General features of circulation
The otitis case that changed my business. These 10 top-notch finalists are pros at tackling veterinary practice problems. I don't get the intense tingling which never really bothered me with this product. Iodine is available in small amounts in some salts but health officials do not consider that most of the iodine evaporates while sitting on the kitchen table. Adequacy of food supplies both in quality and diversity for adequate intake of nutrients and in quantity for adequate energy intakes. Price died in The range of daily iodine intake was from 50 mg to mg per day.
The suitability of land for each crop may be assessed and defined in terms of a percentage range of the maximum yields attainable.
Land areas capable of yielding 80 percent or more of the maximum yields attainable are classified as very suitable; areas yielding from 40 to 80 percent of the maximum are suitable; areas yielding from 20 to 40 percent are marginally suitable; and areas yielding less than 20 percent are classified as not suitable.
Under the current conditions in Africa, the most extensive area of land million hectares is suited to the cultivation of cassava, followed by maize million hectares , sweet potato million hectares , soybean million hectares and sorghum million hectares. In the Sudano-Sahelian region millets are recommended as the primary crop, suitable for the largest area of land, since they require less moisture, while sorghum is dominant in subhumid and semi-arid southern Africa.
Maize is to be preferred in terms of suitability for the largest areas in humid and subhumid West Africa and subhumid and mountainous East Africa. In humid Central Africa, the most appropriate crop choice for the widest land area is cassava. Table 13 gives the yield ranges of 11 important crops on land classified by suitability for each crop.
The yield differences between very suitable and unsuitable land are substantial. The data also confirm the significant impact of higher levels of inputs on yields. A first approach to food security could be the promotion of a regional 1 food security system based on "comparative advantage", in which countries would grow mainly the crops most likely to yield well under prevailing national conditions and would meet other food needs through interregional trade.
The Southern African Development Community SADC has made moves in the direction of a regional food security policy based on crop specialization, but the issues are still being defined. Sorghum may be the most suitable crop to select as the national food staple on ecological grounds, but many farmers and many governments will switch resources to the production of maize for several reasons: Risks of failure are greater for maize because it is particularly sensitive to the types of moisture shortfall that are typical in East Africa: However, sorghum is not without its problems; for example, it is particularly susceptible to attack by seed-eating birds.
A strategy of crop specialization that tends towards a narrowing of the food base is risky, especially in areas that are ecologically fragile and those that lack an efficient transport and marketing system to ensure rapid distribution of a variety of different foodstuffs throughout the country. In addition, a food production system in which the main food crop is also the main cash crop, as is the case with maize in eastern and southern Africa, is open to considerable risks, especially for resource-poor subsistence farmers.
In Africa, a large proportion of the population is still dependent on small-scale agriculture for food. Therefore, policies that alter land use and farming systems at the subsistence level have a direct effect on food availability, access and consumption. Traditional systems of land use, farming practices and cropping patterns are all changing as small-scale farmers face growing demands from markets and government to increase productivity. The farmers are required simultaneously to produce a food surplus for urban consumption, to feed and maintain their own households and often to increase their output of selected cash crops for export.
These diverse demands often put a considerable strain on the land, labour and time of the farming household. Food security at the household level may be affected by this transition.
Traditionally, food production in Africa remained at subsistence level and the farming system was based on shifting cultivation and bush fallow farming. Under these practices, soil fertility was periodically restored to cultivated land by the shifting of cultivation to fresh, rested ground, allowing the recently cultivated land to rest and recover. The use of external inputs such as chemical fertilizers was minimal, with farmers occasionally applying organic manure.
Similarly, animal production was practiced as an extensive free-range system in which pastoralists moved with their herds to seek new pastures by following the seasonal rains. Such systems of agriculture were ecologically appropriate and sustainable under low population densities. However, with increasing numbers of people and animals, more settled cropping patterns were established, and the fallow period was gradually reduced.
As a result, cultivation practices became more intensive; crop rotation, multiple cropping and intercropping were adopted as effective strategies to maximize land productivity without endangering soil fertility. Land-use patterns were complex, involving the production of a wide variety of food crops for domestic consumption; this strategy ensured a varied diet and helped to stabilize the food supply against climatic and seasonal shortages.
Gradual monetization of the economy and a shift in the socioeconomic environment increased the need for cash. For example, there was increased demand for education, better housing, health services and communications.
Cash crop production was increasingly adopted by small-scale farmers as they strived to generate cash both for themselves and as foreign exchange for their countries. In most cases, governments adopted the policy of balancing the production of exportable cash crops and food crops. The governments of several countries of eastern and southern Africa identified maize as the most appropriate food and cash crop for small-scale production, and cropping packages already adopted by commercial growers were promoted.
