Case 12- absorption Flashcards
Essential amino acids
(His, Ile, Leu, Lys, Met, Phe, Thr, Trp and Val) are those we cant synthesise or make enough of from non-protein sources.
Semi-essential amino acids
Cys, Tyr, Arg- have to be consumed in the diet under certain circumstances, for example during childhood
Digestion of protein in the stomach
Through HCL (hydrochloric acid) and pepsin. In the stomach proteins undergo limited proteolysis forming smaller peptides and amino acids. Pepsin cleaves preferentially at the C-terminal side of aromatic amino acids like phenylalanine, tryptophan and tyrosine. Only 20% of peptide bonds are cleaved
Protein digestion- HCL
- Produced by parietal cells, in response to gastrin.
- The pH of the stomach (pH 2) is not enough to hydrolyse proteins directly but functions to denature (deform) the proteins.
- This denaturing exposes more of the protein to the action of proteases.
- Other roles for HCl include protection from pathogens, such as bacteria, killing them before they enter the intestines.
Protein digestion- Pepsin
- Pepsin is produced by chief cells as an inactive precursor (or zymogen) called pepsinogen.
- In the presence of HCl, pepsinogen undergoes autoproteolysis (self-cleavage) to release the active pepsin plus a tag.
- Residual pepsin that had been formed in an earlier digestive event will also act on pepsinogen to increase the efficiency of the activation step.
Small intestine bicarbonate release
Bicarbonate is secreted from acinar cells through a sodium and bicarbonate cotransporter that opens because of membrane depolarisation caused by the cystic fibrosis transmembrane conductance regulator (CTFR.
Role of bicarbonate in the SI
Stomach acid is neutralised by bicarbonate from the Pancreas. The pH is raised to 7.5-8 which is the optimum pH for pancreatic enzymes
Key Pancreatic protease’s
- Trypsin (secreted as trypsinogen)
- Chymotrypsin (secreted as chymotrypsinogen)
- Carboxypeptidase A (secreted as pro-carboxypeptidase A)
- Carboxypeptidase B (secreted as pro-carboxypeptidase B)
- Elastase (secreted as pro-elastase)
Activating the Pancreatic enzymes
The membrane bound Enterpeptidase cleaves Trypsinogen to Trypsin. Trypsin then cleaves the remaining Zymogens to their active forms.
Trypsin’s cleavage pattern
Trypsin cleaves peptide chains mainly at the carboxyl side of amino acids with basic side chains (lysine or arginine).
Chymotrypsin cleavage pattern
Chymotrypsin cleaves peptide chains mainly at the carboxyl side of amino acids with large hydrophobic side chains (e.g. tyrosine, tryptophan, and phenylalanine).
How does the SI ensure the proteins are absorbed
There is multiple digestion products giving a mix of small peptides and amino acids. These approach the brush border of the intestine where aminopeptidases trim larger oligopeptides into smaller peptides or free amino acids which can be absorbed.
Amino acid transporters
Several on enterocytes
Exist on apical and basolateral membrane
Often cotransporter with ions
PepT1
Small peptides that are absorbed by PepT1 enter the cell and are processed to amino acids by cell resident proteases (i.e. the proteasome) before export to the portal system.
Examples of monosaccharides
Glucose, fructose and galactose which are all isomers. As they have the same chemical formula they can be interconverted by isomerases (cf. phosphoglucose isomerase in glycolysis).
Examples of Disaccharides
- Lactose (galactose + glucose)
- Sucrose (glucose + fructose)
- Maltose (glucose + glucose)
Oligosaccharides definition
Two to ten sugar molecules
Different forms of glucose
Glucose switches between being in a chain (open-chain form) and being in a hexagon (Pyranose form), the majority of glucose is in the pyranose form.
Enantiomers
Mirrored images of other compounds, I.e. D-glucose and L-glucose.
Anomers
Special forms of D or L glucose, where the OH and H+ are switched to different positions on the first carbon.
