Tazzini Nicola

Tuscany-diet.net was created and is updated to provide information regarding biochemistry and human nutrition under physiological conditions.

Keto acids or ketoacids are organic compounds containing two functional groups: a carboxyl acid group (−COOH) and a carbonyl group (˂C=O). Based on the position of the carbonyl group relative to the carboxylic acid group, to which the IUPAC nomenclature rules assign the highest priority, ketoacids are classified as alpha-keto acids, beta-keto acids, and gamma-keto acids.[2]

In oxidative deaminations, amino acids are converted into the corresponding alpha-keto acids by removing the amino group, which is converted to ammonia and replaced by a carbonyl group. Since the reaction is reversible, ketoacids are also precursors of amino acids. Note: ammonia is a toxic compound, and is converted into the safer compound urea via the urea cycle in the liver.[4] Pyruvate, oxaloacetate and alpha-ketoglutarate, the latter via oxaloacetate, are the entry points into gluconeogenesis of the carbon skeleton of many glucogenic amino acids.[4] It has also been observed that, in vitro, murine and human tumor cell lines secrete 2-chetoacids into the tumor microenvironment, such as α-ketoisocaproate, α-keto-β-methylvalerate and α-ketoisovalerate, which are capable to influence the anti-tumor activity of macrophages.[1]

They have the carbonyl group at the third carbon from the carboxylic acid. An example is levulinic acid, the simplest one, which arises from the catabolism of cellulose.

Let us consider the conversion of A into B, which proceeds at a rate of 100, and B into A, which proceeds at a rate of 90. This results in a net flow of 10. Suppose that an effector increases the rate of conversion of A into B by 30 percent, to 130 percent, and reduces the rate of conversion of B into A by 30 percent, to 63 percent. The resulting net flux is equal to 130-63 = 67, namely, a 30 percent change in the rates of the opposing reactions has led to a 570 percent increase in the net flux.[1] A mechanism of this type could, at least in part, explain the even 1000-fold increase in carbon flux down the glycolysis in the initial phase of intense exercise.

In the course of evolution, the selection of different enzymes to catalyze irreversible and opposing reactions has made possible to avoid or put under strict control futile cycles. How? The selection of one enzyme that catalyzes the conversion of A into B, and another enzyme that catalyzes the opposing reaction, whose activities are regulated separately, allows the control of the net flux.[3][4] Enzymatic activities are controlled by:

In this way, it is possible to obtain a coordinated regulation of the two opposing pathways, thus avoiding an uncontrolled futile cycle. Obviously, such a fine regulation could not be achieved if a single enzyme would operate in both directions.

If glycolysis, which converts glucose into pyruvate with the production of ATP, and gluconeogenesis, which converts pyruvate into glucose with the consumption of ATP, run simultaneously at high rate in the same cell, the net result would be a net consumption of ATP, therefore a futile cycle. This is avoided by the control of the irreversible steps of the two metabolic pathways, in particular the reactions catalyzed by phosphofructokinase-1 or PFK-1 (EC 2.7.1.11), and by fructose-1,6-bisphosphatase or FBPase (EC 3.1.3.11), mainly by the allosteric effector fructose 2,6-bisphosphate.[3][4]

It should be noted that in glycolysis, the control involves all the irreversible reactions, whereas in gluconeogenesis, the key regulatory points are the reactions catalyzed by pyruvate carboxylase (EC 6.4.1.1) and fructose 1,6-bisphosphatase.

In the Cori cycle, lactic acid produced from glucose in the muscle and other extrahepatic tissues reaches the liver, where it is converted back into glucose, which, released into the circulation, returns to the muscle and other extrahepatic tissues, thereby closing the cycle. From an energetic point of view, the Cori cycle can be considered a futile cycle because it results in a net consumption of 4 ATP with no other overall effect.[2] However, it allows many different types of extrahepatic cells to work at the expense of the liver.

In the triglyceride/fatty acid cycle, triglycerides in adipose tissue are partially or completely hydrolyzed to free fatty acids and glycerol, in a process called lipolysis; the released fatty acids are then used to resynthesize new molecules of triglycerides.[2][4][5] Four moles of ATP are consumed for every mole of triglycerides that completes the cycle. This futile cycle can take place:

In some cases a futile cycle has the only function of producing heat through the hydrolysis of ATP. This occurs, for example, in the flight muscles of bumblebees, which, in order to fly, must maintain a thoracic temperature of about 30 °C, even when the external temperature is 10 °C.[1] The thoracic temperature is maintained at the optimal levels for flight thanks to the futile cycle between the reactions catalyzed by PFK-1 and FBPase. In fact, flight muscle FBAase is not inhibited by AMP, which suggests that, during evolution, this protein has been selected for the generation of heat. Unlike bumblebees, flight muscles of honeybees contain almost no FBPase, and therefore these insects cannot fly when the external temperature is low.

Short-chain fatty acids or SCFAs are saturated fatty acids with a straight or branched carbon-chain made of 2-5 carbon atoms, and are acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and 2-methylbutyric acid.[1] In humans, they are, along with secondary bile salts, the main metabolites produced by bacteria of the gut microbiota in the cecum and colon, and derive almost entirely from the anaerobic fermentation of non-digestible carbohydrates.[11] The most abundant are acetic acid, propionic acid and butyric acid, which represent 90-95 percent of the produced SCFAs.[6] The remaining percentage is made of the branched SCFAs. They are the major anions present in the colon. Their concentration is higher in the cecum and in the proximal colon than in the distal part, where the substrates for their synthesis are depleted.[1][2][4] They are able to reduce colonic pH value and thus acidify the stool. About 90-95 percent of the SCFAs are absorbed in the cecum and colon, whereas 5-10 percent are excreted with the feces.[13] They are thought to provide about 70 percent of the energy needs of colonocytes.[4] Short-chain fatty acids are able to modulate the physiology and composition of the gut microbiota.[7] Furthermore, a growing body of research suggests that they play a important role in maintaining human health.[4]

Short-chain fatty acids have carbon chains made of 2-5 carbon atoms, a characteristic that strongly affects the physical properties.[9] Acetic acid, propionic acid, butyric acid and valeric acid are straight-chain fatty acids, whereas isobutyric acid, isovaleric acid and 2-methylbutyric acid are branched-chain fatty acids.

