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Protein Digestion and Peptide / Amino Acid Absorption For the body to assimilate nutritional protein, it must first be broken down into small peptide fragments and free amino acids. - this occurs to a limited extent in the stomach - the majority hydrolysis and absorption occurs in the small intestine Digestion and absorption supplies circulating blood with a small amount of bioactive peptides and a “pool” of amino acids. In this absorptive state, amino acids are trans ported via portal blood to the liver then on to subsequent organs and tissues. Recommended Daily Allowances RDA 57 kg Female 46 g/day 70 kg Male 57 g/day 31-50 y.o. Adult Typical Ingestion 65 g/day 100 g/day Endogenous proteins The body digests an additional 50 – 100 g of endogenous protein / day. - Secreted or sloughed into the lumen of the gastrointestinal tract. - Saliva - Gastric Juice - Pancreatic Enzymes and other Secretions - Sloughed Intestinal Cells - Proteins that leak into the intestinal lumen from the blood Exogenous and endogenous protein Approximately 115 – 200 g protein / day. Only about 1.6 g Nitrogen (approx. 10 g protein) lost in fecal mass - endogenous protein or dietary protein not absorbed in the intestine - represented in the microflora mass in the large intestine Central Nervous System Dietary Protein Limited Gastric Hydrolysis and Denaturation HCl Pepsin Pancreatic Release of Zymogens CCK Endogenous Proteins Digestion within Intestinal lumen Activated Pancreatic Carboxypeptidases Absorptive Enterocyte Apical Membrane Transport Enterocyte Apical Membrane Aminopeptidases Selected Metabolism within Enterocytes AA Pool in Enterocyte Cytosol Basolateral Membrane Transport Portal Blood Circulation Protein Digestion in Phases 1. Gastric hydrolysis of peptide linkages in the protein 2. Digestion of protein to smaller peptides by action of pancreatic proteases, which are secreted as zymogens and activated in the lumen of the small intestine 3. Hydrolysis of peptide linkages in oligopeptides by brushborder (apical) membrane peptidases and transport of amino acids and di- and tripeptides across the brushborder membrane of absorptive enterocytes Protein Digestion in Phases 4. Further digestion of di- and tripeptides by cytoplasmic peptidases in the enterocyte 5. Metabolism of amino acids within the enterocyte 6. Transport of amino acids across the basolateral membrane of the enterocyte into the interstitial fluid from which the amino acids enter the venous capillaries and hence the portal blood Pancreatic Acinar Cell Intestinal Epithelial Endocrine Cell Zymogens released into Intestine Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase A Procarboxypeptidase B Vagus Nerve Duodenal Enterocyte Enteropeptidases (+) Trypsin (+) Active enzymes in Intestine Chymotrypsin Elastase Carboxypeptidase A Carboxypeptidase B 1. brush-border membrane peptidases 2. brush-border membrane amino acid transporters 3. brush-border membrane di- and tripeptide transporters 4. intracellular peptidases 5.basolateral-membrane amino acid carriers 6. basolateral membrane di- and tripeptide carriers Monomeric Amino Acid Transporters and Transport Systems in the Small Intestine System Name A Common Name SNAT2 B or Bo BoAT1 Bo+ ATBo+ Y+ X-ag IMINO Iminoacid CAT-1 EAAT3 SIT1 PAT1 GLY T Creatine Pept1 GLYT1 TAT1 CRTR PEPT1 Ion Dependency Na+ Substrate Ala, Asn, Cys, Glu, Gly, His Met, Pro, Ser neutral AAs Na+ Glu neutral and Na+,Cldibasic Aas, Arg, D-Ser Arg, dibasic AAs none Glu, Arg H+, Na+,K+ Pro, pipecolate Na+ Pro, Gly, Ala, H+ GABA, Tau, Ser Glycine Na+, Claromatic AAs, none Creatine Na+, Cldi, tripeptides, H+ with NHE3 Car, B-lactam, antibiotics, Angiotensin converting enzyme inhibitors Location Basolateral Apical Apical Basolateral Apical Apical Apical Basolateral Basolateral Apical Apical Heterodimeric Amino Acid Transporters and Transport Systems in the Small Intestine System Name asc Common Name asc-1 plus y+L y+LAT plus Arg, dibasic and neutral AAs x- c xCT plus Cys/Glu exchange none Basolateral L LAT2 plus BCAA, neutral AAs none Basolateral bo+ boA+T plus dibasic AAs, Arg, none Cys, large neutral Aas, exchanges extracellular dibasics with intracellular neutral AAS. Apical Substrate neutral D,L-Aas, Ala, D-Ser Ion Dependency none none (or Na+ for large Aas) Location Basolateral Basolateral Selected Bioactive Peptides Derived from Food Source Name Physiological Activity Meat L-carnosine Wheat Wheat Gliadorphin Gluten exorphin-AS Milk Milk Milk Milk B-lactorphin B-casokinin -7 Caseoplatelin Lacottransferrin thrombic inhibitory peptide Lactoferricin Phosphopeptide antiinflammatory, antioxident, prevents glycation Opioid agonist inhibition of stress induced pain, CNS opioid agonist ACE inhibitor ACE inhibitor inhibits platelet aggregation inhibits platelet aggregation Milk Milk antimicrobial calcium/phosphate stabilizing to enhance absorption Paracellular uptake Paracellular uptake occurs by movement Of peptides between the mucosal cells instead of through mucosal cells. This occurs when tight junctions between epithelial cells are damaged and become “leaky”. Leaky junctions increase non-specific permeability of the intestinal epithelium to all macromolecules. Polypeptide uptake and transport In the presence of healthy mucosa, milligram amounts of of intact poly peptides can be absorbed via endocytotic uptake across the brushborder membrane and followed by exocytosis across the basolateral membrane. Intact large peptides 1. IgA/M-cell presentation to Peyer’s Patches 2. Enterocyte endocytosis/lysosome/exocytosis 3. Paracellular movement across leaky junctions Crypt of Lieberkuhn Lymphoid tissue Immune response