Starch
Formed from amylose which is a linear chain α-D-glucose molecules covalently attached via an α-1,4 glycosidic linkage. It is also formed from Amylopectin which is highly branches, It is made from α-1,4 glycosidic linkages and also α-1,6 glycosidic linkages.
Glycogen
A polysaccharide of α-D-glucose, similar in structure to amylopectin, highly branched with α-1,4 glycosidic linkages and α-1,6 glycosidic linkages. It is more branched then starch.
Cellulose
Made from β-D-glucose and contains β-1,4 linkages only (no branching). It is a linear structure stacked in layers.
Endoglycosidase enzymes
Enzymes which break down carbohydrates. Works through Hydrolyses (adding water to the two molecules)
Carbohydrate digestion in the mouth
Alpha-amylase present in the saliva. Cleaves α-1,4-glycosidic linkages on Polysaccharides, but wont cleave α-1,4 bonds if one of the glucose molecules has an α-1,6 linkage (i.e. won’t cleave around the branch points). The end products will be maltose and what is referred to as α-limit dextrins. Alpha-amylase doesn’t work in the stomach because acid neutralises it. Digests the carbohydrates on pathogens, neutralising them.
Carbohydrate metabolism in the stomach
Gastric juices contain a weak amylase
Carbohydrate digestion in the intestine
Pancreatic juices contain pancreatic alpha amylase which continues the digestion of polysaccharides.
Products of carbohydrate digestion in the intestine
The products are maltose (glucose dimer), trimaltose (glucose trimer) and α-limit dextrins (remnants of branch points).
Transporters for the absorption of monosaccharides
On apical membrane of enterocytes
Taken up by facilitated transport
In the duodenum and jejenum
Carbohydrate digestion- brush border cells
Within the intestine. The brush border disaccharides cause the products of alpha-amylase digestion to be broken down into Monosaccharides. Also digest dietary disaccharides
What digests A-limit dextrins
A-limit dextrins are produced by starch and glycogen due to their a-1,6-glycosidic bonds
Therefore we have glucoamylase and isomaltase to digest these
Glucose and galactose absorption
The sodium co-transporter sGLT1
Fructose absorption
Fructose Is absorbed by the GLUT5 transporter. When Fructose levels increase a signalling cascade is triggered that ultimately up-regulates the expression of GLUT5.
GLUT2 transporter
As levels of the monosaccharides increase, they are exported to the portal system by the basolateral transporter GLUT2.
Colonic fermentation
Non-starch polysaccharides (e.g. cellulose and pectin) are not digested in the small intestine. Because Mammalian enzymes cannot digest β-1,4 linkages. The undigested cellulose passes into the large intestine which contains bacteria that can ferment the cellulose as they express β-amylase
Lactose deficiency
Inability to digest lactose, various forms
Types of lactose deficiency
- Primary, due to ageing, normal decline in the amount of lactase produced
- Secondary, due to injury, including IDB or Crohn’s
- Developmental lactose intolerance, in premature babies, improves usually as infant ages
- Congenital, rare, no functional lactase produced due to a genetic defect
Isomaltase/sucrase deficiency
Inability to digest sucrose and alpha 1,6 bonds of Isomaltase. Deficiency results in a condition known as Congenital sucrase-isomaltase deficiency (CSID).
Maltase-glucoamylase deficiency
Inability to digest starch/glycogen. If Disaccharides can not be metabolised the sugar will enter the large intestine where bacterial flora will ingest causing the bacteria to grow. Results in gas production, abdominal bloating, osmotic diarrhoea, cramps, nausea and vomiting.
Glucose-galactose malabsorption
A rare mutation of sGLT-1 results in a defective transporter. It is osmotic diarrhoea due to glucose and galactose malabsorption. Infants present with diarrhoea, failure to thrive (FTT) and malnutrition. Treatment is fructose-containing formula and avoidance of glucose and galactose.