Short-chain fatty acids appear to play a crucial role in maintaining human health.[4] Their activity seems to occur through direct and/or indirect effects on cellular processes such as proliferation, differentiation and gene expression, thus contributing to the regulation of processes such as glucose homeostasis, intestinal and immune function, and the regulation of the gut-brain axis.[6] Their health effects seem to be confirmed also by studies showing that intestinal dysbiosis appears to be implicated in metabolic pathologies, such as disorders involving glucose homeostasis, and behavioral and neurological pathologies, such as depression, and Alzheimer’s and Parkinson’s.[11]

In humans, the enzyme equipment carrying out carbohydrate digestion lacks the enzymes capable of digesting fiber and resistant starch, the latter so called precisely because it resists the action of alpha-amylase. On the contrary, the bacteria of the gut microbiota code for a large number of different glycoside hydrolases, more than 260, which also hydrolyze fibers and resistant starch, releasing the constituent monosaccharides.[7] Hexoses and deoxyhexoses enter glycolysis, and pentoses enter the pentose phosphate pathway, to give pyruvate which is the main precursor for the synthesis of short-chain fatty acids.[2][4][5] The synthesis of SCFAs is affected by several factors; below are some examples.[4][11][13]

Acetic acid and propionic acid are mainly produced by species of the phylum Bacteroides, while butyric acid, for whose synthesis resistant starch is particularly important, by species of the phylum Firmicutes.[6]

Acetic acid, the most abundant SCFA in the colon, can be synthesized via the Wood-Ljungdahl pathway in the reductive direction, through the reduction of CO2 to acetate, or from acetyl-CoA, the most important metabolic pathway, responsible of the production of about two thirds of butyric acid present in the intestinal lumen.[4]

Propionic acid can be synthesized through three different metabolic pathways: the acrylate and succinate pathways, which use lactic acid produced by other bacteria, and the propanediol pathway, in which the precursors are deoxyhexoses.[2][3][10] The acrylate pathway converts lactic acid to propionyl-CoA, via lactoyl-CoA. In the final step, propionyl-CoA is hydrolyzed to propionic acid. In the succinate pathway, lactate is reduced to pyruvate, which is carboxylated to oxaloacetate, which, through a pathway that has malate, fumarate, succinate, and methylmalonyl-CoA as intermediates, is converted to propionyl-CoA, which in turn is hydrolyzed to propionic acid. The succinate pathway is thought to be the dominant pathway for propionic acid synthesis in the gut. In the propanediol pathway, some deoxyhexoses, such as fucose and rhamnose, are converted via 1,2-propanediol to propionyl-CoA and then propionic acid.

The synthesis of butyric acid can follow two routes.[7][10] In most butyric acid-producing bacteria, the short-chain fatty acid is synthesized through a pathway that begins with the condensation of two acetyl-CoA to acetoacetyl-CoA, which, through a pathway that has beta-hydroxybutyryl-CoA and crotonyl-CoA as intermediates, is converted to butyryl-CoA. The final step is the release of butyric acid from butyryl-CoA.[8] In a small number of bacterial species, butyryl-CoA is converted to butyryl phosphate, from which butyric acid is released.[2]

Acetic acid, propionic acid and butyric acid can also be produced from amino acids obtained from peptide and protein degradation, although the amount produced by these pathways is small.[7] These synthesis occur in the distal part of the colon, often by non-commensal bacteria, as in the case of glutamate and lysine fermentation.[3] Different short-chain fatty acids are produced by the metabolism of different amino acids; below are some examples.[4]

The pH of the intestinal lumen influences the metabolism of proteins by the gut microbiota; for example, their breakdown into amino acids is more likely at neutral or weakly alkaline pH. It should be noted that potentially toxic compounds, such as ammonia, sulphites and phenols, are also produced from the intestinal metabolism of amino acids.

Short-chain fatty acids can bind to specific receptors on the plasma membrane, the G protein-coupled receptors, including GPR41, GPR43 and GPR109A.[6] The effects produced by the binding of the SCFAs on the receptors depend on the cell type. For example, binding to receptors on intestinal L cells is associated with the release of glucagon-like peptide-1, or GLP-1, and peptide YY, hormones that affect appetite and food intake. The binding to enterochromaffin cells induces the release of serotonin, which may affect intestinal motility. Finally, binding to receptors on pancreatic beta-cells increases insulin release.[11] The different short-chain fatty acids have different ability to activate the receptors: GPR43 is more likely to be activated by acetic and propionic acids, GPR41 by propionic and butyric acids, while GPR109A by butyric acid.[4]

In colonocytes, short-chain fatty acids have energy and regulatory function. When used for energy purposes, acetic acid and butyric acid are converted to acetyl-CoA, and propionic acid to propionyl-CoA. Through the production of ATP, SCFAs contribute to the maintenance of cellular homeostasis, but also, for example, to the maintenance of the integrity of the tight junctions at the cell apex, and therefore of the integrity of the intestinal barrier.[11] Of the three major short-chain fatty acids produced by gut microbiota, butyric acid is the major source of energy for colonocytes, while acetic and propionic acids are poorly metabolized and mostly drained by the portal vein.[2][13] Considering the regulatory role, SCFAs are, for example, capable of inhibiting histone deacetylases (EC 3.5.1.98), enzymes that catalyze the removal of acetyl groups from lysine residues of histone proteins, acetyl groups previously inserted by histone acetyltransferase (EC 2.3.1.48).[7] The R groups of deacetylated lysines have positive charges, which allows histone proteins to wrap the DNA more tightly. This makes the nucleosome more compact, and consequently more difficult to carry out transcription and gene expression. The different short-chain fatty acids have different abilities to inhibit histone deacetylases:

This mode of action on histone deacetylases has been observed not only in the gut and associated immune tissue, but also in the central and peripheral nervous systems.[11]

The liver is an important site for short-chain fatty acids metabolism.[13] It can to absorb about 40 percent of the acetic acid and 80 percent of the propionic acid from the portal vein. Propionic acid is mostly metabolized in the liver, where it can also be used as a substrate for gluconeogenesis.[7] A small amount of the gut derived SCFAs, about 36 percent for acetic acid, 9 percent for propionic acid and only 2 percent for butyric acid, reach, through the systemic circulation, the peripheral tissues. In muscle, acetic acid can be used for lipid synthesis or be oxidized for energy production. Furthermore, it is thought that SCFA concentrations in the systemic circulation, even if small, are capable of influencing the metabolism and physiology of peripheral cells and tissues.