However, in many cases there were unforeseen problems, and the maize production of the small-scale farmers failed to meet consumer demand. The transition from subsistence farming to cash crop farming offers the opportunity to increase income, but it also harbours considerable risks.
These include the food security risks of increased dependence on a limited number of crops, capital risks linked to prices and socio-economic dependence on the lender when credit is obtained. Poor farmers in particular have often failed to reap the benefits of technological change or commercialization, or have even lost from them. On the whole, cash crop production can be expected to have a positive impact on nutrition when the income it provides more than offsets not only the food production that is foregone, but also any rise in food prices that may result from an increased demand for purchased food and the freeing of prices.
Changes in cropping patterns resulting from the transition to commercial production may affect household food security. Traditional farmers have generally adapted food production practices to meet environmental, economic and technological limitations. They minimize risk by planting a variety of staple crops that mature at different times during the year.
Monocropping may encourage seasonal shortages; traditional intercropping practices provide a cushion during seasons of insufficient food see Chapter 5. In many communities, a major staple is grown as both food and cash crop. If there is an efficient marketing organization, this crop will be sold, often by the household head male or female , as the major cash source for the household.
These secondary crops are used for various purposes such as home consumption, beer brewing, sale in the informal sector, food for poultry or small livestock, food in case of drought especially cassava or informal exchange or barter during the season in return for seeds, small livestock, poultry or other goods.
In the Wedza communal area of Zimbabwe, cultivation and consumption patterns are circumscribed to a large extent by the needs of households to earn money and to subsist see Box A variety of activities are undertaken, including the production of enough food for daily needs, together with a minimal store of food, usually the basic staple, to last at least until the following season.
In some cultures, the provision of food for family use is the responsibility of both husband and wife. In other cultures, it is largely the responsibility of women, who may have their own fields specifically for home food production see Box In the African context, cash crop promotion and commercialization are of particular significance for women.
Commercialization has often taken place through expansion of cultivated land rather than through substitution of modern varieties or cash crops on previously cultivated land. Frequently, the overall result of adopting cash crop production has been an increased demand for labour, especially women's labour.
Some of the effects of new agricultural technology on women's workload and the shift in control over resources have been well documented Kumar, The timing of inputs, including labour, is often crucial to securing maximum yields when hybrid varieties are used; thus not only the quantity of labour but also the seasonal application of labour is important.
In many cases, this will result in diversion of labour from other activities, including domestic work, home gardening, child care and regular preparation of well-balanced meals. When adult energy requirements increase, so does food demand, which is likely to be met at the expense of children's food intake. On the other hand, the nutritional status of overworked adult women stands to be compromised if the food available is insufficient to meet their increased body requirements for energy.
Box 12 - Cash and food production strategies of households in the Wedza communal area, Zimbabwe. Most households in this area try to combine several methods of improving their living standards. Box 13 - Gender roles in agricultural production in the Wedza communal area, Zimbabwe.
Traditionally, even today, it is considered the responsibility of women to provide for the daily food needs of household members "from the field to the plate".
This has its origins in certain traditional divisions of labour between men and women, with men being the hunters and cattle owners and being responsible for heavy labour such as land clearing and ploughing. As landholders through usufruct and cattle owners, men also have controlled the households' most valuable assets. Today, the division is not as strict as it once was, with many women, by force of circumstances, taking on more responsibilities for ploughing, herding and other tasks.
Most households reported that women take the main responsibility for the production of most crops in terms of labour and decision-making. In half the survey households, the income accruing from maize sales was said to be received jointly by the husband and wife, and in two-fifths by the wife only.
Practically all other crops excepting sunflower and cotton which are cash crops are said to be "women's crops". A previous study in Wedza showed that despite this responsibility, men are still key decision-makers when it comes to allocation of land to particular crops, access to loans and control of income accruing from crop sales.
Among the survey households, there appeared to be some disagreement over those issues Women in Wedza suggested that they must have access to land in their own right or jointly with their husbands to overcome the disparity. Women have joined farmer groups in large numbers as a way of overcoming some of the constraints they face. Production of cash crops often requires a variety of additional inputs. To increase yields, farmers are encouraged to purchase hybrid or improved seeds in place of their own local varieties saved from the previous harvest.
The farmer often requires credit to purchase not only the improved seeds but also the appropriate fertilizers and pesticides. A farmer growing cash crops therefore faces the risk of going into debt, especially if payment for the previous cash crop is delayed. These circumstances may limit the family's cash flow resources and reduce household food security. Despite the potential risks, commercial agriculture can provide opportunities for household food security and nutritional improvement, particularly if it is managed so as to benefit the rural poor.
