chain fatty acids , and acetyl-CoA , all signs that the cell is in an optimal energy status.
Alanine , too, that can be synthesized from pyruvate through a transamination reaction, is an allosteric inhibitor of pyruvate kinase; its accumulation signals that building blocks for biosynthetic pathways are abundant.
Conversely, pyruvate kinase is allosterically activated by fructose 1,6-bisphosphate , the product of the first committed step of glycolysis. Therefore, F-1,6-BP allows pyruvate kinase to keep pace with the flow of intermediates. It should be underlined that, at physiological concentration of PEP, ATP and alanine, the enzyme would be completely inhibited without the stimulating effect of F-1,6-BP.
The hepatic isoenzyme , but not the muscle isoenzyme, is also subject to regulation through phosphorylation by:. Phosphorylation of the enzyme decreases its activity, by increasing the K m for phosphoenolpyruvate, and slows down glycolysis. For example, when the blood glucose levels are low, glucagon-induced phosphorylation decreases pyruvate kinase activity. The phosphorylated enzyme is also less readily stimulated by fructose 1,6-bisphosphate but more readily inhibited by alanine and ATP.
Conversely, the dephosphorylated form of pyruvate kinase is more sensitive to fructose 1,6-bisphosphate, and less sensitive to ATP and alanine. In this way, when blood glucose levels are low, the use of glucose for energy in the liver slows down, and the sugar is available for other tissues and organs, such as the brain. However, it should be noted that pyruvate kinase does not undergo glucagon-induced phosphorylation in the presence of fructose 1,6-bisphosphate.
The dephosphorylated enzyme is more readily stimulated by its allosteric activators F-1,6-BP, and less readily inhibited by allosteric inhibitors alanine and ATP. The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export.
Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. Biochem Soc Trans ;31 6: Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate. Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors. Gluconeogenesis is a metabolic pathway that leads to the synthesis of glucose from pyruvate and other non-carbohydrate precursors, even in non-photosynthetic organisms. It occurs in all microorganisms, fungi, plants and animals, and the reactions are essentially the same, leading to the synthesis of one glucose molecule from two pyruvate molecules.
Glycogenolysis is quite distinct from gluconeogenesis: The following discussion will focus on gluconeogenesis that occurs in higher animals, and in particular in the liver of mammals. During fasting, as in between meals or overnight, the blood glucose levels are maintained within the normal range due to hepatic glycogenolysis, and to the release of fatty acids from adipose tissue and ketone bodies by the liver.
Fatty acids and ketone bodies are preferably used by skeletal muscle, thus sparing glucose for cells and tissues that depend on it, primarily red blood cells and neurons. However, after about 18 hours of fasting or during intense and prolonged exercise, glycogen stores are depleted and may become insufficient.
At that point, if no carbohydrates are ingested, gluconeogenesis becomes important. In higher animals, gluconeogenesis occurs in the liver, kidney cortex and epithelial cells of the small intestine, that is, the enterocytes.
The key role of the liver is due to its size; in fact, on a wet weight basis, the kidney cortex produces more glucose than the liver. In the kidney cortex, gluconeogenesis occurs in the cells of the proximal tubule, the part of the nephron immediately following the glomerulus. Much of the glucose produced in the kidney is used by the renal medulla, while the role of the kidney in maintaining blood glucose levels becomes more important during prolonged fasting and liver failure.
It should, however, be emphasized that the kidney has no significant glycogen stores, unlike the liver, and contributes to maintaining blood glucose homeostasis only through gluconeogenesis and not through glycogenolysis. Part of the gluconeogenesis pathway also occurs in the skeletal muscle, cardiac muscle, and brain, although at very low rate. In adults, muscle is about 18 the weight of the liver; therefore, its de novo synthesis of glucose might have quantitative importance.
However, the release of glucose into the circulation does not occur because these tissues, unlike liver, kidney cortex, and enterocytes, lack glucose 6-phosphatase EC 3. Therefore, the production of glucose 6-phosphate, including that from glycogenolysis , does not contribute to the maintenance of blood glucose levels, and only helps to restore glycogen stores, in the brain small and limited mostly to astrocytes.
For these tissues, in particular for skeletal muscle due to its large mass, the contribution to blood glucose homeostasis results only from the small amount of glucose released in the reaction catalyzed by enzyme debranching EC 3. With regard to the cellular localization , most of the reactions occur in the cytosol, some in the mitochondria, and the final step within the endoplasmic reticulum cisternae.
The irreversibility of the glycolytic pathway is due to three strongly exergonic reactions, that cannot be used in gluconeogenesis, and listed below. In gluconeogenesis, these three steps are bypassed by enzymes that catalyze irreversible steps in the direction of glucose synthesis: Below, such reactions are analyzed.
The first step of gluconeogenesis that bypasses an irreversible step of glycolysis, namely the reaction catalyzed by pyruvate kinase , is the conversion of pyruvate to phosphoenolpyruvate.