Starch phosphorylase or alpha-glucan phosphorylase (EC 2.4.1.1) is a multimeric protein, with enzymatic and regulatory activity, that plays an important role in carbohydrate metabolism, both in prokaryotes and eukaryotes.[10] The enzyme catalyzes the transfer of a glucosyl unit from glucose 1-phosphate to the non-reducing end of a nascent α-(1→4)-glucan, to which glucose is linked by an α-(1→4) glycosidic linkage.[6][8]The reaction is reversible and the direction depends on the phosphate/glucose-1-phosphate ratio present in vivo.[2] The enzyme, like starch synthase (EC 2.4.1.21), which is involved in the synthesis of amylose and amylopectin, the polysaccharides which make up starch granules, glycogen phosphorylase (EC 2.4.1.1), an enzyme involved in glycogenolysis, and glycogen synthase (EC 2.4.1.11), which is involved in glycogen synthesis, belongs to the family of glucosyltransferases (EC 2.4).[6] Note that, while starch synthase uses ADP-glucose as glucosyl donor, and glycogen synthase uses UDP-glucose, starch phosphorylase uses glucose 1-phosphate.[2] Starch phosphorylase appears to be involved in both the synthesis and degradation of amylose and amylopectin.[9] Industrially, the phosphorolytic action of starch phosphorylase is used in the production of glucose-1-phosphate and in the preparation of carbohydrates such as glucans and modified starches.[6]

Although alpha-amylase (EC 3.2.1.1) is the first enzyme to intervene in the polysaccharide degradation during the early stages of germination, and beta-amylase (EC 3.2.1.2) is the first enzyme to intervene in the transient starch degradation in chloroplasts, other enzyme activities have also been implicated, such as alpha-glucan water dikinase (EC 2.7.9.4) and phospho-glucan water dikinase (EC 2.7.9.5), and the debranching enzyme.[10] Of the two isoenzymes of starch phosphorylase, Pho1 seems to have an indirect or regulatory action capable of influencing the activity of the other enzymes involved in starch degradation, while Pho2 is capable of degrading starch granules and other branched glucans.

In most starches, α-1,6 glycosidic bonds account for about 5 percent of all glycosidic bonds, a lower percentage than that found in glycogen molecule, about 9 percent, where the branches are more evenly distributed. The length and distribution of the branches directly affect the physicochemical properties of amylopectin, such as solubility, viscosity, ease of retrogradation, and gelatinization and pasting temperature.[3] For example, glycogen is water soluble whereas amylopectin and starch are not.

Amylopectin chains can be classified on the basis of their length or the presence or absence of branches. The classification according to the length identifies two main types of chains: short and long chains. Short chains have a degree of polymerization of 6-36 glucosyl units, although the upper limit depends on the source of amylopectin, whereas long chains have a degree of polymerization greater than or equal to 36. In most starches, the molar distribution of long to short chains is about 19-6, and is generally higher in A-crystalline starches, such as cereal endosperm starches, than in B-crystalline starches, such as those in potatoes.[17] The classification on the basis of their connections to other chains identifies three categories: A-chains, B-chains and C-chains.[7]

Note that, unlike glycogen synthase, starch synthase uses ADP-glucose and not UDP-glucose as the glucosyl donor. The mode of action of starch synthase I, II, III, and IV is different from that of GBSS in that they are able to catalyze the addition of only one glucose unit per substrate encounter, a mode of action defined as distributive, whereas GBSS is able to catalyze the addition of more than one glucose unit per substrate encounter, a mode of action defined as processive.[17]

Amylopectin, similarly to glycogen, binds phosphate groups in variable amounts depending on the botanical origin of the starch. For example, potato starch has a relatively high content of phosphate groups, with a degree of substitution of about 0.1 to 0.3 percent, whereas cereal endosperm starches have a phosphate content generally lower than 0.01 percent.[9] The phosphorylations of amylopectin are catalyzed by two dikinases present in plastids: alpha-glucan water dikinase (EC 2.7.9.4) and phospho-glucan water dikinase (EC 2.7.9.5). These enzymes transfer the beta-phosphate group of ATP to a glucosyl unit of an alpha-glucan chain, while the gamma-phosphate group is transferred to water. Specifically, alpha-glucan water dikinase catalyzes the phosphorylation of the hydroxyl group at C6 position, whereas phospho-glucan water dikinase catalyzes the phosphorylation of the hydroxyl group at C3 position, generally of a prephosphorylated glucan chain.[13] About two thirds of the phosphate groups are bound at the C6 position, while about 20-30% at the C3 position. Phosphate groups are also present at the C2 position, although in a small percentage compared to the other positions. The enzyme which catalyze this phosphorylation in not known. With regard to substrate specificity, it seems that phosphorylations accumulate more easily on longer chains. Furthermore, it seems to exist an inverse correlation between the total phosphate content and the frequency of amylopectin branching. The negative charges carried by the phosphate groups cause the mutual repulsion between neighboring phosphorylated oligosaccharides. These repulsions appear to allow the opening and hydration of the chains, thus affecting the activity of the biosynthesis enzymes and making the chains more susceptible to attack by amylases as well.[21]

Starch granules are made up mostly of amylopectin and amylose.[12] The two polysaccharides are present in varying percentages, with amylose making up no more than 35 percent of the dry weight of the granule.[5] However, there are plants whose starch granules consist mostly, or almost exclusively, of amylopectin, and whose starches are defined as waxy starches, and plants whose starch granules consist mostly, or almost exclusively, of amylose.[19] The amylose/amylopectin ratio influences the physicochemical properties of starch, such as the ability to absorb water, gelatinization, retrogradation, or resistance to enzymatic hydrolysis, the latter important in establishing the rate with which, during carbohydrate digestion, amylose and amylopectin are hydrolyzed to maltose and maltotriose by alpha-amylase.[3] Therefore, the amylose/amylopectin ratio influences the effects of the different types of starch on health, as well as their industrial uses.

Hypertension is defined as a mean resting arterial pressure of 140/90 mm Hg or higher and/or current use of antihypertensive drugs. It is the most common public health problem in developed countries. Often referred to as the “silent killer”, as affected individuals may be asymptomatic for many years and then suffer a fatal heart attack, it is a major risk factor for developing coronary artery disease, myocardial infarction, heart failure, stroke, and a leading cause of morbidity and mortality. However, among the risk factors for cardiovascular disease, it is the most modifiable. It is often classified as primary or essential hypertension and secondary hypertension. Primary hypertension, responsible for about 95 percent of cases, is probably the consequence of environmental factors, genetic factors, and their interaction. Among the environmental factors, diet plays a central role. Among the genetic factors, interest has focused on factors influencing the blood pressure response to salt intake, and several genotypes have been identified, many of which influence the renin-angiotensin-aldosterone system or renal salt handling. Secondary hypertension is due to other diseases, usually endocrine, such as hyperthyroidism, hyperaldosteronism, and Cushing’s syndrome.

Above-optimal blood pressure levels, not yet in the hypertensive or prehypertensive range, confers an increased risk of cardiovascular disease, as shown by the fact that nearly one-third of blood pressure-related deaths from coronary heart disease are estimated to occur in non-hypertensive individuals with systolic blood pressure of 120-139 mm Hg, or diastolic blood pressure of 80-89 mm Hg. This means that the risk of cardiovascular disease increases throughout the blood pressure range, starting from 115/75 mm Hg.

The prevalence of hypertension increases with increasing age, as shown by the fact that more than half of the adult population over 60 years old is hypertensive. Age-related risk is a function of variables such as weight gain, low physical activity, excessive use of salt, fats and saturated fatty acids, alcohol, hypercholesterolemia, and low intake of fruits and vegetables, rather than of aging per se. For example, studies of vegetarians living in industrialized countries have shown that such dietary habits are associated with a lower increase in blood pressure with increasing age, and with a markedly lower blood pressure compared to non-vegetarians.