To obtain such benefits it may be necessary to increase the productivity of small-scale farmers through targeted measures such as production incentives, development of marketing infrastructure and more research on rain-fed and other disadvantaged areas. The impact of such programmes can be strikingly enhanced if they are accompanied by effective extension services, farmer education and nutrition education programmes. Programmes to increase production and incomes in enterprises controlled by women can also contribute to the improvement of household food security; many studies have shown that earnings by women are likely to be utilized for increasing family food consumption.
However, projects targeted towards women with the goal of income generation need to be sensitive to competing demands on their time - particularly demands generated by child care. A policy for self-sufficiency in food production or adoption of a "food first" policy that emphasizes food crops to the exclusion of cash crops is not necessarily desirable or crucial for alleviating malnutrition, when market infrastructure and transportation do not impede trade.
Where market infrastructure is not well developed, it should be strengthened in the long-term interest of achieving food security on a sustainable basis. In the short and medium term, the joint promotion of food crops and cash crops, especially home gardening and small animal rearing, is required in support of food security enhancement.
Selling cash crops on the market instead of producing only food crops often increases household income and may thus also be likely to increase food consumption, provided the switch to cash crops does not lead to a change in income control at the household level and consequently to decisions for its disposal that could reduce expenditure on food.
Additional employment and income can also be derived from the development of small-scale agro-industries involving post-harvest activities, from cleaning and sorting of crops to storage, processing and marketing of foods and other agricultural crops.
This is a key factor both in overall development and in providing income to poorer sectors of the population. Commercialization of agriculture, the development of labour-intensive agro-industries and an active food system, supported by an appropriate policy environment, provide the only way out of subsistence agriculture and allow communities and governments to generate the wealth required to pay for needed social and infrastructural improvements.
To ensure that agricultural growth will benefit the poor and to meet the consumption needs of present and future populations, the creation and dissemination of nutrition-enhancing agricultural technologies developed to suit different agro-ecological areas and farmer groups are of major importance. In many humid and subhumid areas, people commonly cultivate compound farms or home gardens, which are sometimes also referred to as backyard or kitchen gardens Figures 14 and The home garden is only one of several field systems operated by a farmer or farm household Figure 16 , except in urban and pert-urban areas and in areas of land scarcity, where the home garden may be the only cultivated plot.
The home garden is thus one of the components of the whole farming system and is under the same household management or subject to related multiple decision-making processes Okigbo, The home garden often includes a permanent agricultural plot or forest garden which contains an ecologically balanced mixture of perennial and annual crops. The garden forms a hub' with the homestead at its centre, from which paths lead to other field systems and other production units devoted to annual crops for the market and for home consumption.
Home gardens are often highly diversified. Crop mixtures found in home gardens are mainly the result of deliberate selection and cultivation of a wide variety of herbs and trees occupying complementary levels and playing supportive roles. The gardens provide farmers with a mixture of food and cash crops Table Livestock, including sheep, goats, poultry and to some extent cattle and pigs, are also kept, although on a small scale, providing food, income and manure. Mixed tree and herb cropping systems have greatly extended harvesting periods and thus ensure continuous availability of some food.
Tree species, once established, require only minimal labour and inputs for maintenance. They provide a continual food supply for years without the need for annual replanting.
The biological diversity and complexity of home gardens decline with the transition from the humid to the semi-arid and arid areas of the Sahelian countries. Precipitation exceeds potential evapotranspiration for two to seven months of the year. Rainfall tends to be erratic, both in timing and areas covered, and this problem is worse in the low-rainfall areas. The dry season is a period of drought, with hot days and warm nights. In some areas, rainfall is less than 30 mm per month for five to seven months of the year.
Thus plant growth is limited for a considerable part of the year. FIGURE 16 - Schematic diagram of compound farms in relation to associated field systems in traditional farming systems of the humid tropics of Africa. An increase in land productivity in these areas is essential to reduce the pressure to extend into even more marginal areas, which could provoke further land degradation.
As the drylands are characterized by marked seasons, the availability of resources changes through the yearly cycle. Insufficient water is one of the major constraints to successful gardening in dryland areas; however, through effective soil management and cheap and effective solutions for harvesting and storing water, crops can be kept growing through some of the dry periods. Gardens in dryland areas can contribute greatly to the nutritional and economic well-being of households by reducing the level and duration of seasonal food shortages and introducing an increased variety of nutrient-rich foods into the household diet.