Phosphoenolpyruvate is synthesized through two reactions catalyzed, in order, by the enzymes:. Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, with the consumption of one ATP. The enzyme requires the presence of magnesium or manganese ions. The enzyme, discovered in by Merton Utter, is a mitochondrial protein composed of four identical subunits, each with catalytic activity.
An allosteric binding site for acetyl-CoA is also present in each subunit. It should be noted that the reaction catalyzed by pyruvate carboxylase, leading to the production of oxaloacetate, also provides intermediates for the citric acid cycle or Krebs cycle. Phosphoenolpyruvate carboxykinase is present, approximately in the same amount, in mitochondria and cytosol of hepatocytes.
The isoenzymes are encoded by separate nuclear genes. PEP carboxykinase requires the presence of both magnesium and manganese ions. The reaction is reversible under normal cellular conditions. During this reaction, a CO 2 molecule, the same molecule that is added to pyruvate in the reaction catalyzed by pyruvate carboxylase, is removed. Carboxylation-decarboxylation sequence is used to activate pyruvate, since decarboxylation of oxaloacetate facilitates, makes thermodynamically feasible, the formation of phosphoenolpyruvate.
More generally, carboxylation-decarboxylation sequence promotes reactions that would otherwise be strongly endergonic, and also occurs in the citric acid cycle, in the pentose phosphate pathway , also called the hexose monophosphate pathway, and in the synthesis of fatty acids.
The levels of PEP carboxykinase before birth are very low, while its activity increases several fold a few hours after delivery.
This is the reason why gluconeogenesis is activated after birth. The sum of the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase is:. This is due to the fast consumption of phosphoenolpyruvate in other reactions, that maintains its concentration at very low levels.
Therefore, under cellular conditions, the synthesis of PEP from pyruvate is irreversible. It is noteworthy that the metabolic pathway for the formation of phosphoenolpyruvate from pyruvate depends on the precursor: The bypass reactions described below predominate when alanine or pyruvate is the glucogenic precursor. These proteins , associating, form a hetero-oligomer that facilitates pyruvate transport.
Pyruvate can also be produced from alanine in the mitochondrial matrix by transamination, in the reaction catalyzed by alanine aminotransferase EC 2.
Since the enzymes involved in the later steps of gluconeogenesis, except glucosephosphatase , are cytosolic, the oxaloacetate produced in the mitochondrial matrix is transported into the cytosol.
The transfer to the cytosol occurs as a result of its reduction to malate, that, on the contrary, can cross the inner mitochondrial membrane.
The reaction is catalyzed by mitochondrial malate dehydrogenase EC 1. Once in the cytosol, the malate is re-oxidized to oxaloacetate in the reaction catalyzed by cytosolic malate dehydrogenase. Malate-aspartate shuttle is the most active shuttle for the transport of NADH-reducing equivalents from the cytosol into the mitochondria. It is found in mitochondria of liver, kidney, and heart. The reaction enables the transport into the cytosol of mitochondrial reducing equivalents in the form of NADH.
Finally, the oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by PEP carboxykinase. Lactate is one of the major gluconeogenic precursors. It is produced for example by:. When lactate is the gluconeogenic precursor, PEP synthesis occurs through a different pathway than that previously seen. The production of cytosolic NADH makes unnecessary the export of reducing equivalents from the mitochondria.
Pyruvate enters the mitochondrial matrix to be converted to oxaloacetate in the reaction catalyzed by pyruvate carboxylase. In the mitochondria, oxaloacetate is converted to phosphoenolpyruvate in the reaction catalyzed by mitochondrial pyruvate carboxylase. Phosphoenolpyruvate exits the mitochondria through an anion transporter located in the inner mitochondrial membrane, and, once in the cytosol, continues in the gluconeogenesis pathway.
The second step of gluconeogenesis that bypasses an irreversible step of the glycolytic pathway , namely the reaction catalyzed by PFK-1, is the dephosphorylation of fructose 1,6-bisphosphate to fructose 6-phosphate. This reaction is catalyzed by the catalytic subunit of glucose 6-phosphatase , a protein complex located in the membrane of the endoplasmic reticulum of hepatocytes, enterocytes and cells of the proximal tubule of the kidney.
Glucose 6-phosphatase complex is composed of a glucose 6-phosphatase catalytic subunit and a glucose 6-phosphate transporter called glucose 6-phosphate translocase or T1. Glucose 6-phosphatase catalytic subunit has the active site on the luminal side of the organelle.
This means that the enzyme catalyzes the release of glucose not in the cytosol but in the lumen of the endoplasmic reticulum. Glucose 6-phosphate, both resulting from gluconeogenesis, produced in the reaction catalyzed by glucose 6-phosphate isomerase or phosphoglucose isomerase EC 5. Its transport is mediated by glucosephosphate translocase.
And, like the reaction catalyzed by fructose 1,6-bisphosphatase , this reaction leads to the hydrolysis of a phosphate ester. It should also be underlined that, due to orientation of the active site , the cell separates this enzymatic activity from the cytosol, thus avoiding that glycolysis, that occurs in the cytosol, is aborted by enzyme action on glucose 6-phosphate. Similar considerations can be made for the reaction catalyzed by FBPase Glucose and P i group seem to be transported into the cytosol via different transporters, referred to as T2 and T3, the last one an anion transporter.