According to a study conducted by a team of researchers from Johns Hopkins University, prevention of hypertension starts in childhood. Furthermore, a meta-analysis on studies from diverse populations, studies published between January 1970 and July 2006, have examined the tracking of blood pressure from childhood to adulthood showing that childhood blood pressure is associated with blood pressure in later life, and that a high values in childhood are likely to help predict hypertension in adulthood. Finally, other studies have also shown that increased blood pressure among children is related to the growing obesity epidemic.

A downward trend in blood pressure has been documented in the USA over the last two decades, and the adoption of healthy lifestyle have contributed to this trend. Lifestyle modifications that effectively lower blood pressure are:

These changes are the first line of defense in preventing high blood pressure, and need not be made one at a time: the best results are achieved when they occur simultaneously, as demonstrated by two studies in which multicomponent interventions lowered blood pressure in hypertensive and nonhypertensive individuals. Finally, it has been demonstrated that there is also a relationship between alcohol and hypertension.

Potassium, an essential nutrient for humans, is the most abundant cation in intracellular fluids. It is therefore widely distributed in foods that come from living tissues, both animal and vegetable, but which have not undergone salting and/or drying. Cooking methods tend to lower the amount of potassium, as well. Considering vegetables, the worst cooking method is boiling in plenty of water, for more than an hour, whereas the best is microwave cooking.

A high dietary potassium intake and blood pressure are inversely correlated, as demonstrated by animal studies, observational epidemiological studies, clinical trials, controlled feeding studies, such as the DASH Study and the OmniHeart trial, and meta-analysis. Furthermore, a high potassium intake also increases urinary sodium excretion. The optimal strategy for increasing potassium intake is to consume foods naturally rich in the mineral, such as seasonal fruit and vegetables, and legumes, typical foods of the Mediterranean diet. It is therefore not difficult to reach the recommended daily intake, for the healthy population, equal to 4.7 g per day.

Sodium is the most abundant cation in extracellular fluids, of which it strongly affects the osmotic pressure values. There are three main source of sodium. The most intuitive source is table salt, which represents up to 20 percent of the daily intake. It is important to note the terms salt and sodium are often used interchangeably, but this is incorrect. On a weight basis, salt is 40 percent sodium and 60 percent chlorine. A second source is salt or sodium compounds added during food preparation or processing. Between 35 to 80 percent of the daily sodium intake comes from processed foods such as:

There are also many sodium-based food additives, often used as preservatives and flavour enhancers. The third source is negligible, namely, the sodium naturally present in foods, generally low in fresh foods. A high sodium intake contributes to the increase in blood pressure and the development of hypertension. This is supported by many epidemiological, animal, and migration studies, and meta-analysis, with the final evidence coming from carefully controlled dose-response studies. Furthermore, in primitive societies, where sodium intake is very low, people rarely develop hypertension, and blood pressure does not increase with increasing age. Therefore, a reduction in sodium intake is recommended to prevent the development of hypertension. In view of the available food supply and the high daily sodium intake, a reasonable recommendation may be to limit its intake to 2.3 g per day, equal to 5.8 g per day of salt. How can this level be achieved?

Clinical studies have documented that a reduced sodium intake is able to lower blood pressure even the setting of antihypertensive therapy, and can facilitate hypertension control. Some components of the diet may modify the blood pressure response to sodium. A high dietary intake of foods rich in potassium and calcium may prevent or attenuate the increase in blood pressure for a given increase in sodium intake. Conversely, some data, mainly observed in animal models, suggest that a high sucrose intake could enhance salt sensitivity of blood pressure.

Note: high sodium intakes may contribute to the development of osteoporosis by increasing renal calcium excretion, particularly if daily calcium intake is low.

Physical activity produces a drop in systolic and diastolic blood pressure. Therefore, for the primary prevention of hypertension, it is important to increase physical activity of low or moderate intensity for 30-45 minutes 3-4 times a week up to an hour most days, as recommended by the World Health Organization. Conversely, less active people are 30 to 50 percent more likely to develop hypertension than active people.

And dietary cholesterol? There is not a direct correlation between blood cholesterol and cholesterol intake. Dietary cholesterol may increase plasma cholesterol only when it is consumed with trans fats and saturated fatty acids. However, if you want to reduce your cholesterol intake, we advise to reduce the use of animal products and/or use semi-skimmed or skimmed milk, light cheese, light yogurt, and lean meat.

A risky factor for hypercholesterolemia is a high intake of saturated fatty acids, a group of lipids that can be easily used for the endogenous synthesis of cholesterol. These fatty acids are present in meat, diary products, and in abundance in vegetal fats and oils, such as margarine, palm oil, palm seed oil, and coconut oil, which are much used in the confectionery industry. What to do:

Trans fatty acids or trans fats are an extremely risky factor, and not only for hypercholesterolemia. Studies have observed a high atherogenic potential caused by changes in plasmatic lipoproteins, where a decrease of HDL levels, and an increase of LDL and triglyceride levels occur. Where can they be found?

As regards to the content of saturated and trans fatty acids, there is often no difference between classic products and “natural” or “organic” ones. What can we do? To avoid to buy products that contain vegetal fats and/or hydrogenated fatty acids, and to avoid to buy fried products.

A significant body fat gain contributes to hypercholesterolemia. In a lot of people, the decrease in the intake of satured and trans fatty acids doesn’t reduce the cholesterolemia levels till weight starts to drop. What to do:

Starch synthase (EC 2.4.1.21) is an enzyme that catalyzes the transfer of glucose molecules from ADP-glucose to the non-reducing end of a pre-existing α-(1→4) linked glucan chain, to which the monosaccharides are linked by an α-(1→4) glycosidic bond.[4]

PTST1 appears to associate, in the plastid stoma, with GBSS. The complex binds to the nascent starch granule, the protein dissociates from the enzyme, that begins to catalyze the elongation of the malto-oligosaccharides, while the protein returns to the stroma where it recruits another GBSS.

After the Seven Countries Study, many studies have shown the effectiveness of this dietary pattern in primary and secondary prevention of the main chronic diseases, from cardiovascular diseases to depressive disorders, as well as a reduction in mortality in general. Here are some examples.

The mediterranean diet is able to improve public health also by contributing to the reduction of greenhouse gas emissions, namely, carbon dioxide or CO2, methane, nitrous oxide and similar, from the livestock sector, responsible for 4/5 of emissions related to agriculture. These emissions are greater than those due to transport, and second only to those of energy production. Adding to this that world population is growing, and that this growth is accompanied by an increase in per capita consumption of meat, with estimates that by 2030 there will be an increase in meat production of 85% compared to 2000, the role of the mediterranean diet in reducing greenhouse gas emissions is even more evident. Analyzing in detail the greenhouse gas emission from cattle farming, the major contributor of the emissions in the livestock sector:

The table above compares CO2 emission from the production of different foods, considering portions of 225 g, with those from a gasoline car that travels about 12 km per litre of fuel. So producing 225 grams of beef releases to the atmosphere an amount of greenhouse gases almost 13 times greater than that released producing an equal amount of chicken, and even 57 times greater if we consider potatoes. To take another example, to produce 41 kilograms of beef, the amount annually consumed by the average American, it releases the same amount of CO2 of a car traveling about 3,000 km.