Boxes 14 and 15 describe some of the gardening principles and suitable plants for home gardens in the semi-arid tropics. As Africa's marginal lands are much greater in area than its fertile rain-fed or irrigable lands, even modest increases in local food supplies in the semi-arid areas could contribute considerably to the food security of the continent. Ecologically the compound farm or home or forest garden, together with animals, forms one of the most sustainable traditional farming systems; it maximizes biological production, protects the soil against erosion and can provide a varied and nutritious diet on a continuous basis, thus ensuring food security at the household level.
However, with increasing population density farmers have sometimes adopted farming practices that have led to tree removal, thus enhancing soil erosion and decreasing crop yields and returns to labour. Tree removal has often culminated in serious environmental degradation. Continuing replacement of home gardens and traditional farming systems with row crop production systems has also resulted in increased soil erosion, soil degradation and deterioration of the environment.
Box 14 - Gardening for food in the semi-arid tropics. A garden may surround a house or be located in a family field or in a community gardening area on the edge of, or some distance from, the village. It may be a home garden for one family, an income-generating project for a group of village women or a youth group, a school project or a health centre garden. The following suggestions advocate the use of indigenous design and systems rather than a fixed model.
The structure of the garden is adapted to the semi-arid tropical environment. It provides a diversity of foods over a long harvest period. Unlike the neat rows of annual crops characteristic of the industrialized countries in the temperate zone, the mature mixed garden consists of a dense mixture of annual crops and perennial trees.
The mixed garden makes maximum use of limited space and maximizes the total yield, even though some of the individual plants would yield more it given more space and sun. It is multi-storied, making full use of the air space with a maximum of trees, bushes, climbing plants on poles or branches, erect and spreading plants and ground-trailing plants.
The roots also exploit different levels underground, with some close to the surface and others, including the trees, reaching to the moisture further down. A good design for a mixed garden takes account of the way different plants can share light, air and root space and leave little room for weeds. The multi-storied garden provides "canopy mulch" and protects the soil and the plants from the wind, excessive sun and rain.
Soil fertility is increased by composting, mulching and the incorporation of dead plant material, which in turn increases crop production and conserves soil moisture. Leguminous trees and plants build fertility, and companion planting decreases pest buildup. Economically, the mixed garden is a low-capital, high-return cropping system. Local planting materials, if they cannot be stored by the family, are usually available at low cost through trade or purchase.
Most crops that are native or have become adapted to the environment over time are relatively resistant to many pests and diseases. These crops are generally less dependent on fertilizer and water than temperate species.
The appearance of the garden changes dramatically according to the season. During the rainy season there is an impressive mass of greenery. In the dry season the absence of greenery is noticeable, except for a dark-green mass of trees usually surrounding the home compound, and a small watered area. A larger mixed garden provides an ongoing supply of vegetables and fruits that contribute significant quantities of energy, protein, vitamin A, iron and vitamin C to the family diet.
Also the garden, and especially the trees, is an amenity for the household and the surrounding area. Why does this phosphoryl group have a high free energy of hydrolysis? Although phosphoenolpyruvate and 2-phosphoglycerate contain nearly the same amount of metabolic energy with respect to decomposition to CO 2 , H 2 0 and P i , 2-PG dehydration leads to a redistribution of energy such that the standard free energy of hydrolysis of the phosphoryl groups vary as described below:.
What happens is that the phosphoryl group traps PEP in its unstable enol form. When, in the last step of glycolysis, phosphoenolpyruvate donates the phosphoryl group to ADP, ATP and the enol form of pyruvate are formed. The enol form of pyruvate is unstable and tautomerizes rapidly and nonenzymatically to the more stable keto form, that predominates at pH 7. So, the high phosphoryl-transfer potential of PEP is due to the subsequent enol-keto tautomerization of pyruvate.
In the final step of the glycolytic pathway, pyruvate kinase EC 2. This is the second substrate-level phosphorylation of glycolysis. The enzyme is a tetramer and, like PFK-1 , is a highly regulated. Indeed, it has binding sites for numerous allosteric effectors. Moreover, in vertebrates, there are at least three isozymes of pyruvate kinase, of which the M type predominates in muscle and brain, while the L type in liver.
These isozymes have many properties in common, whereas differ in the response to hormones such as glucagon, epinephrine and insulin. And, of the The remaining energy, While the reaction catalyzed by phosphoglycerate kinase, in the seventh step of the glycolytic pathway, pays off the ATP debt of the preparatory phase, the reaction catalyzed by pyruvate kinase allows a net gain of two ATP. Such pathways allow, therefore, maintenance of the redox balance of the cell. 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. Deep Valley Farm Inc. Exel International Exhibitor Labs Inc. Figuerola Laboratories Filters Inc.
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