Proteins are constantly being turned over in body tissues as old cells die and are replaced by new ones. Approximately 300 g of new protein is made each day in the human body. The amino acids used to make new proteins are, in general, derived partly from proteins digested in the gastrointestinal tract and partly from those released by intracellular proteolysis. Of the 20 amino acids commonly found in nature, 9 cannot be made by humans and must be supplied in the diet, as they are "essential" to sustain life. These nine essential amino acids, alternatively termed "indispensable," include valine, methionine, threonine, isoleucine, leucine, phenylal-anine, lysine, tryptophan, and histidine. The daily dietary requirement for essential amino acids to sustain normal nitrogen balance in the human female weighing 65 kg ranges from 260 mg/day for tryptophan to 2535 mg/day for leucine.13 Sulfur-containing amino acids and threonine appear to be the most critical essential amino acids, since studies in swine showed that the greatest rate of protein loss in the body occurred when swine were fed diets in which sulfur amino acids or threonine were omitted.13 The relevance of these findings to humans has been debated because the sulfur amino acid requirements of humans appear to be lower than those of swine.14
Inadequate protein and energy intake from food (protein energy malnutrition, PEM), in association with deficiencies micronutrients, can lead to kwashiorkor (malnutrition with edema), which develops more commonly in children because they are more sensitive to protein deficiency than adults. Another condition known as marasmus (malnutrition with severe wasting) develops in children and adults whose diets are deficient in both energy and protein.
During the last two decades, additional dietary sources of single amino acids are being obtained from the use of nutritional supplements to enhance physical performance as well as psychological effects.15 Amino acid exposures from dietary supplement use may far exceed levels that would be obtained from consumption of food. Concerns over the safety of these high exposures have been raised, and the safety of high amino acid intake has been reviewed.15,16 The latter review concluded that "[T]here was little evidence for serious adverse effects in humans from most amino acid supplements."15 The most toxic amino acids were methionine, cysteine, and histidine when consumed in excess.15 It is interesting that sulfur amino acids, which appear to be the most important in amino acid deficiencies, are also the most toxic when consumed in excess.
Since humans require essential amino acids, the gastrointestinal (GI) tract is designed to efficiently degrade proteins in the gut into their constituent amino acids and small peptides to liberate the essential amino acids for absorption. The protein sources can be from ingested food as well as intestinal fluids, cells, and gut flora. The average American man consumes 100 g of protein per day and the average woman 70 g per day.17 The Dietary Reference Intake (DRI) Committee of the Institute of Medicine's Food and Nutrition Board has suggested a recommended protein requirement for adults of 0.8 g/kg or 56 g/day for a 70-kg-body-weight adult.14 Others have recommended even higher (112 g/day per adult) protein intakes for weight control; higher rates of protein intake are also recommended for women during the last trimester of pregnancy.14 The 70 to 100 g of proteins ingested in the diet is derived primarily from foods such as meat, milk, eggs, and plant sources (legumes, nuts, etc.). Since humans synthesize approximately 300 g of protein per day, additional sources of amino acids besides food must supply the needed amino acids. This need is largely met by amino acids released by tissue protein degradation (recycling). Some may also be derived from amino acids produced by the microflora residing in the human digestive tract,14 although this process occurs mainly in ruminant animals and has not been well characterized in humans. Not all of the amino acids absorbed are directed toward protein synthesis. Tryptophan is the least efficiently utilized for protein synthesis because more than 50% of that absorbed is not used to make new protein but, rather, is directed toward gluconeogenesis.14
In the GI tract, the degradation of proteins starts in the stomach, where the combined action of acidic pH and the enzyme pepsin begins the process of breaking peptide bonds that link amino acids together. The structure and function of proteins are dependent on the content and the sequence of amino acids that make up the protein. The amino acids contribute to the tertiary and quaternary structure of proteins that impart their particular biological function. The structures that proteins assume are influenced in part by the external environment in which the proteins exist, such as pH. Changes from the optimal pH can result in loss of function of the protein, including loss of structure. In particular, the low pH of the stomach leads to loss of protein tertiary structure, and pepsin (which functions in the low-pH environment of the stomach) starts the process of breaking peptide bonds in the protein. The denaturation process for proteins always results in loss of protein function, as in the case of enzymes where the catalytic site is destroyed following loss of tertiary structure.6 Proteases recognize denatured protein conformations and rapidly degrade them. Other enzymes are released into the intestinal tract, such as endopep-tidases that attack internal peptide bonds, liberating large peptide fragments that are then sequentially cleaved at the amino or carboxy end by exopeptidases. The luminal surface of the small intestine contains additional endopeptidases, amino-peptidases, and dipeptidases that degrade small peptides into free amino acids and di- and tri-peptides (two to three amino acids) that are absorbed across the luminal surface by amino acid or peptide transport systems.6 The process of protein digestion is very efficient, as only 6-12 g of the 200-300 g of protein (food, intestinal enzymes, and mucosal cells) entering the GI tract each day is lost in feces.6
In consideration of the efficient degradation of ingested protein, the potential for systemic absorption of intact proteins is considered to be negligible. Only during a short period after birth is the human GI tract permeable to the passive transfer of immunoglobins from the mother's colostrum and milk to help protect the infant against disease-causing organisms. Shortly thereafter, gut permeabilty is effectively closed, limiting passage of intact dietary or bacterial proteins into the systemic circulation of infants.
The potential uptake of intact protein macromolecules from the GI tract is also limited by their large size when compared to ions, amino acids, glucose, and nucle-otides, which cross intestinal cell membranes either through passive diffusion or active transport. As shown in Table 1.1, the molecular weight of protein macromol-ecules that can be consumed in the diet range typically from thousands to more than 1 million Daltons, indicating that their potential for intact absorption from the GI tract is exceedingly low. This has been confirmed with proteins that are not readily digested in the GI tract and are considered to be human food allergens (ovalbumin, b-lactoglobulin, etc.). When administered as large-bolus doses to rodents by stomach tube, or when eaten by humans as components of foods, the absorption of these less-digestible proteins is estimated to be no more than one thousandth of one percent (1.0 x 10-5) or less of the ingested dose.18-23 Thus, even proteins that are poorly digested have very limited absorption from the GI tract.
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