Amylose molecules have a molecular weight of about 106 daltons, are mostly linear and made up of α-D-glucose units, hereinafter referred to as glucose, linked by α-(1→4)-glycosidic bonds, namely, covalent bonds between C-1 of one unit and the hydroxyl group on the C-4 of the next unit.[1] The linear chains are made up of a number of monosaccharides ranging from a few hundred to several thousand; therefore, they are much longer than amylopectin chains.[17]

A similar bimodal distribution of the length of the branches is also observed for amylopectin, whose fractions are indicated as AP1, shorter and more abundant, and AP2. The intraspecies variation of the distribution of the AM1 and AM2 fractions is relatively small, whereas it is large between different species, variation that has a genetic basis.[19]

The precise location of amylose in the starch granule is not known, although it is believed that most are found in the amorphous regions. However, some studies have suggested that its localization is not restricted to the amorphous regions, but is also present between amylopectin chains and on the surface of the granules.[13] Hence, amylose could have several locations within the granule.

Amylose synthesis requires the presence of a protein of the PTST family, namely PTST1, which was discovered more than fifty years after GBSS.[15] PTST1 has no catalytic activity, but allows the binding of GBSS to the starch granule, an activity that seems more important in chloroplasts, and therefore for the synthesis of transient starch, than in amyloplasts. It was proposed that PTST1 associates with the synthase in the plastid stroma, the complex binds to the nascent starch granule, PTST1 dissociates from the enzyme which initiates the synthesis of amylose, while the PTST1 returns to the plastid stroma to recruit another GBSS molecule. The importance of PTST1 is underlined by the fact that it is conserved throughout the plant kingdom, and its loss causes the enzyme to detach from the nascent starch granule.

In the starch granules of land plants, amylose is almost always present, in variable percentages, generally between 5-35%.[5] The variability occurs not only between different species, but also within the same species based on the organ or tissue considered, and, in tubers and seeds, based on the stage of development, being the content generally low in the early stages, then increasing until the final value is reached, a pattern consistent with the synthesis of amylose within an amylopectin matrix.[13] However, there are plants whose amylose content is very low, or even absent. Their starch is referred to as waxy, due to the appearance of the endosperm of the raw grains which resembles wax. Conversely, there are plants with starch granules containing mostly, or entirely, amylose.[20] Although its role has not yet been clarified, its near-constant presence seems to indicate this polysaccharide plays an important structural role in the starch granule, and provides the plant some advantage in the growth and development phase.[13] The amylose/amylopectin ratio strongly influences the physicochemical properties of starch, such as its ability to absorb water, which influences processes such as starch retrogradation and gelatinization, or its resistance to enzymatic hydrolysis, which determinates, for example, the rate at which maltose and maltotriose are released during starch degradation by alpha-amylase or beta-amylase.[10] These properties, in turns, are able to affect the industrial applications of starch as well as its effects on health.

The Leloir pathway is the main pathway for galactose metabolism. Discovered by Leloir L.F. and colleagues in 1948, it leads to the conversion of galactose into glucose 1-phosphate, namely, to the inversion of the configuration of hydroxyl group at C4 of galactose, one of the chirality centers of the monosaccharide.[9] The metabolic intermediates involved in this isomerization are building blocks in many metabolic pathways, such as glycosylation reactions of proteins and lipids or glycogen synthesis, depending on the stage of development, the metabolic state of the cell, and the type of tissue.[6] Except for the first step, the other reactions of the Leloir pathway may proceed in both directions, depending on substrate levels and metabolic demands of the tissue. This allows the interconversion of galactose and glucose.[4] The importance of the Leloir pathway, and therefore of galactose, is emphasized by the fact that it is highly conserved in nature, from bacteria to plants and animals, and, in humans, by the severity of the consequences due to mutations in one of the genes encoding the enzymes of the pathway, mutations that cause the genetic metabolic disorder known as galactosemia.[2][8]

Galactose, together with glucose and fructose, is one of the monosaccharides that can be absorbed in the intestine. The main dietary source of galactose is lactose, which, with maltose, trehalose and sucrose, is one of the disaccharides found in food. Since there are no transporters for disaccharides, in the last stage of carbohydrate digestion their glycosidic bonds are hydrolyzed with the release of the constituent monosaccharides, which for lactose are glucose and galactose. Then follows the absorption of monosaccharides which, through the portal system, reach the liver, which is the main site for the metabolism of galactose and absorbs, through passive diffusion mediated by the GLUT2 transporter, most of it, about 88%.[3] The residual circulating quantity reaches other organs and tissues, such as the mammary gland that, during the lactation phase, uses it for the production of lactose and the glycosylation of milk proteins and lipids.[4]

The Leloir pathway consists of four reactions catalyzed by the enzymes galactose mutarotase or aldose 1-epimerase (EC 5.1.3.3), galactokinase (EC 2.7.1.6), galactose 1-phosphate uridylyltransferase or GALT (EC 2.7.7.12) and UDP-galactose 4-epimerase or GALE (EC 5.1.3.2).[8]

The cleavage of the β-(1→4) glycosidic bond of lactose leads to the release of glucose and beta-galactose. Galactokinase, the enzyme that catalyzes the second step of the Leloir pathway, is specific for the alpha anomer of galactose. The conversion of beta-galactose to alpha-anomer is catalyzed by galactose mutarotase. The enzyme is also able to interconvert alpha and beta-configurations of glucose, xylulose, maltose and lactose, albeit with variable efficiency.[12]

In the second step, alpha-galactose is phosphorylated to galactose 1-phosphate, in a reaction catalyzed by galactokinase.[8] The phosphorylation of galactose has some functions.

The reaction catalyzed by galactokinase is the irreversible step of the Leloir pathway.[4] Unlike hexokinase and glucokinase (EC 2.7.1.1), which phosphorylate the hydroxyl group at C6 of glucose, galactokinase and fructokinase (EC 2.7.1.4) phosphorylate the hydroxyl group at C1 of galactose and fructose, respectively.[11] The conversion of galactose 1-phosphate to glucose 1-phosphate requires two reactions, the third and fourth of the Leloir pathway, respectively.