Finally, glucose leaves the hepatocyte via the membrane transporter GLUT2, enters the bloodstream and is transported to tissues that require it. Conversely, under physiological conditions, as previously said, glucose produced by the kidney is mainly used by the medulla of the kidney itself.
Like glycolysis , much of the energy consumed is used in the irreversible steps of the process. Six high-energy phosphate bonds are consumed: Furthermore, two molecules of NADH are required for the reduction of two molecules of 1,3-bisphosphoglycerate in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase.
Also these energetic considerations show that gluconeogenesis is not simply glycolysis in reverse, in which case it would require the consumption of two molecules of ATP, as shown by the overall glycolytic equation. If glycolysis and gluconeogenesis were active simultaneously at a high rate in the same cell, the only products would be ATP consumption and heat production, in particular at the irreversible steps of the two pathways, and nothing more. Two reactions that run simultaneously in opposite directions result in a futile cycle or substrate cycle.
These apparently uneconomical cycles allow to regulate opposite metabolic pathways. In fact, a substrate cycle involves different enzymes, at least two, whose activity can be regulated separately. A such regulation would not be possible if a single enzyme would operate in both directions.
The modulation of the activity of involved enzymes occurs through:. Allosteric mechanisms are very rapid and instantly reversible, taking place in milliseconds. The others, triggered by signals from outside the cell, such as hormones, like insulin, glucagon, or epinephrine, take place on a time scale of seconds or minutes, and, for changes in enzyme concentration, hours. This allows a coordinated regulation of the two pathways , ensuring that when pyruvate enters gluconeogenesis, the flux of glucose through the glycolytic pathway slows down, and vice versa.
The regulation of gluconeogenesis and glycolysis involves the enzymes unique to each pathway , and not the common ones. While the major control points of glycolysis are the reactions catalyzed by PFK-1 and pyruvate kinase , the major control points of gluconeogenesis are the reactions catalyzed by fructose 1,6-bisphosphatase and pyruvate carboxylase.
The other two enzymes unique to gluconeogenesis, glucosephosphatase and PEP carboxykinase , are regulated at transcriptional level. The metabolic fate of pyruvate depends on the availability of acetyl-CoA, that is, by the availability of fatty acids in the mitochondrion. Acetyl-CoA is a positive allosteric effector of pyruvate carboxylase, and a negative allosteric effector of pyruvate kinase.
Moreover, it inhibits pyruvate dehydrogenase both through end-product inhibition and phosphorylation through the activation of a specific kinase. This means that when the energy charge of the cell is high, the formation of acetyl-CoA from pyruvate slows down, while the conversion of pyruvate to glucose is stimulated.
Therefore acetyl-CoA is a molecule that signals that additional glucose oxidation for energy is not required and that glucogenic precursors can be used for the synthesis and storage of glucose. Conversely, when acetyl-CoA levels decrease, the activity of pyruvate kinase and pyruvate dehydrogenase increases, and therefore also the flow of metabolites through the citric acid cycle.
This supplies energy to the cell. Summarizing, when the energy charge of the cell is high pyruvate carboxylase is active, and that the first control point of gluconeogenesis determines what will be the fate of pyruvate in the mitochondria. The second major control point in gluconeogenesis is the reaction catalyzed by fructose 1,6-bisphosphatase.
The enzyme is allosterically inhibited by AMP. This means that, as previously seen, FBPase-1 is active when the energy charge of the cell is sufficiently high to support de novo synthesis of glucose. The liver plays a key role in maintaining blood glucose homeostasis: Two hormones are mainly involved: This molecule is structurally related to fructose 1,6-bisphosphate, but is not an intermediate in glycolysis or gluconeogenesis. In the subsequent year, the same researchers showed that it is also a potent inhibitor of FBPase Fructose 2,6-bisphosphate, by binding to the allosteric site on PFK-1 , reduces the affinity of the enzyme for ATP and citrate, allosteric inhibitors, and at the same time increases the affinity of the enzyme for fructose 6-phosphate, its substrate.
PFK-1 , in the absence of fructose 2,6-bisphosphate, and in the presence of physiological concentrations of ATP, fructose 6-phosphate, and of allosteric effectors AMP, ATP and citrate, is practically inactive. Conversely, the presence of fructose 2,6-bisphosphate activates PFK-1 , thus stimulating glycolysis in the hepatocytes. At the same time fructose 2,6-bisphosphate slows down gluconeogenesis by inhibiting fructose 1,6-bisphosphatase, even in the absence of AMP.
Fructose-2,6-bisphosphate concentration is regulated by the relative rates of synthesis and degradation. It is synthesized from fructose 6-phosphate in the reaction catalyzed by phosphofructokinase-2 or PFK-2 EC 2.
These two enzymatic activities are located on a single bifunctional enzyme or tandem enzyme. In the liver, the balance of these two enzymatic activities is regulated by insulin and glucagon, as described below.