Fructose malabsorption
A mutation in GLUT5 results in high levels of fructose in the gut
Essential lipids
Linoleic acid
The first (minor) phase of lipid digestion
In the mouth and stomach
• Lingual lipase is secreted by the serous glands in the tongue. This is an acid-stable triacylglycerol lipase which functions primarily in the stomach
• Gastric lipase secreted by the gastric mucosa in the stomach. Acid stable triacylglycerol lipase
Mechanism of action of lipases in the first phase
Both lipases digest Triacylglycerols (TAGS)→ Diacylglycerols (DAGs) + 1 Fatty acid. The reaction is through Hydroxylation (adding water). Tend to act on the fatty acid at position 3. TAG’s with fatty acid chains of 13 and above are not digested.
Second (major) phase of lipase digestion
Peristalsis mixes the lipids with the bile salts to allow for emulsification. The end result is a Mixed Michelle. These are small droplets (4-8 nm) with hydrophobic cores of lipid surrounded by a charged outer later layer. These increase the surface area for enzymes
How the bile interacts with the lipid
Bile salts are amphipathic compounds (have both a hydrophobic and hydrophilic part). The hydrophobic portion interacts with the lipid molecule whilst the charge part interacts with the solvent.
Pancreatic enzymes used in TAG digestion
- Key enzymes: Pancreatic lipase (PLase, technically it is an esterase as it cleaves an ester bond)
- Requires COLIPASE (secreted as pancreatic pro-colipase, activated by trypsin)
- Colipase anchors PLase to the micelle, protects from inhibitor effects of bile salts
- Products are 1x Monoacylglycerol + 2x FAs, note in adipocytes when TAGs are digested the products are 3 FAs and glycerol. The reaction is a hydrolytic reaction which requires the addition of water.
Phospholipid digestion
- Key enzyme: Pancreatic Phospholipase A2
- Secreted as pancreatic pro-Phospholipase A2, activated by trypsin
- Requires bile salts for maximal activity
- Removes a single FAs from the lipid leaving a lysophospholipid
Cholesterol digestion
Most cholesterol is in the free (non-esterified) form and will be taken up by enterocytes in the jejenum. 15% of cholesterol is esterified by the addition of a fatty acid. The fatty acid is removed through Hydrolyses by the pancreatic Cholesterol Ester Hydrolyase (Cholesterol esterase; CEase). The activity of this enzyme is enhanced by salts.
The final products of lipid digestion
- Fatty Acids
- Monoacylglycerols
- Cholesterol
- (Lyso-) Phospholipids
- Phospho-glycerol head groups
- Fat-soluble vitamins
Absorption of fats
Within the Jejenum. The mixed micelles move towards the brush border membrane of the enterocytes in the small intestine. The brush border contains microvilli that are separated from the liquid in the lumen by an ‘unstirred water layer.’ This layer is more acidic due to H+ ions being pumped in in proton-coupled transporters.
Absorption of short and medium chained FAs
They are soluble in water so can diffuse out of the micelle and across the enterocyte membrane
Absorption of medium chained FA’s
They diffuse out of the micelle, but due to the level of hydrophobicity are trapped in membrane. Eventually, the membrane is recycled and these “trapped” FAs are eventually absorbed by the cell.
Absorption of longer chained FA’s
Proteins involved in transport
Fatty acid transporter
CD36 or Fatty Acid Translocase (FAT) is the major transporter of FAs across cell membranes. It can also transport collagen and LDL’s. Defects can cause Alzheimer’s and glucose intolerance. The gut adapts to an increase in fat by upregulating expression
Problems with CD36
It is known to be highly active in cancer cells. Can cause CVD when there are reduced levels of the transporter.
FATP/FATPbm
FATPs are a family of transporters involved in the uptake of long-chain fatty acids (FATPbm is the form found in the basolateral cell membrane).
Cholesterol absorption
Cholesterol is absorbed from micelles using the NPC1L1 transporter (Niemann-Pick C1-Like 1). Upon uptake, the cholesterol is re-esterified by ACAT (Acyl-CoA cholesterol acyltransferase). The esterified cholesterol is packaged into Chylomicrons for transport into peripheral tissues.