The Leloir pathway allows the cell to use galactose or the derived glucose in many metabolic pathways, both anabolic and catabolic, depending on the metabolic state of the cell or tissue. Furthermore, since the reaction catalyzed by UDP-galactose 4-epimerase is reversible, conversion of glucose to galactose and nucleotide derivatives is possible.[4][6] UDP-galactose can be used:

Glycosylations are post-translational modifications that play a key role in enabling and regulating many biological processes. Glycosylation defects have been related to many pathological conditions such as cancer, diabetes, and congenital inborn errors of metabolism such as congenital disorders of glycosylation, which are mainly autosomal recessive monogenic disorders.[5] Congenital disorders of glycosylation include galactosemia, which was first described by von Reuss A. in 1908.[14] Galactosemia is due to mutations in one of the genes encoding the four enzymes of the Leloir pathway, and four types have been identified:

The accumulation of galactose fuels alternative metabolic pathways such as the synthesis of galactitol and galactonate. The symptoms of galactosemia include the early onset of cataracts, usually within the first two years of life, and in the most severe cases, brain, liver, and kidneys damages, too.[12] It seems that one of the factors triggering cataracts is the reduction of galactose, accumulated in the lens of the eye, to galactitol, in a reaction catalyzed by aldose reductase (EC 1.1.1.21).[10] Galactitol, which is poorly metabolized, does not diffuse through cell membranes due to its poor lipophilicity and, being osmotically active, increases the intracellular osmotic pressure causing a net flow of water inside the cell. Moreover, its synthesis, depleting NADPH levels, may reduce glutathione reductase (EC 1.8.1.7) activity and lead to free radical accumulation.[3] The osmotic effect and the build-up of free radicals may ultimately damage cell integrity and cause cell death. Furthermore, it has been reported that galactitol is a galactose mutarotase inhibitor, so its accumulation may lead to further accumulation of unmetabolized galactose.[12]

In 1906, the Russian-American chemist Martin André Rosanoff, working at that time at New York University, chose glyceraldehyde, a monosaccharide, as the standards for denoting the stereochemistry of molecules with at least one chirality center, such as carbohydrates. This nomenclature system was called the Fischer-Rosanoff convention, or Rosanoff convention, or D-L system.[7] Because Rosanoff didn’t know the absolute configuration of glyceraldehyde, he assigned in a completely arbitrary manner:

Although Fischer rejected this nomenclature system, it was universally accepted and used to obtain the relative configurations of the chiral molecules.[3] How? The configuration about a chiral center is related to that of glyceraldehyde by converting its groups to those of the monosaccharide through reactions that occur with retention of configuration, namely, reactions that do not break any of the bonds to the chiral center. This means that the spatial arrangement of the groups around the chiral center in the reagents and products is same. The Fischer convention allows to divide the chiral molecules, such as amino acids and monosaccharides, into two classes, known as the D series and the L series, depending on whether the configuration of the groups around the chiral center is related to that of D-glyceraldehyde or L-glyceraldehyde.

Note: there is no correlation between retention of configuration and sign of the rotatory power: the D-L system does not specify the sign of the rotation of plane-polarized light caused by the chiral molecule, but simply correlates the configuration of the molecule with that of the glyceraldehyde.[6]

Monosaccharides can be aldoses or ketoses. Aldoses, and ketoses with more than three carbon atoms have at least one chiral center, and, by convention, they belong to the D series or to the L series if the configuration of the chiral carbon farthest from the carbonyl carbon, the carbon with the highest oxidation state, is same as that of D-glyceraldehyde or L-glyceraldehyde, respectively. In Fischer projections the longest chain of carbon atoms is oriented vertically, and the atoms are numbered so that the carbonyl carbon has the lowest possible number, then, C-1 in aldoses and C-2 in ketoses.[8] Note: in Nature, D-sugars are much more abundant than L-sugars.

If the sign of the rotation of plane-polarized light must be specified in the name, the prefixes (+) or (-) can be employed in addition to the D and L prefixes. For example, fructose, which is levorotatory, can be named D-(-)-fructose, whereas glucose, which is dextrorotatory, can be named D-(+)-glucose.

α-Amino acids belong to the D series or to the L series if the configuration of the –NH2, –COOH, –R, and H groups attached to the α-carbon, the chiral center, is the same of the hydroxyl, aldehyde (–CHO), and hydroxymethyl (–CH2OH), and H groups of D-glyceraldehyde or L-glyceraldehyde, respectively.[6][8] In Fischer projections the molecules are arranged so that the carboxylic group, namely, the carbon with the highest oxidation state, is at the top, and the R group at the bottom. Among α-amino acids, proteinogenic amino acids, with the exception of glycine whose α-carbon is not chiral, have the L configuration, hence, they are L-α-amino acids.

When Rosanoff arbitrarily assigned the D prefix to (+)-glyceraldehyde and the L prefix to (-)-glyceraldehyde, he had 50/50 chance of being correct.[5] In the early 1950s, a new technique, the x-ray diffraction analysis, made possible to establish the absolute configuration of chiral molecules. In 1951 a Dutch chemist, Johannes Martin Bijvoet established the absolute configuration of sodium rubidium (+)‐tartrate tetrahydrate and, comparing it with glyceraldehyde, demonstrated that Rosanoff’s guess was right.[1] Consequently, the configurations of the chiral compounds obtained by relating them to that of glyceraldehyde were the same as their absolute configurations: hence, the relative configurations became absolute configurations.

In these cases, the RS system, developed in 1956 by Robert Sidney Cahn, Christopher Ingold, and Vladimir Prelog, labeling each chiral center, allows to describe accurately the stereochemistry of the molecule.[2][8] In the case of D-(+)-glucose, the molecule has the (2R,3S,4R,5R)-configuration. It should also be noted that depending on the chiral center taken as the reference center, the same molecule can belong to both the D and L series.

Since Fischer projections represent three-dimensional molecules on a two-dimensional sheet of paper, some rules must be respected to avoid changing the configuration.

The RS system assigns a priority sequence to the groups attached to the chirality center and, tracing a curved arrow from the highest priority group to the lowest, labels each chiral center R or S.[2][4]

For example, if an oxygen atom, O, atomic number 8, a carbon atom, C, atomic number 6, a chlorine atom, Cl, atomic number 17, and a bromine atom, Br, atomic number 35 are attached to the chiral center, the order of priority is: Br > Cl > O > C. For isotopes, the atom with the highest atomic mass is assigned the highest priority.

When different groups are attached to the chiral center through identical atoms, the priority sequence is assigned based on the atomic number of the next atoms bound, then moving outward from the chirality center until the first point of difference is reached. If, for example, –CH3, –CH2CH3 and –CH2OH groups are attached to a chiral center, there are three identical atoms directly attached to the chiral center. Analyzing the next atoms bound, we have:

Because the atomic number of oxygen is higher than that of carbon, that, in turn, is higher than that of hydrogen, the order of priority is –CH2OH > –CH2CH3 > –CH3 The order of priority of some groups is:

Once the priority sequence has been established, the molecule is oriented in space so that the group with the lowest priority is pointed away from the viewer, then behind the chiral center. Now, trace a curved arrow, a circle, from the highest priority group to the lowest.

This is the third rule of the RS system, by which we can determine the configuration of a chirality center when there are double or triple bonds in the groups attached to the chirality center. To assign priorities, the atoms engaged in double or triple bonds are considered duplicated and tripled, respectively.

In the case of a C=Y double bond, one Y atom is attached to the carbon atom, and one carbon atom is attached to the Y atom. In the case of a C≡Y triple bond, two Y atoms are attached to the carbon atom, and two carbon atoms are attached to the Y atom.

When two or more chirality centers are present in a molecule, each center is analyzed separately using the rules previously described. Consider 2,3-butanediol. The molecule has two chiral centers, carbon 2 and carbon 3, and exists as three stereoisomers: two enantiomers and a meso compound. What is the RS configuration of the chiral centers of the enantiomer shown in figure?

Consider carbon 2. The order of priority of the groups is –OH > –CH2OHCH3 > –CH3 > –H. Rotate the molecule so that the hydrogen, the lowest priority group, is pointed away from the viewer. Tracing a path from –OH, the highest priority group, to –CH3, the lowest priority group, we move in a clockwise direction: the configuration of the carbon 2 is, therefore, R. Applying the same procedure to carbon 3, its configuration is R. Then, the enantiomer shown in figure is (2R,3R)-2,3-butanediol.

Two enantiomers of a chiral molecule, being non-superimposable, are different compounds. How do they differ? Each pair of enantiomers has identical physical and chemical properties towards achiral properties, such as melting point, boiling point, refractive index, infrared spectrum, the solubility in the same solvent, or the same reaction rate with achiral reagents. The differences emerge when they interacts with chemical and physical phenomena that have chiral properties.

The optical activity of materials such as quartz and, more importantly, of organic compounds such as sugars or tartaric acid, was discovered in 1815 by the French scientist Jean-Baptiste Biot. Chiral molecules can be classified based on the direction in which plane-polarized light is rotated when it passes through a solution containing them.

In 1848, thirty three years after Biot’s work, studies on the optical activity of molecules led Louis Pasteur, who had been a student of Biot, to note that, following the recrystallization of a concentrated aqueous solution of sodium ammonium tartrate, optically inactive, two kinds of crystals precipitated, that were non-superimposable mirror images of each other. After separating them with tweezers, Pasteur discovered that the solutions obtained by dissolving equimolar amounts of the two kind of crystals were optically active and, interestingly, the rotation angle of plane-polarized light was equal in magnitude but opposite in sign. Because the differences in optical activity were due to the dissolved sodium ammonium tartrate crystals, Pasteur hypothesized that the molecules themselves should be non-superimposable mirror images of each other, like their crystals: they were what we now call enantiomers. And it is Pasteur who first used the term asymmetry to describe this property, then called chirality by Lord Kelvin.

A solution containing an equal amount of each member of a pair of enantiomers is called racemic mixture or racemate. These solutions are optically inactive: there is no net rotation of plane-polarized light since the amount of dextrorotatory and levorotatory molecules is exactly the same. Unlike what happens in biochemical processes, the chemical synthesis of chiral molecules that does not involve chiral reactants, or that is not followed by methods of separation of enantiomers, inevitably leads to the production of a racemic mixture. The pharmaceutical chemistry is among the sectors most affected by this. As previously mentioned, two enantiomers are different compounds. Many chiral drugs are synthesized as racemic mixtures, but most often the desired pharmacological activity resides in one enantiomer, called eutomer; the other, called distomer, is less active or inactive. An example is ibuprofen, an arylpropionic acid derivative, and anti-inflammatory drug: only the S enantiomer has the pharmacological activity.

Arylpropionic derivatives are sold as racemic mixtures: a racemase converts the distomer to the eutomer in the liver. However, it is also possible that the distomer causes harmful effects and must be eliminated from the racemic mixture. A tragic example is thalidomide, a sedative and anti-nausea drug sold as a racemic mixture from the 1950s until 1961, and taken also during pregnancy.

The distomer, the S enantiomer, could cause serious birth defects, particularly phocomelia. This is probably the most striking example of the importance of the chiral properties of molecules, which prompted health care organizations to promote the synthesis of drugs, including thalidomide, containing a single enantiomer by the pharmaceutical industry.

Any tetrahedral atom that bears four different substituents can be a chirality center. Carbon atom is the classic example, but also other atoms from group IVA of the periodic table, such as the semimetals silicon (Si) and germanium (Ge), have a tetrahedral arrangement and can be chiral centers. Another example is the phosphorus atom in organic phosphate esters that has a tetrahedral arrangement, then, when it binds four different substituents it is a chiral center. The nitrogen atom of a tertiary amine, an amine in which the nitrogen is bounded to three different groups, is a chiral center. In these compounds, nitrogen is located at the center of a tetrahedron and its four sp3 hybrid orbitals point to the vertices, three of which are occupied by the three substituents, whereas the nonbonding electron pair points towards the fourth.

At room temperature, nitrogen rapidly inverts its configuration. The phenomenon is known as nitrogen inversion, namely, a rapid oscillation of the atom and its ligands, during which nitrogen passes through a planar sp2-hybridized transition state. As a consequence, if the nitrogen atom is the only chiral center of the molecule, there is no optical activity because a racemic mixture exists. The inversion of configuration does not occur only in some cases in which nitrogen is part of a cyclic structure that prevents it. Therefore, the presence of a chiral center could be not sufficient to allow the separation of the respective enantiomers.

Meso compounds or meso isomers are stereoisomers with two or more chiral centers that are superimposable on their mirror image, then achiral and, as such, optically inactive. Moreover, they have an internal mirror plane that bisects the molecule, with each half a mirror image of the other. Then, meso compounds can be classified as diastereomers, namely, stereoisomers which are not enantiomers. For a molecule with n chirality centers, the maximum number of possible stereoisomers is 2n. Consider 2,3-butanediol. The molecule has two chirality centers, the carbons 2 and 3, so there are 22 = 4 possible stereoisomers, whose structures are depicted in the figure, in the Fischer projections, indicated as A, B, C, D.

Structures A and B are mirror images of each other and non-superimposable, then they are a pair of enantiomers. Structures C and D are mirror images of each other, but are superimposable. In fact, if we rotate structure C or D of 180 degrees, the two structures are superimposable. Then, they are not a pair of enantiomers: they are the same molecule with opposite orientation. Moreover, they have an internal mirror plane, that bisects the molecule, giving two halves, each a mirror image of the other. Structure C, or D, is therefore a meso compound because it has chiral centers, is superimposable on its mirror image, and has internal mirror plane that divides the molecule into two mirror‐image halves.

In structural isomerism, also called constitutional isomerism, isomers differ from each other in that the constituent atoms are linked in different ways and sequences. There are several subtypes of structural isomerism: positional, functional group and chain isomerism.

Optical isomerism occurs in molecules that have one or more chirality centers or chiral centers, namely, tetrahedral atoms that bear four different ligands.[2] The chiral center can be a carbon, phosphorus, sulfur or nitrogen atom.

Note: the word chirality derives from the Greek cheiros, meaning “hand”. Optical isomers lack of a center of symmetry or a plane of symmetry, are mirror image of each other, and cannot be superimposed on one another. Such stereoisomers are called enantiomers, from the Greek enántios, meaning “opposite”, and meros, meaning “part”. Unlike the other isomers, two enantiomers have identical physical and chemical properties with two exceptions.

An example of geometrical isomerism due to the presence of a carbon-carbon double bond is stilbene, C14H12, of which there are two isomers. In one isomer, called cis isomer, the same groups are on the same side of the double bond, whereas in the other, called trans isomer, the same groups are on opposite sides.

In solution, solvent molecules tend to move from a region of higher concentration to one of lower concentration. When two different solutions are separated by a semipermeable membrane, namely, a membrane that allows certain ions or molecules to pass, in this case the solvent molecules, a net flow of solvent molecules from the side with higher concentration to the side with lower concentration will occur. This net flow through the semipermeable membrane produces a pressure called osmotic pressure, indicated as Π, that can be defined as the force that must be applied to prevent the movement of the solvent molecules through a semipermeable membrane.

Osmotic pressure, together with boiling point elevation, freezing point depression, and vapor pressure lowering, is one of the four colligative properties of solutions, properties that do not dependent of the chemical properties of the solute particles, namely ions, molecules or supramolecular structures, but depend only on the number of solute particles present in solution. For a solutions of n solutes, the equation that describes osmotic pressure is the sum of the contributions of each solute:

For non ionizable compounds, such as glucose, glycogen or starch, n = 1, and i = 1. For compounds that completely dissociate, such as strong acids and strong bases or salts, the van ‘t Hoff factor is a whole number greater than one, as α = 1 and n is equal to at least 2. For example, if we consider sodium chloride, NaCl, potassium chloride, KCl, or calcium chloride, CaCl2, in dilute solution:

So in the first two cases i = 2, whereas with calcium chloride, i = 3. Finally, for substances that do not completely ionize, such as weak acids and weak bases, i is not an integer.

The product of the van ’t Hoff factor and the molar concentration of the solute particles, ic, is the osmolarity of the solution, namely, the concentration of the solute particles osmotically active per liter of solution.

Osmosis can be defined as the net movement or flow of solvent molecules through a semipermeable membrane driven by osmotic pressure differences across the membrane, to try to equal the concentration of the solute on the two sides of the membrane itself. In biological systems, water is the solvent and plasma membranes are the semipermeable membranes. Plasma membranes allow water molecules to pass, due to protein channels, known as aquaporins, as well as small non-polar molecules that diffuse rapidly across them, whereas they are impermeable to ions and macromolecules. Inside the cell there are macromolecules, such as nucleic acids, proteins, glycogen, and supramolecular aggregates, for example multienzyme complexes, but also ions in a higher concentration than that of the extracellular environment. This causes osmotic pressure to drive water from outside to inside the cell. If this net flow of water toward the inside of the cell is not counterbalanced, cell swells, and plasma membrane is distended until the cell bursts, that is, an osmotic lysis occurs. Under physiological conditions, this does not happen because during evolution several mechanisms have been developed to oppose, and in some cases even exploit, these osmotic forces. Two of these are energy-dependent ion pumps and, in plants, bacteria and fungi, the cell wall.

Ion pumps reduce, at the expense of ATP, the intracellular concentrations of specific ions with respect to their concentrations in the extracellular environment, thereby creating an unequal distribution of the ions across the plasma membrane, namely, an ion gradient. In this way the cell counterbalances the osmotic forces due to the ions and macromolecules trapped inside it. An example of energy-dependent ion pump is Na+/K+ ATPase, which reduces the concentration of Na+ inside the cell relative to the outside.

Plant cells are surrounded by an extracellular matrix, the cell wall, that, being non expandable and positioned next to the plasma membrane, allows cell to resist osmotic forces that would cause its swelling and finally the lysis. How? Inside mature plant cells, the vacuoles are the largest organelles, occupying about 80% of the total cell volume. Large quantities of solutes, for the most part organic and inorganic acids, are accumulated within them and osmotically draw water, causing their swelling. In turn, this causes the tonoplast, the membrane that surrounds the vacuole, to press the plasma membrane against the cell wall, that mechanically opposes to these forces and avoids the osmotic lysis. This osmotic pressure is called turgor pressure, and can reach up 2 MPa, that is, 20 atmospheres, a value about 10 times higher than the air pressure in tires. It is responsible for the rigidity of non woody parts of plants, is involved in plant growth, as well as in:

Even in bacteria and fungi, the plasma membrane is surrounded by a cell wall that stably withholds the internal pressure, then preventing osmotic lysis of the cell.

By comparing the osmotic pressure of two solutions separated by a semipermeable membrane, it is possible to define three types of solutions, briefly described below.

In addition to ion pumps and the cell wall, in the course of evolution multicellular organisms have developed another mechanism to oppose the osmotic forces: to surround the cells with an isotonic solution or close to isotonicity that prevents, or at least limits, a net inflow or outflow of water. An example is plasma, that is, the liquid component of blood, which, due to the presence of salts and proteins, primarily albumin in humans, has an osmolarity similar to that of the cytosol.

In the presence of diseases that cause non-absorbed and osmotically active solutes accumulation in the distal portion of the small intestine and in the colon, a condition known as osmotic diarrhea occurs. Causes can be, for example, bacterial infections, pancreatic diseases, celiac disease, an autoimmune enteropathy due to gluten intake in genetically predisposed subjects, or a congenital deficiency of one of the disaccharidases of the brush border of enterocytes, such as in lactose intolerance. In these conditions, an incomplete carbohydrate digestion can occur as a consequence of a deficit of alpha-amylase and/or of one or more disaccharidases. Moreover, unabsorbed osmotically active solutes pass into the colon where they can be fermented by bacteria of gut microbiota, which is part of the human microbiota, resulting in production of excessive gas, such as hydrogen, carbon dioxide and methane, and short-chain fatty acids, mainly butyric acid, aceticacid and propioni acid. This causes a condition known as osmotic-fermentative diarrhea. Osmotic diarrhea can also result from the use of osmotic laxatives such as polyethylene glycol or PEG, and magnesium sulfate. Osmotically active solutes deriving from incomplete digestion, and osmotic laxatives lead to an increase in intraluminal osmotic pressure and inhibit the normal absorption of water and electrolytes, causing a reduction in the consistency of the stool and an increase in intestinal motility.

Galactose, glucose and fructose are the monosaccharides that are absorbed in the intestine. Galactose is metabolized mostly in the liver, and to a lesser extent by other organs and tissues. After conversion to UDP-g